Sickle Cell Anemia - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers 0497112922, 9780497112929, 9781429496452

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SICKLE CELL ANEMIA

A

3- i n- 1

Me d i c a l

Re f e r e n c e

A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers TO INTERNET REFERENCES

SICKLE CELL ANEMIA A BIBLIOGRAPHY AND DICTIONARY FOR PHYSICIANS, PATIENTS, AND GENOME RESEARCHERS

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. 7404 Trade Street San Diego, CA 92121 USA Copyright 2007 by ICON Group International, Inc. Copyright 2007 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., 1960Sickle Cell Anemia: A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers/ James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-11292-2 1. Sickle Cell Anemia-Popular works. I. Title.

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

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

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on sickle cell anemia. 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 Chaired Professor of Management Science 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. 7404 Trade Street San Diego, CA 92121 USA Fax: 858-635-9414 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON SICKLE CELL ANEMIA .............................................................................. 3 Overview........................................................................................................................................ 3 Genetics Home Reference ............................................................................................................... 3 What Is Sickle Cell Disease? .......................................................................................................... 3 How Common Is Sickle Cell Disease?............................................................................................ 4 What Genes Are Related to Sickle Cell Disease? ........................................................................... 4 How Do People Inherit Sickle Cell Disease?.................................................................................. 5 Where Can I Find Additional Information about Sickle Cell Disease?.......................................... 5 References....................................................................................................................................... 8 What Is the Official Name of the HBB Gene?................................................................................ 8 What Is the Normal Function of the HBB Gene? .......................................................................... 9 What Conditions Are Related to the HBB Gene? .......................................................................... 9 Where Is the HBB Gene Located? ................................................................................................ 10 References..................................................................................................................................... 10 Federally Funded Research on Sickle Cell Anemia ...................................................................... 11 The National Library of Medicine: PubMed ................................................................................ 68 CHAPTER 2. ALTERNATIVE MEDICINE AND SICKLE CELL ANEMIA ............................................ 111 Overview.................................................................................................................................... 111 National Center for Complementary and Alternative Medicine................................................ 111 Additional Web Resources ......................................................................................................... 116 General References ..................................................................................................................... 117 CHAPTER 3. PATENTS ON SICKLE CELL ANEMIA ......................................................................... 118 Overview.................................................................................................................................... 118 Patent Applications on Sickle Cell Anemia ............................................................................... 118 Keeping Current ........................................................................................................................ 120 CHAPTER 4. BOOKS ON SICKLE CELL ANEMIA ............................................................................. 121 Overview.................................................................................................................................... 121 Book Summaries: Online Booksellers......................................................................................... 121 The National Library of Medicine Book Index ........................................................................... 124 CHAPTER 5. MULTIMEDIA ON SICKLE CELL ANEMIA .................................................................. 126 Overview.................................................................................................................................... 126 Bibliography: Multimedia on Sickle Cell Anemia...................................................................... 126 APPENDIX A. HELP ME UNDERSTAND GENETICS ....................................................................... 129 Overview.................................................................................................................................... 129 The Basics: Genes and How They Work..................................................................................... 129 Genetic Mutations and Health................................................................................................... 140 Inheriting Genetic Conditions ................................................................................................... 146 Genetic Consultation ................................................................................................................. 154 Genetic Testing .......................................................................................................................... 156 Gene Therapy ............................................................................................................................. 162 The Human Genome Project and Genomic Research................................................................. 165 APPENDIX B. PHYSICIAN RESOURCES ........................................................................................... 168 Overview.................................................................................................................................... 168 NIH Guidelines.......................................................................................................................... 168 NIH Databases........................................................................................................................... 169 Other Commercial Databases..................................................................................................... 172 APPENDIX C. PATIENT RESOURCES .............................................................................................. 173 Overview.................................................................................................................................... 173 Patient Guideline Sources.......................................................................................................... 173 Finding Associations.................................................................................................................. 175

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Resources for Patients and Families........................................................................................... 176 ONLINE GLOSSARIES................................................................................................................ 177 Online Dictionary Directories ................................................................................................... 181 SICKLE CELL ANEMIA DICTIONARY ................................................................................... 182 INDEX .............................................................................................................................................. 248

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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 sickle cell anemia 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 sickle cell anemia, 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 sickle cell anemia, from the essentials to the most advanced areas of research. Special attention has been paid to present the genetic basis and pattern of inheritance of sickle cell anemia. 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 sickle cell anemia. 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 sickle cell anemia, 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. We hope these resources will prove useful to the widest possible audience seeking information on sickle cell anemia. The Editors

1

From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/.

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CHAPTER 1. STUDIES ON SICKLE CELL ANEMIA Overview In this chapter, we will show you how to locate peer-reviewed references and studies on sickle cell anemia. For those interested in basic information about sickle cell anemia, we begin with a condition summary published by the National Library of Medicine.

Genetics Home Reference Genetics Home Reference (GHR) is the National Library of Medicine’s Web site for consumer information about genetic conditions and the genes or chromosomes responsible for those conditions. Here you can find a condition summary on sickle cell anemia that describes the major features of the condition, provides information about the condition’s genetic basis, and explains its pattern of inheritance. In addition, a summary of the gene or chromosome related to sickle cell anemia is provided.2 The Genetics Home Reference has recently published the following summary for sickle cell anemia:

What Is Sickle Cell Disease?3 Sickle cell disease is a group of disorders that affects hemoglobin, the molecule in red blood cells that delivers oxygen to cells throughout the body. People with this disorder have atypical hemoglobin molecules called hemoglobin S, which can distort red blood cells into a sickle, or crescent, shape. Signs and symptoms of sickle cell disease usually begin in early childhood. Characteristic features of this disorder include a low number of red blood cells (anemia), repeated infections, and periodic episodes of pain. The severity of symptoms varies from person to 2 3

This section has been adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/.

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/condition=sicklecellanemia.

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person. Some people have mild symptoms, while others are frequently hospitalized for more serious complications. The signs and symptoms of sickle cell disease are caused by the sickling of red blood cells. When red blood cells sickle, they break down prematurely, which can lead to anemia. Anemia can cause shortness of breath, fatigue, and delayed growth and development in children. The rapid breakdown of red blood cells may also cause yellowing of the eyes and skin, which are signs of jaundice. Painful episodes can occur when sickled red blood cells, which are stiff and inflexible, get stuck in small blood vessels. These episodes deprive tissues and organs of oxygen-rich blood and can lead to organ damage, especially in the lungs, kidneys, spleen, and brain. A particularly serious complication of sickle cell disease is high blood pressure in the blood vessels that supply the lungs (pulmonary hypertension). Pulmonary hypertension occurs in about one-third of adults with sickle cell disease and can lead to heart failure.

How Common Is Sickle Cell Disease? Sickle cell disease affects millions of people worldwide. It is most common among people whose ancestors come from Africa; Mediterranean countries such as Greece, Turkey, and Italy; the Arabian Peninsula; India; and Spanish-speaking regions in South America, Central America, and parts of the Caribbean. Sickle cell disease is the most common inherited blood disorder in the United States, affecting 70,000 to 80,000 Americans. The disease is estimated to occur in 1 in 500 African Americans and 1 in 1,000 to 1,400 Hispanic Americans.

What Genes Are Related to Sickle Cell Disease? Mutations in the HBB (http://ghr.nlm.nih.gov/gene=hbb) gene cause sickle cell disease. Hemoglobin consists of four protein subunits, typically, two subunits called alpha hemoglobin and two subunits called beta hemoglobin. The HBB gene provides instructions for making beta hemoglobin. Various versions of beta hemoglobin result from different mutations in the HBB gene. One particular HBB mutation produces an abnormal version of beta hemoglobin known as hemoglobin S (HbS). Other mutations in the HBB gene lead to additional abnormal versions of beta hemoglobin such as hemoglobin C (HbC) and hemoglobin E (HbE). HBB mutations can also result in an unusually low level of betahemoglobin; this abnormality is called beta thalassemia. In people with sickle cell disease, at least one of the beta hemoglobin subunits in hemoglobin is replaced with hemoglobin S. In sickle cell anemia, which is a common form of sickle cell disease, hemoglobin S replaces both beta hemoglobin subunits in hemoglobin. In other types of sickle cell disease, just one beta hemoglobin subunit in hemoglobin is replaced with hemoglobin S. The other beta hemoglobin subunit is replaced with a different abnormal variant, such as hemoglobin C. For example, people with sickle-hemoglobin C (HbSC) disease have hemoglobin molecules with hemoglobin S and hemoglobin C instead of beta hemoglobin. If mutations that produce hemoglobin S and beta thalassemia occur together, individuals have hemoglobin S-beta thalassemia (HbSBetaThal) disease.

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Abnormal versions of beta hemoglobin can distort red blood cells into a sickle shape. The sickle-shaped red blood cells die prematurely, which can lead to anemia. Sometimes the inflexible, sickle-shaped cells get stuck in small blood vessels and can cause serious medical complications.

How Do People Inherit Sickle Cell Disease? This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder each carry one copy of the altered gene but do not show signs and symptoms of the disorder.

Where Can I Find Additional Information about Sickle Cell Disease? You may find the following resources about sickle cell disease helpful. These materials are written for the general public.

NIH Publications - National Institutes of Health •

National Center for Biotechnology Information: Genes and Disease: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.ShowSection&rid=gn d.section.98

•

National Heart, Lung, and Blood Institute: http://www.nhlbi.nih.gov/health/dci/Diseases/Sca/SCA_WhatIs.html

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National Human Genome Research Institute: http://www.genome.gov/page.cfm?pageID=10001219

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National Institutes of Health: http://www.nih.gov/about/researchresultsforthepublic/SickleCellDisease.pdf

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National Library of Medicine: Changing the Face of Medicine: http://www.nlm.nih.gov/exhibition/changingthefaceofmedicine/activities/sickle_cell. html

MedlinePlus - Health Information •

Encyclopedia: Sickle cell anemia: http://www.nlm.nih.gov/medlineplus/ency/article/000527.htm

•

Encyclopedia: Sickle cell test: http://www.nlm.nih.gov/medlineplus/ency/article/003666.htm

•

Health Topic: Newborn Screening: http://www.nlm.nih.gov/medlineplus/newbornscreening.html

•

Health Topic: Sickle Cell Anemia: http://www.nlm.nih.gov/medlineplus/sicklecellanemia.html

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Educational Resources - Information Pages •

About Sickle Cell Disease: http://www.sicklecellinfo.net/

•

American Academy of Family Physicians: http://familydoctor.org/handouts/550.html

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Ask the Geneticist: http://www.askthegen.org/question.php?question_id=322

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Department of Energy Gene Gateway: http://www.ornl.gov/hgmis/posters/chromosome/sca.html

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Duke Center for Human Genetics: http://www.chg.duke.edu/diseases/sicklecell.html

•

Illinois Department of Public Health: http://www.idph.state.il.us/HealthWellness/fs/sickle.htm

•

Information Center for Sickle Cell and Thalassemic Disorders: http://sickle.bwh.harvard.edu/menu_sickle.html

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Lab Tests Online: http://www.labtestsonline.org/understanding/conditions/sickle.html

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Madisons Foundation: http://www.madisonsfoundation.org/content/3/1/display.asp?did=89

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Merck Manual of Medical Information, Second Home Edition: http://www.merck.com/mmhe/sec14/ch172/ch172g.html

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Michigan Department of Community Health: http://www.michigan.gov/documents/sicklecell_79213_7.pdf

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Nemours Foundation: http://kidshealth.org/parent/medical/heart/sickle_cell_anemia.html

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NetWellness: http://www.netwellness.org/healthtopics/sicklecell/

•

New York Online Access to Health (NOAH): http://www.noah-health.org/en/blood/sicklecell/

•

Northern California Comprehensive Thalassemia Center: Variant Hemoglobins: http://www.thalassemia.com/variant_hemo.html

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Orphanet: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=232

•

Save Babies Through Screening Foundation: http://www.savebabies.org/diseasedescriptions/sicklecell.php

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Swedish National Board of Health and Welfare: http://www.sos.se/smkh/2005-110-14/2005-110-14.htm

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Texas Department of State Health Services: http://www.dshs.state.tx.us/newborn/sickle.shtm

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University of Arkansas: http://k12education.uams.edu/scvlab/montage.htm

Studies

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University of Rochester Medical Center: http://www.urmc.edu/medicine/genetics/sickleCell.aspx

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Virginia Department of Health: http://www.vahealth.org/genetics/ParentfactsPDF/SickleCellAnemia_NBSE.pdf

•

Washington State Department of Health: http://www.doh.wa.gov/EHSPHL/PHL/Newborn/hbgo.htm

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Patient Support - for Patients and Families •

American Sickle Cell Anemia Association: http://www.ascaa.org

•

Iron Disorders Institute: http://www.irondisorders.org/Disorders/Sickle-Cell.asp

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March of Dimes: http://www.marchofdimes.com/pnhec/4439_1221.asp

•

National Organization for Rare Disorders (NORD): http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Sickle+Cell+Di sease

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Sickle Cell Disease Association of America: http://www.sicklecelldisease.org

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Sickle Cell Society (UK): http://www.sicklecellsociety.org/education/healthpr.htm

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The Family Village: http://www.familyvillage.wisc.edu/lib_scd.htm

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The Sickle Cell Information Center: http://www.scinfo.org

Professional Resources You may also be interested in these resources, which are designed for healthcare professionals and researchers. •

Gene Reviews - Clinical summary: http://www.genetests.org/query?dz=sickle

•

Gene Tests - DNA tests ordered by healthcare professionals: http://ghr.nlm.nih.gov/condition=sicklecelldisease/show/Gene+Tests

•

Genetic Tools - Teaching cases: http://www.genetests.org/servlet/access?fcn=y&filename=/tools/cases/sickle-34/

•

ACTion Sheets - Newborn screening follow up: http://ghr.nlm.nih.gov/condition=sicklecelldisease/show/ACTion+Sheets

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ClinicalTrials.gov - Linking patients to medical research: http://clinicaltrials.gov/search/condition=%22sickle+cell+anemia%22?recruiting=false

•

PubMed - Recent literature: http://ghr.nlm.nih.gov/condition=sicklecelldisease/show/PubMed

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•

Online Books - Medical and science texts: http://books.mcgrawhill.com/getommbid.php?isbn=0071459960&template=ommbid&c=181

•

OMIM - Genetic disorder catalog: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603903

References These sources were used to develop the Genetics Home Reference condition summary on sickle cell disease. •

Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review. Am J Epidemiol. 2000 May 1;151(9):839-45. Review. PubMed citation

•

Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder WC, Schechter AN, Rodgers GP, Castro O, Ognibene FP. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004 Feb 26;350(9):886-95. PubMed citation

•

Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Outcome of sickle cell anemia: a 4decade observational study of 1056 patients. Medicine (Baltimore). 2005 Nov;84(6):36376. PubMed citation

•

Schnog JB, Duits AJ, Muskiet FA, ten Cate H, Rojer RA, Brandjes DP. Sickle cell disease; a general overview. Neth J Med. 2004 Nov;62(10):364-74. Review. PubMed citation

•

Serjeant GR. The emerging understanding of sickle cell disease. Br J Haematol. 2001 Jan;112(1):3-18. Review. No abstract available. PubMed citation

•

Stuart MJ, Nagel RL. Sickle-cell disease. Lancet. 2004 Oct 9;364(9442):1343-60. Review. PubMed citation

•

Vichinsky E. New therapies in sickle cell disease. Lancet. 2002 Aug 24;360(9333):629-31. Review. PubMed citation

•

Vichinsky EP. Pulmonary hypertension in sickle cell disease. N Engl J Med. 2004 Feb 26;350(9):857-9. No abstract available. PubMed citation

A summary of the gene related to sickle cell anemia is provided below:

What Is the Official Name of the HBB Gene?4 The official name of this gene is “hemoglobin, beta.” HBB is the gene's official symbol. The HBB gene is also known by other names, listed below.

4 Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=hbb.

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What Is the Normal Function of the HBB Gene? The HBB gene provides instructions for making a protein called beta hemoglobin. Beta hemoglobin is a subunit of a larger protein called hemoglobin, which is located inside red blood cells. Hemoglobin normally consists of four protein subunits: two subunits called beta hemoglobin and two subunits called alpha hemoglobin. The instructions for alpha hemoglobin are carried in a separate gene. Each protein subunit of hemoglobin carries an iron-containing molecule called heme. Heme molecules are necessary for red blood cells to pick up oxygen in the lungs and deliver it throughout the body. A complete hemoglobin protein is capable of carrying four oxygen molecules at a time. Oxygen binding to hemoglobin gives blood its bright red color.

What Conditions Are Related to the HBB Gene? Beta Thalassemia - Caused by Mutations in the HBB Gene More than 200 HBB mutations that cause beta thalassemia have been identified. Most of the mutations involve a change in a single DNA building block (nucleotide) within or near the HBB gene. Other mutations insert or delete a small number of nucleotides in the HBB gene.

Methemoglobinemia, Beta-Globin Type - Caused by Mutations in the HBB Gene More than 200 HBB mutations that cause beta thalassemia have been identified. Most of the mutations involve a change in a single DNA building block (nucleotide) within or near the HBB gene. Other mutations insert or delete a small number of nucleotides in the HBB gene.

Sickle Cell Disease - Caused by Mutations in the HBB Gene Mutations in specific regions of the HBB gene cause red blood cells to produce an abnormal form of hemoglobin called hemoglobin M. This form of hemoglobin disrupts the protein's interaction with iron and interferes with the delivery of oxygen to cells. As a result, people with this condition may have a bluish cast to their skin, mucous membranes, and underneath their fingernails.

Other Disorders - Caused by Mutations in the HBB Gene Sickle cell anemia, a common form of sickle cell disease, is caused by a particular mutation in the HBB gene. This mutation results in the production of an abnormal version of beta hemoglobin called hemoglobin S or HbS. In this condition, hemoglobin S replaces both beta hemoglobin subunits in hemoglobin. The mutation changes a single protein building block (amino acid) in beta hemoglobin. Specifically, the amino acid glutamic acid is replaced with the amino acid valine at position 6 in beta hemoglobin, written as Glu6Val or E6V. Replacing glutamic acid with valine causes the abnormal HbS subunits to stick together and form long, rigid molecules. The rigid HbS molecules bend red blood cells into a sickle (crescent) shape. The sickle-shaped cells die prematurely, which can lead to a shortage of red blood cells

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(anemia). The sickle-shaped cells can also block small blood vessels, causing pain and organ damage.

Where Is the HBB Gene Located? Cytogenetic Location: 11p15.5 Molecular Location on chromosome 11: base pairs 5,203,271 to 5,204,876

The HBB gene is located on the short (p) arm of chromosome 11 at position 15.5. More precisely, the HBB gene is located from base pair 5,203,271 to base pair 5,204,876 on chromosome 11.

References These sources were used to develop the Genetics Home Reference gene summary on the HBB gene. •

Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review. Am J Epidemiol. 2000 May 1;151(9):839-45. Review. PubMed citation

•

Bellelli A, Brunori M, Miele AE, Panetta G, Vallone B. The allosteric properties of hemoglobin: insights from natural and site directed mutants. Curr Protein Pept Sci. 2006 Feb;7(1):17-45. Review. PubMed citation

•

Cohen AR, Galanello R, Pennell DJ, Cunningham MJ, Vichinsky E. Thalassemia. Hematology Am Soc Hematol Educ Program. 2004;:14-34. Review. PubMed citation

•

Flatz G, Sanguansermsri T, Sengchanh S, Horst D, Horst J. The 'hot-spot' of Hb E [beta26(B8)Glu-->Lys] in Southeast Asia: beta-globin anomalies in the Lao Theung population of southern Laos. Hemoglobin. 2004 Aug;28(3):197-204. PubMed citation

•

Fu XH, Liu DP, Liang CC. Chromatin structure and transcriptional regulation of the beta-globin locus. Exp Cell Res. 2002 Aug 1;278(1):1-11. Review. PubMed citation

•

Hagberg A, Barbany G, Landegren U, Birgegard G. Beta-globin mRNA increases rapidly during erythropoietin treatment. Scand J Clin Lab Invest. 2003;63(3):239-45. PubMed citation

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•

Mahajan MC, Weissman SM. Multi-protein complexes at the beta-globin locus. Brief Funct Genomic Proteomic. 2006 Mar;5(1):62-5. Epub 2006 Feb 22. Review. PubMed citation

•

Mansouri A, Lurie AA. Concise review: methemoglobinemia. Am J Hematol. 1993 Jan;42(1):7-12. Review. PubMed citation

•

Mehanna AS. Sickle cell anemia and antisickling agents then and now. Curr Med Chem. 2001 Feb;8(2):79-88. Review. PubMed citation

•

Nagel RL, Steinberg MH. Role of epistatic (modifier) genes in the modulation of the phenotypic diversity of sickle cell anemia. Pediatr Pathol Mol Med. 2001 MarApr;20(2):123-36. Review. PubMed citation

•

Park KW. Sickle cell disease and other hemoglobinopathies. Int Anesthesiol Clin. 2004 Summer;42(3):77-93. Review. No abstract available. PubMed citation

•

Sadelain M, Rivella S, Lisowski L, Samakoglu S, Riviere I. Globin gene transfer for treatment of the beta-thalassemias and sickle cell disease. Best Pract Res Clin Haematol. 2004 Sep;17(3):517-34. Review. PubMed citation

•

Scriver, Charles R; The metabolic & molecular bases of inherited disease; 8th ed.; New York : McGraw-Hill, c2001. p4571-4636. NLM Catalog

•

Steinberg MH. Hydroxyurea treatment for sickle cell disease. ScientificWorldJournal. 2002 Jun 25;2:1706-28. Review. PubMed citation

•

Stuart MJ, Nagel RL. Sickle-cell disease. Lancet. 2004 Oct 9;364(9442):1343-60. Review. PubMed citation

•

Thein SL. Genetic insights into the clinical diversity of beta thalassaemia. Br J Haematol. 2004 Feb;124(3):264-74. Review. No abstract available. PubMed citation

•

Tisdale J, Sadelain M. Toward gene therapy for disorders of globin synthesis. Semin Hematol. 2001 Oct;38(4):382-92. Review. PubMed citation

Federally Funded Research on Sickle Cell Anemia The U.S. Government supports a variety of research studies relating to sickle cell anemia. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.5

CRISP (Computerized Retrieval of Information on Scientific Projects) CRISP 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 sickle cell anemia.

5 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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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 sickle cell anemia. The following is typical of the type of information found when searching the CRISP database for sickle cell anemia: •

Project Title: DISCOVERY

A SIMPLE

VASO-OCCLUSION MODEL FOR SCD

DRUG

Principal Investigator & Institution: Fisher, Timothy C.; Physiology and Biophysics; University of Southern California Department of Contracts and Grants Los Angeles, Ca 90033 Timing: Fiscal Year 2005; Project Start 26-SEP-2005; Project End 31-JUL-2007 Summary: (provided by applicant): In the 55 years since the molecular defect responsible for sickle cell disease (SCD) was discovered, researchers have searched for anti-sickling agents to prevent the complications of the disease, but with little success. However, the total number of different chemical compounds that could have been evaluated over this period must be relatively small, due the limitations of the available technology. Recently, automated high throughput screening (HTS), has made it possible to rapidly screen libraries of hundreds of thousands of different small molecules to find promising drug candidates or possible new targets for drug development. At present, there are no assays for direct-acting anti-sickling agents that are well-suited for HTS. Assays that use hemoglobin S solutions are simple and amenable to automation, but do not address drug uptake or any other possible targets in the RBC, while morphologic sickling assays with intact RBCs are slow and difficult to automate and standardize. The aim of this study is to develop a simple and robust HTS compatible 384-well screening assay based upon a simplified model of vaso-occlusion. The assay measures the trapping of deoxygenated RBCs in the narrow channels formed between the beads in a Sephacryl column, and has a simple and stable endpoint that is read by optical imaging. The primary screen will detect whether the RBCs are trapped (the negative result) or pass through the gel (a positive "anti-sickling" result). Secondary assays will measure the activity (dose-response) and examine the mechanisms of action for each "hit". The phases of development will be: Examination of the contribution of all important assay variables, in particular, the influence of variation in the test RBCs; developing optimal assays and protocols that are robust, reproducible and sensitive; development of quality control procedures to insure reproducible performance of the test RBCs; and finally testing and further refinement of the assays and procedures during a semi-automated screen of >1500 compounds to simulate the use of the assays in a HTS environment. •

Project Title: ALLOGENEIC CHIMERISM IN MURINE SICKLE CELL DISEASE Principal Investigator & Institution: Archer, David R.; Assistant Professor; Pediatrics; Emory University 1784 North Decatur Road, Suite 510 Atlanta, Ga 30322 Timing: Fiscal Year 2005; Project Start 08-JUL-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Sickle cell disease is a debilitating inherited hemoglobin disorder that is the most common single-gene disease in the world. Hematopoietic stem cell transplantation is the only curative therapy for SCD; however toxic myeloablative conditioning regimens and barriers to allotransplantation have limited its use to children with major complications and HLA matched donors. New myelosuppressive/immunosuppressive transplant strategies are emerging to reduce morbidity and mortality and to make cell transplantation available to a larger number of patients by intentionally inducing mixed hematopoietic chimerism. However, these protocols raise significant issues that can be best addressed in a preclinical model. Using

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a murine model of sickle cell disease that expresses exclusively human sickle hemoglobin we have defined a non-myeloablative transplant protocol that induces mixed hematopoietic chimerism and tolerance to MHC disparate donors while correcting hematologic and pathologic manifestations of the disease. In Aim 1, we will extend these studies to determine the levels of donor chimerism that provide hematologic and/or physiologic cure of sickle cell disease. We will determine if very low levels of stem cell chimerism can induce and maintain allogeneic tolerance, and whether genetically modified cell populations can be expanded to provide a permanently corrective mixed chimeric state. Sickle cell disease is now recognized as having complex inflammatory interactions between multiple cell types that lead to pathological outcomes. These interactions may also be responsible for the increased rate of rejection found in stem cell transplantation for sickle cell disease. In Aim 2 we will investigate inflammatory and immunological mechanisms involved in this rejection process. We will investigate co-stimulation blockade resistant rejection, immune effector populations, adhesion molecules and cytokines for their involvement and contribution to allogeneic rejection. These aims provide a comprehensive systematic approach to studying the relationship between mixed chimerism and sickle pathophysiology and the enhanced rejection rate found in transplantation for sickle cell disease. Both Aims address basic mechanisms of transplantation tolerance and rejection as well as providing the critical preclinical data that are required for the design of future nonmyeloablative transplants protocols. •

Project Title: AMELIORATING ATTENTION PROBLEMS IN CHILDREN WITH SCD Principal Investigator & Institution: Brown, Ronald T.; Professor and Associate Dean; Public Health; Temple University 1601 N. Broad Street Philadelphia, Pa 19122 Timing: Fiscal Year 2006; Project Start 01-JUN-2006; Project End 31-MAY-2008 Summary: (provided by applicant): Much research has attested to impairments associated with attention and concentration in children with sickle cell disease. However, few methods of remediation for these cognitive sequelae have been tested empirically. Due to the dearth of clinical trials specifically examining the safety and efficacy of pharmacotherapy for the remediation of cognitive sequelae associated with neurological complications in pediatric sickle cell disease, we propose two pilot studies designed to evaluate the efficacy and safety of methylphenidate (MPH), a widely used stimulant medication. Thus, a general hypothesis of this pilot research program is that MPH is effective in reducing cognitive impairments associated with neurological complications among children with the HbSS genotype of sickle cell disease. Specifically, in a randomized, double-blind, placebo-controlled, cross-over trial, we plan to establish the acute efficacy of MPH on laboratory-based measures of sustained attention, reaction time, executive functions, and verbal short-term memory in children with sickle cell disease. In the second pilot study, we plan to evaluate the ecological validity of MPH in pediatric sickle cell disease, by conducting a randomized, doubleblind, placebo-controlled, cross-over trial, to establish the short-term efficacy of MPH in enhancing attention at home as rated by caregivers, attention in the classroom as rated by teachers, behaviors associated with executive dysfunction as rated by caregivers and teachers, and social skills as rated by caregivers and teachers. In addition, an evaluation of safety and cognitive toxicity of MPH will be conducted. Thus, the proposed study represents a first stage of research in the psychopharmacology of cognitive impairments and learning problems among children with sickle cell disease. As a follow-up to the proposed pilot study, we plan to examine by means of a long-term clinical trial, the

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enduring effectiveness and safety of stimulant medication in the management of attentional problems in children and adolescents with sickle cell disease. •

Project Title: ATLANTA CONSORTIUM

SICKLE

CELL

DISEASE

CLINICAL

RESEARCH

Principal Investigator & Institution: Lane, Peter A.; Director; Pediatrics; Emory University 1784 North Decatur Road, Suite 510 Atlanta, Ga 30322 Timing: Fiscal Year 2006; Project Start 17-APR-2006; Project End 31-MAR-2011 Summary: (provided by applicant): The purpose of the RFA for a Sickle Cell Disease (SCD) Clinical Research Network (CRN) is to establish an infrastructure with 15 clinical centers that will design and perform multi-center therapeutic trials to improve health outcomes in persons with sickle cell disease. Clinical investigators from the Emory and Morehouse Schools of Medicine propose to establish one of the 15 clinical centers in Atlanta. The proposal includes three elements: The Clinical Research Core will contribute to the design and implementation of SCD CRN studies, and enroll subjects at Children's Healthcare of Atlanta and the Grady Health System. Project 1 will test the hypothesis that losartan, an angiotensin receptor antagonist, will reduce the rate of progression of renal disease in patients with sickle nephropathy. The hypothesis will be tested in two groups: patients with macroalbuminuria and overt nephropathy, and patients with microalbuminuria. In addition to determining the effect on progressive renal disease, the study will compare the safety and tolerability of losartan vs. placebo when administered long-term in albuminuric patients with sickle cell nephropathy. Project 2 is a prospective phase III randomized trial to test the hypothesis that nalbuphine is superior to morphine in the treatment of vaso-occlusive pain in SCD because patients will suffer fewer episodes of acute chest syndrome and will suffer fewer side effects because of less respiratory suppression and reduced release of histamine. A second hypothesis is that high-dose PCA with low-dose infusion of analgesic is superior to low-dose PCA with high-dose infusion. The hypothesis will be tested by a four-arm study that will compare morphine to nalbuphine and low-dose continuous infusion with high-dose PCA to high-dose infusion with low-dose PCA for each analgesic. The work of the CRN will contribute importantly to lessening morbidity and mortality from complications of SCD. Two proposed projects will improve treatment of pain, the most common and disabling manifestation of SCD and lessen the impact of chronic kidney disease. (End of abstract) •

Project Title: BIOMAKERS HYDROXYUREA

IN

SICKLE

CELL

ANEMIA:

RESPONSE

TO

Principal Investigator & Institution: Stuart, Marie J.; Professor; Pediatrics; Thomas Jefferson University 201 South 11Th St Philadelphia, Pa 191075587 Timing: Fiscal Year 2004; Project Start 04-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): In a landmark clinical trial, oral hydroxyurea (HU) decreased the frequency of vaso-occlusive crises and acute chest syndrome, and reduced the need for transfusions and hospitalizations in adult patients with homozygous SS disease (HbSS). While the consensus from this study, and others is that HU has pleotropic modes of action in HbSS with effects on HbF, dense cells, reticulocytes, white cells and red cell-endothelial interactions, the relative merits of these individual modes of action on disease amelioration are not known. The NHLBI will be conducting a pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) in which HU will be tested in a randomized double-blinded, placebo-controlled trial for the prevention of chronic organ damage in 200 infants with HbSS. As a prelude to the major study, in 2003, a pilot

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15

Baby HUG randomized placebo-controlled, two-year trial of 40 infants (ages 12 to 17 months at study entry) will be conducted to ascertain the feasibility of the larger proposal. The validity of primary and secondary end points, i.e. splenic and renal function, and CNS involvement will be ascertained, and the effects of HU on growth, physical and cognitive development in this young cohort will be assessed. Organ evaluations will include splenic scintigraphy and pitted red cell counts; glomerular filtration rate, and evaluation for microalbuminuria and urine concentrating ability; brain MRI/MRA and transcranial doppler (TCD) measurements. This study provides us the unique opportunity for an evaluation of various biomarkers to assess whether HU modulates activation of the circulating cellular elements of blood, and cell-cell interactions, with resulting ameliorative effects on the HbSS infant's vascular pathology and clinical course. Biomarkers to be evaluated will include functional assessment of erythrocyte adhesion to endothelium and to immobilized extra-cellular matrix proteins, F cell numbers, erythrocyte markers including CD71 (stress reticulocyte), various red cell adhesion molecules and phosphatidylserine (PS) positivity. Markers of coagulation activation will include whole blood tissue factor activity (WBTF) and prothrombin fragment F1.2 levels. Endothelial activation will be assessed by plasma sol VCAM-1 and a quantitative and qualitative assessment of circulating endothelial microparticles. Platelet and white cell activation will be evaluated by sol P-selectin and L-selectin levels respectively. We predict that HU therapy, when compared to placebo will result in a pattern of biomarker changes suggestive of a treatment effect. Our evaluations will also provide information delineating the mechanisms by which HU modulates these cell-cell interactions. The two-year follow-up evaluations of clinical course and organ dysfunction in the BABY HUG pilot protocol will also provide us the unique opportunity to assess whether abnormal values of a specific biomarker(s) will predate or occur in conjunction with specific organ dysfunction, or vascular pathology. Large differences will be detectable in these comparisons, while smaller differences will provide the basis for further specimen collection and analysis in the additional 160 children to be later entered in the Phase III Clinical trial. Since our Center possesses significant past experience in biomarker evaluations in infants with HbSS, the incorporation of these appropriately chosen biologic markers to assess disease progression will complement this pilot protocol. Our ancillary proposal should enhance the long-term benefits and scientific productivity of this important multiinstitutional NHLBI-sponsored research. In addition, findings from this study could have significant implications for other disease states associated with vasculopathy. •

Project Title: BOSTON SICKLE CELL RESEARCH CONSORTIUM Principal Investigator & Institution: Mcmahon, Lillian E.; Director; Boston Medical Center One Boston Medical Center Place Boston, Ma 02118 Timing: Fiscal Year 2006; Project Start 01-MAY-2006; Project End 31-MAR-2011 Summary: (provided by applicant): The conference, "New Directions for Sickle Cell Therapy in the Genome Era" was held at the National Institutes of Health in November, 2003. The participants concluded that "the time is propitious to bring to bear the developing tools and approaches of genomics to develop markedly more effective therapies for sickle cell disease" and as "over 95% of affected individuals are living outside the United States, the application of genomics to sickle cell disease requires a global perspective and involvement." A key recommendation was that "An innovative multidisciplinary Sickle Cell Disease Research Network with a central prospective registry of well phenotyped patients should be established" and that "Features of such a network might include: Respositories of DNA, cell lines, mRNA, and plasma (the latter two from individuals when both symptomatic and asymptomatic), Standardized

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Sickle Cell Anemia

phenotypes, Open access to materials and data, Longitudinal follow-up and a Clinical trials database." To meet these challenges we propose to establish a clinical core encompassing Medical Centers in Boston, New Haven and Paris, France. The French Center has more that almost 1500 well characterized patients and has partnered before with Boston investigators. The Yale Center brings 150 new pediatric patients to our Clinical Core. Neither of these centers have participated in recent clinical trials in the United States. Our research topics include 1- basic hemoglobin genotyping and erythrocyte phenotyping of all National Sickle Cell Disease Clinical Research Network patients and the transfer of biological samples to a repository for future use by all investigators; 1-a phase I I/I 11 trial of inhaled nitric oxide for sickle cell vasoocclusive painful episode. (End of abstract) •

Project Title: BRIDGING THE GAP: A PATIENT-CENTERED CURRICULUM FOR CULTURAL COMPETENCE Principal Investigator & Institution: Bickley, Lynn; Internal Medicine; Texas Tech University Health Scis Center Health Sciences Center Lubbock, Tx 79430 Timing: Fiscal Year 2006; Project Start 18-SEP-2006; Project End 31-MAY-2011 Summary: (provided by applicant): As in the nation, health disparities undercut the health and well-being of the multicultural populations of West Texas and the TexasMexico Border. Improving the cultural competence of health care providers is critical for spanning the fault lines of the health care divide: enthnicity and acculturation; socioeconomic status; health belief systems; language and intercultural communication; and provider skills, to name but a few. The Patient-Centered Cultural Competence Curriculum proposed by the Texas Tech Univeristy Health Sciences Center School of Medicine (TTUHSC-SOM) will develop and implement curricular activities and training programs to enhance the cultural competence of medical students, residents, faculty and community physicians, and health care professionals to better address the needs and health outcomes of the West Texas and Border populations. The specific aims of the Texas Tech Cultural Competence Curriculum are to: (1) to develop and implement a patient-centered community-based Cultural Competence Curriculum; (2) to improve the cultural competence of faculty, practicing physicians, and allied disciplines in West Texas through a new Cultural Competence Faculty Development and Continuing Medical Education Program; and (3) to disseminate curricular activities, project evaluation reports, and scholarship on the impact of the Cultural Competence Curriculum to West Texans, the NHBLI Coordinating Centers, and the national medical education community through a Cultural Competence Education Network and website, two symposia on Measuring Cultural Competence in Medical Education, and Project publications. An interdisciplinary Health Disparities Project Team will develop curricular activities targeting cardiovascular, pulmonary, hematological, and sleep disorders with known health disparities in our region-hypertension, asthma, sickle cell anemia, and obesity/sleep disorders. A Health Disparities Advisory Board will help anchor this curriculum to new knowledge about health disparities from the ultimate arbiters of culturally competent care, the patients and the community. This Curriculum will be embedded in the first new undergraduate program at the TTUHSCSOM in 30 years. The Curriculum features a variety of learning exercises in all 4 years, such as taking patient life histories in the community, learning medical Spanish, serving as patient navigators, and analyzing cases of cultural mismatch or health inequities. An intensive Project evaluation program is planned. (End of Abstract)

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•

17

Project Title: CEREBROVASCULAR DISEASE IN SICKLE CELL ANEMIA Principal Investigator & Institution: Lerner, Norma; Associate Professor of Pediatrics; Pediatrics; University of Rochester 517 Hylan Bldg., Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2005; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Candidate - Dr. Lerner is a pediatric hematologist/oncologist who has recently redirected her focus to patient-oriented investigation. She has completed the course work for an MPH degree and has established working relationships with experienced clinical investigators at the University of Rochester Medical Center. Environment -The Medical Center has the experienced clinical researchers and requisite resources to ensure Dr. Lerner's success. In particular, a Consultant Committee will provide support for this proposal. The Clinical Trials Coordinating Center and Strong Children's Research Center will lend additional expertise. Research - Neurologic complications secondary to cerebrovascular disease are prevalent in children with homozygous sickle cell disease. It is hypothesized that daily low-dose aspirin therapy will safely diminish the incidence and progression of cognitive deficit as well as the predisposition to overt and silent stroke in these children. In order to maximize the design of a future Phase III trial to test this hypothesis, a pilot study has been approved by the NINDS. Its primary objective is to evaluate the safety and tolerability of aspirin. This K24 application proposes additional studies to augment the trial. These will investigate the prognostic relationship of laboratory markers of inflammation and coagulation to the incidence and progression of cerebrovascular damage. Subsequent investigations will evaluate the change secondary to aspirin therapy in those laboratory parameters with prognostic capability. Later proposed studies include investigations regarding magnetic resonance imaging in children with documented stroke on chronic transfusion therapy and tailored educational modifications to improve performance in children with neurocognitive deficits. Mentorship -The principle investigator will provide clinical research training to qualified MDs with a particular interest in pediatric cerebrovascular disease, hemoglobinopathies, and/or neurocognitive function. Trainees will be recruited from: Pediatric Hematology/Oncology fellows, Masters in Public Health (clinical track) candidates, participants in programs of the Department of Neurology, and residents. The program will include core educational instruction, seminar series, and individualized guidance. Trainees will participate in the conduct of the pilot trial and a multi-center phase III study, should this be funded. The additional studies proposed in this application will serve as initial individual clinical research opportunities. Outcome measures will be used to assess the efficacy of the mentoring program.

•

Project Title: CLINICAL HEMATOLOGY RESEARCH DEVELOPMENT PROGRAM (K12) AT JOHNS HOPKINS Principal Investigator & Institution: Casella, James F.; Professor and Director; Pediatrics; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2006; Project Start 01-SEP-2006; Project End 31-AUG-2011 Summary: (provided by applicant): This proposal seeks to establish a Clinical Hematology Career Development Program in benign hematology at the Johns Hopkins Medical Institutions (JHMI). The next generation of clinical researchers in benign hematology will need to include individuals with the skills, attitudes, early research training and experience to capitalize on rapidly developing progress in benign hematology. In developing this program, we will use established research infrastructure, including free-standing Divisions of Hematology in Pediatrics and Internal Medicine that are dedicated to the care and study of benign hematologic

18

Sickle Cell Anemia

disorders, as well as our Graduate Training Program in Clinical Investigation (GTPCI) at the Johns Hopkins University School of Medicine and Johns Hopkins University Bloomberg School of Public Health. Our specific aims are: a) To identify, train and develop creative and successful clinical investigators, with the capability to interact with, participate in, and lead multidisciplinary teams involved in clinical research, address complex problems and become national leaders in pediatric, adolescent and adult benign hematology; b) To provide trainees with the requisite skills, knowledge, attitude and experience for successful careers in clinical research in benign hematology. This training will include exposure to national and international leaders and curriculum in the multiple disciplines necessary for successful clinical research, including benign hematology, clinical trials design, epidemiology, statistics, research ethics and human subjects protection; c) To provide a rich mentoring environment. We will integrate multiple research resources and investigators available at the JHMI to provide optimal exposure of trainees to research experiences and training. We will focus our efforts in six areas where we feel there is particular strength within our institution: bone marrow failure and stem cell biology, sickle cell disease (SCD), myeloproliferative disorders, transfusion medicine, outcomes research and genetics. We will work with several established investigators and mentors to develop a structured curriculum in benign hematology and strong mentored research experiences for trainees. Careful and extensive mentoring will be the cornerstone of these efforts, with exposure to cutting edge research experiences. Through this program, we ultimately aim to provide a cadre of clinical researchers, who will become creative, independent investigators, care for patients and assume leadership roles in benign clinical hematology. •

Project Title: COMPARATIVE APPROACHES TO BIO-KNOWLEDGE DISCOVERY Principal Investigator & Institution: Kim, Junhyong; Professor; Biology; University of Pennsylvania Office of Research Services Philadelphia, Pa 19104 Timing: Fiscal Year 2005; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): In this planning grant to establish a Program of Excellence in Biomedical Computing, the University of Pennsylvania and the Children's Hospital of Philadelphia propose to develop a new organization that will serve as a central conduit of biomedical computing research tying together the activities of three schools and six research institutes. The organization will consist of a scientific steering committee with internal and external members to oversee research activities, an oversight committee to provide institutional support, an executive committee to govern day-to-day activities, and an office of education to coordinate the training activities. The organizational structure will be generated under the umbrella of the Penn Genomics Institute and the Penn Center for Bioinformatics to leverage existing resources. Interdisciplinary research interactions will be promoted by funding 12 new seed grants (made possible by matching funds) focusing on comparative approaches to biomedical knowledge discovery. In the first year, four projects will be funded: (1) pattern discovery in comparative genomics; (2) computational phylogeny reconstruction; (3) comparative text mining for cancer research; and (4) comparative informatics approach to sickle-cell disease. In subsequent years, new projects will be added to the first four through an internal solicitation for proposals. The Scientific Steering Committee will review these proposals and four new projects will be funded in Years 2 and 3. Each year, existing projects will be reviewed and at the end of the planning grant, all projects will be reviewed for consolidation into a small number of high impact projects. New interactions between existing computational faculty and biomedical faculty will be encouraged by holding opportunity presentation retreats to introduce researchers from complementary fields to biological problems and computational methods. Faculty basic

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19

education seminars will be held monthly where basic concepts like "transcription" will be discussed in a highly interactive format. The existing core facility for bioinformatics will be augmented with additional high-performance computing hardware, support for teaching basic computational biology tools, and a facility to coordinate dissemination of software tools developed from this grant. An existing PhD level training program in biomedical computing will be supplemented to provide research experience for undergraduates and masters students. •

Project Title: COMPREHENSIVE SICKLE CELL CENTER Principal Investigator & Institution: Wang, Winfred C.; Member; St. Jude Children's Research Hospital 332 N Lauderdale St Memphis, Tn 381052794 Timing: Fiscal Year 2005; Project Start 01-JUL-2003; Project End 31-MAR-2008 Summary: (provided by applicant): The mission of St. Jude Children's Research Hospital (SJCRH) is to find cures for children with catastrophic illnesses through research and treatment, a mission that is directly relevant to the 700 children and adolescents cared for in our Comprehensive Sickle Cell Center. We seek to offer a broad range of therapeutic options. Namely, supportive care, chronic transfusion, drug therapy or stem cell transplantation, to our patients and in so doing to implement effective clinical research protocols to evaluate these options. Project N, the Network (Inter-Center) Proposal, seeks to test combination "chemotherapy" for reducing the frequency of pain crises through a Phase III trial of hydroxyurea and magnesium vs. hydroxyurea and placebo in pediatric and adult patients. In Project 1, a formal Phase I trial of magnesium will be conducted in pediatric patients, and then a Phase II trial will examine the effect of this combination on prevention and/or reversal of central nervous system abnormalities, on red blood cell properties and on nutritional status. In Project 2, we seek to test the feasibility of using parental donors for haploidentical stem cell transplantation to extend potentially curative therapy to more children with sickle cell disease. Project 3, utilizes a murine model of sickle cell disease to explore pathogenesis of pneumococcal infection in the children followed in our Center to examine the effects of penicillin prophylaxis, vaccines and specific antimicrobial therapy on the frequency of antibiotic tolerance and/or resistance. In Project 4, lentiviral vectors designed to express a gamma-globin gene at high levels will be optimized in a murine model of sickle cell disease and we will test the concept of in vivo drug selection to amplify a minority, genetically modified hematopoietic population to achieve effective gene therapy. Project 5 is focused on understanding the regulatory mechanisms that modulate the relative levels of expression of the gamma- and Beta-globin genes in maturing erythroblasts. Activities are integrated through the functions of the Clinical Core, a Patient Services Core and a Central Nervous System Assessment Core. Our Sickle Cell Scholars will have the opportunity to develop a translational research career through mentoring with a focus in the clinic and/or laboratory. Thus our Comprehensive Sickle Cell Center effectively integrates clinical, translational and basic research and thereby fosters multidisciplinary collaborations directed toward the goal of finding effective therapy and ultimately a cure for sickle cell disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: COMPREHENSIVE SICKLE CELL CENTER Principal Investigator & Institution: Johnson, Cage S.; Professor of Medicine; Medicine; University of Southern California Department of Contracts and Grants Los Angeles, Ca 90033 Timing: Fiscal Year 2005; Project Start 01-JUL-2003; Project End 31-MAR-2008

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Sickle Cell Anemia

Summary: The Comprehensive Sickle Cell Center (CSCC) at the Los Angeles County+USC Medical Center: represents the continued collaboration of an investigative group that has devoted a substantial portion of their careers since 1972 towards basic, applied, and clinical research in sickle cell disease. The overall focus and unifying theme of this research continues to be the pathophysiology, clinical consequences and treatment of vascular events in sickle cell disease. Vascular disorders, including vascular occlusion, represent the most important cause of morbidity and mortality in this disease, yet their pathophysiology is still incompletely understood and their treatment remains Largely unsatisfactory. Determining possible genetic bases for the variable clinical severity of the disease and genetic approaches to therapy are also of central interest, yet again our understanding in these areas is less than satisfactory. In the current proposal, this group of investigators will continue to be concerned with vascular disorders in sickle cell disease; in addition, we have incorporated genetics-based components seeking to understand the variable clinical severity and to develop novel therapeutic approaches in this disease. The program described herein consists of five hypothesisbased projects (Projects 1-5), and three Cores (Clinical/Patient Service, Laboratory, Animal) that support these projects and the overall objectives of the Center. Project 1, our Collaborative Clinical Research Component, seeks to examine relations among polymorphisms in specific blood groups and clinical severity; Project 2 examines critical elements of the pathophysiology of pulmonary hypertension; Project 3 seeks to determine the ability of anti-inflammatory agents to block hypoxia-induced decreases of blood flow; Project 4 explores genetic therapy for sickle cell disease via examining the potential benefits of self-inactivating lentiviral vectors; Project 5 seeks to define in detail the molecular mechanisms that lead to the accumulation of monocytes and PMN in the alveolar compartment. We strongly support the Inter-Center Collaborative concept and the Sickle Cell Scholar program, and believe that successful completion of our Projects will yield important new information for improved patient care. •

Project Title: CORE--CLINICAL RESEARCH DIVISION Principal Investigator & Institution: Benjamin, Lennette J.; Associate Professor of Medicine & Clinic; Montefiore Medical Center (Bronx, Ny) 111 East 210Th St Bronx, Ny 104672490 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAR-2008 Summary: The overall clinical goal of the Bronx Comprehensive Sickle Cell Center (BCSCC) is to optimize patient care and the potential for conducting careful research into the pathophysiologic and psychologic manifestations of sickle cell disease that will contribute to the formulation of collaborative biopsychosocial clinical care delivery models based upon scientific evidence and, when needed, expert consensus. To continue the high quality cost-effective management and health care service practices employed in the BCSCC Medical Office and Day Hospital and to extend this care to a larger number of patients.

•

Project Title: CORE--EDUCATION AND PATIENT SERVICES Principal Investigator & Institution: Mcdonald, M L.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2003; Project Start 11-JUL-2003; Project End 31-MAR-2008 Summary: The Cincinnati Comprehensive Sickle Cell Center (CCSCC) conducts extensive educational and counseling activities for pediatric sickle cell patients and families. Currently the Ohio Department of Health provides some funding that address clinic education of children and families affected by sickle cell disease; the follow-up

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and enrollment in medical care of newborns with hemoglobinopathies; and prenatal services. Social work services are provided through Children's Hospital Medical Center. The Education and Patient Services Core has four specific aims which will expand and enhance the goals of the CCSCC: (1) to provide education and psychosocial services to patients with sickle cell disease and other hemoglobinopathies; (2) to provide education and peer education sessions for parents of pediatric patients and adult sickle cell patients through the expansion of the Parent Council and training by parents to healthcare professionals; (3) to continue the Teens and Young Adults (TAYA) transition program for young adults transferring from pediatric care to adult healthcare by ensuring that the adolescent patients acquire knowledge, skills and attitudes to make a successful transition; and (4) to provide the evaluation and coordination of educational and psychosocial programs within the Cincinnati Comprehensive Sickle Cell Center and its collaborative partners. We will continue our collaboration with the Sickle Cell Awareness Group, Inc., a community-based and SCDAA organization. The Sickle Cell Awareness Group, Inc. currently provides supportive and community social work services funded by our current NIH grant. We also plan to develop a new collaboration with the Urban League of Greater Cincinnati to provide job readiness training to patients ages 18-21. We will also implement the services of Project Search to further our commitment to assisting our TAYA (transition) patients with vocational/educational counseling and long term planning for job readiness. •

Project Title: CORE--PATIENT SERVICES CORE Principal Investigator & Institution: Whitworth, Elaine; Duke University 2424 Erwin Rd. Durham, Nc 27705 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAR-2008 Summary: The Duke-UNC Comprehensive Sickle CelLCenter remains committed to helping translate scientific findings on diagnosis and treatment into improved diagnostic services, treatment, and quality of life for patientswith sickle cell disease both those for whom the Center provides clinical care and all sickle cell patients in North Carolina. The Center's Patient Service Core offers the following patient-support activities: (1) Education - The Center is the primary North Carolina state resource for educating health care practitioners via guidelines, quarterly CME newsletters, clinical management videos, and conferences at community hospitals and medical society meetings. The Center promotes awareness of sickle cell disease among lay audiences by conducting educational programs for health and human service professionals, in public schools and colleges, in civic and community organizations, and at health fairs. The educational programs are augmented by the printed materials produced by the Center and shared with local community programs. Further through our Clinical Core activities, we offer patient and family individual and group education sessionsas well as sponsor and facilitate support groups. (2) Community Outreach - The Center has developed liaison activities through the North Carolina Sickle Cell Syndrome Program and participates directly in three outreach community clinics and interactively with the statewide Lay Volunteer Program. Another continuing project is the outreach to the Bridges Pointe Foundation which will provide assisted living and adult day center for young persons disabled by sickle cell disease and provides a prototype for other communities and states. (3) Counseling - In addition to providing scientific updates to the counseling efforts of the NC Sickle Cell Syndrome Program and community-based programs, the Patient Service Core provides direct counseling to persons within the Center's geographic and referral base who have been screened and found to have sickle cell disease and to pregnant patients and their spouses whose child is at risk for sickle cell disease. (4) Diagnostic Testing - Both of the Duke-UNC Comprehensive Sickle Cell

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Sickle Cell Anemia

Center's participating institutions provide laboratory facilities where accurate diagnosis of hemoglobinopathies, including hemoglobin genotyping, is performed. The professional staff of our Patient Service Core is fully integrated through the Internal Advisory Committee with the investigators and clinicians who are highlighted in other cores. These ongoing research-to-practice collaborations help us continuously re-define our concepts of excellence in patient services. In addition, the Center is able to impact understanding and practice of sickle cell disease diagnosis and management across North Carolina through its effective partnerships with state-wide organizations including:The North Carolina Sickle Cell Consortium, the North Carolina Sickle Cell Syndrome Program, the NC Governor's Council, insurers, and professional societies. •

Project Title: DATA COORDINATING CENTER FOR THE SICKLE CELL DISEASE Principal Investigator & Institution: Brambilla, Donald J.; Principal Research Scientist; New England Research Institutes, Inc. 9 Galen St Watertown, Ma 024724515 Timing: Fiscal Year 2006; Project Start 10-APR-2006; Project End 31-MAR-2011 Summary: (provided by applicant): In addressing the responsibilities of the Data Coordinating Center (DCC) described in the RFA HL-05-006, Sickle Cell Disease Clinical Research Network. NERI offers the following highly relevant expertise and experience. (1) The proposed PI, Co-Pi, Network Manager and Protocol Manager each have more than 10 years of experience in coordinating multi-site clinical trials and epidemiological studies, in sickle cell disease, thalassemia and other areas. (2) The DCC team includes physicians with extensive clinical and research experience in sickle cell disease, physicians with whom the DCC Team has worked for more than 10 years. (3) The DCC includes a strong team of statisticians who have designed, monitored and analyzed numerous clinical trials and epidemiological studies in sickle cell disease and other areas. (4) NERI has developed a proprietary, Oracle-based data management system ADEPT - that has been used successfully in numerous multi-center trials, including international trials and that supports web-based data entry. (5) NERI has also developed a computerized randomization system that supports many randomization schemes (simple, permuted blocks, stratified randomization, etc.) and which is fully coordinated with the data management system. (6) NERI is experienced at establishing and running per-patient reimbursement systems, including support of multiple schedules for reimbursement. (7) NERI and the DCC team are experienced at identifying and coordinating central laboratories, endpoint adjudication panels and other central reading panels (e.g. MRI and MRA). (8) The DCC team includes expertise in measuring quality of life and cost effectiveness, experience in the statistical aspects of identifying genetic risk factors for disease, experience in research on children and experience in designing and executing equivalence and noninferiority trials. The NERI team also proposes to incorporate the following features, based on prior experience in clinical trials networks. (1) A registry of patients at the 15 Clinical Centers is proposed to assess the characteristics of the patients and the adequacy of the numbers available for each trial, to provide an immediate training vehicle for data acquisition and management before initiating a complex trial protocol, and to provide an ongoing patient resource database. (2) A web-based data acquisition and protocol management system will be implemented in ADEPT that will provide automated on-line reports, in real time, to the CCs and Program Office at NHLBI, and that will fully support per-patient payments to the sites with automated reports for triggering the payments. NERI has assembled a highly and appropriately experienced team for the DCC and offers the data management system and other resources needed to successfully coordinate the multiple parallel trials and other studies that will be undertaken by the Sickle Cell Disease Clinical Research Network. (End of Abstract)

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Project Title: DATAWEAVER: AN INTERFACE TO COMPLEX CLINICAL DATA Principal Investigator & Institution: Tien, Allen Y.; President and Research Director; Medical Decision Logic, Inc. 724 Dulaney Valley Rd, Ste 2 Towson, Md 21204 Timing: Fiscal Year 2005; Project Start 01-AUG-2005; Project End 31-JAN-2007 Summary: (provided by applicant): Pediatricians routinely need to make rapid decisions based on large amounts of complex and potentially unreliable data. However, this decision-making process has proved difficult to emulate, or even to support, using software systems. An important feature existing systems lack is a user interface allowing pediatricians to quickly and effectively understand and make use of complex interrelated and time dependent data. This proposal seeks to address this deficiency by using an innovative and patented graphical user interface methodology called "DataWeaver." The basis of the DataWeaver display is a hierarchical structure called a "weave" showing intersections of different types and pieces of data in a readily comprehensible way. The DataWeaver methodology is designed to provide the pediatrician with a complete view of the patient's overall status while supporting rapid access to the underlying detailed information, thus saving clinicians time and increasing the quality of care. Despite the attractiveness of the DataWeaver methodology, it has neither been implemented nor field tested. One reason is that mapping the humanoriented DataWeaver interface to the underlying database and to other components has until recently been deemed infeasible. However, recent advances in software engineering make constructing these mappings currently feasible. Specifically, by using model-driven architecture (MDA) methods to specify various components, such as data sources, decision support rules, and graphical components via an abstract model. This in turn allows much of the system's code to be automatically generated instead of needing to be hand-written, greatly reducing coding time and increasing code reliability. Because of the broad scope and complexity of the field of pediatrics, and because of strong interest from the Pediatrics Department at Johns Hopkins University, sickle cell disease content has been chosen for Phase I testing.

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Project Title: DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGY FOR SICKLE CE* Principal Investigator & Institution: Iyamu, Efemwonkiekie; Children's Mercy Hosp (Kansas City, Mo) 2401 Gillham Rd Kansas City, Mo 641084619 Timing: Fiscal Year 2005; Project Start 09-SEP-2004; Project End 31-JUL-2009 Summary: (provided by applicant): The Principal Investigator (P.I.) of this application has completed his post-doctoral fellowship in the Division of Hematology at The Children's Hospital of Philadelphia (CHOP). This proposal describes his 5-year research plan to receive the next level of training for the development of an academic research career in the field of hematology with specific emphasis on sickle cell disease (SCD) and other hemoglobinopathies. This proposal focuses on the efficacy of the combined use of multiple drugs that complement each other in order to reduce the dose of each drug without reducing in their beneficial effects. Based on the preliminary results, P.I. will utilize the isobologram technique, a method that was developed to find the optimum therapeutic regimen, which will not only increase the efficacy but also reduce the adverse effects by reducing the dosage of each drug needed to reveal their beneficial effect. Dr. Toshio Asakura will mentor the P.l.'s scientific development. He is a recognized leader in the field of SCD, and the Director of the NHLBI SCD Reference Laboratory. He has trained several post-doctoral fellows and graduate students, many of whom have become established investigators around the country and the world. In addition, an Advisory Committee of well-established clinical/research investigators will

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provide scientific and career advice to the P.I. To achieve the proposed goal, the P.I. will utilize an assortment of various analytical techniques, Tg sickle mice and isobologram technique. The P.I. will investigate: 1) the effectiveness of the combined use of hydroxyurea (HU) and another type of Hb F-inducing agent in human progenitor cells to find a condition under which the combined use of these two drugs increases the synthesis of Hb F using lesser doses of each of these cytotoxic drugs, 2) the effectiveness of the combined use of HU and Nix-0699, a potent ansickling agent, in Tg sickle mice and 3) the molecular mechanism of the induction of Hb Fsynthesis by the combined use of more than two drugs. This will be the first study to utilize the isobologram technique in the rational design of combinations of therapeutic agents in SCD therapy. CHOP provides an ideal setting for training research scientists by incorporating expertise from diverse resources into a customized program. Such an environment maximizes the potential for the P.I. to establish a scientific niche from which an academic career can be constructed. •

Project Title: DIPYRIDAMOLE/MAGNESIUM TO IMPROVE SICKLE CELL HYDRATION Principal Investigator & Institution: Kalinyak, Karen A.; Medical Director; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2003; Project Start 11-JUL-2003; Project End 31-MAR-2008 Summary: Vaso-occlusivc episodesare common among patients with sickle cell anemia (SCA), causing pain and chronic organ damage. SCA is characterized by the presence of dense, dehydrated sickle red blood cells (SS RBC), which are rheologically abnormal and are selectively trapped during vaso-occlusion. Strategies to prevent cellular dehydration would offer important therapeutic options that might decrease vaso-occlusive episodes. SS RBC dehydration results from cation depletion mediated by two cation transport systems, a sickling-induced (SI) leak pathway and the KCI cotransporter (KCC). Previous work at this Center has shown that di-pyridamole inhibits the SI fluxes of Na, K and Ca in vitro. Increasing cellular magnesium inhibits KCC activity and increases cellular hydration in animal models of SCA. A small clinical study in SCA patients demonstrated that Mg supplementation increased cellular Mg, reduced KCC activity and improved red cell hydration. This study will test the hypothesis that significant reduction in SS RBC dehydration will be seen in patients with SCA treated with either dipyridamole or magnesium. An additive, and possibly synergistic, effect on dense cell formation is hypothesized in patients treated simultaneously with both agents. A prospective, randomized, crossover, repeated measures design will be conducted among 48 patients with SCA, ages 12 years and older. Patients will be recruited from the Cincinnati Comprehensive Sickle Cell Center and the Sickle Cell Program at Wayne State University in Detroit. This design will allow for efficient comparison of the three treatment options; dipyridamole alone, magnesium alone or a combination of both. We anticipate that these therapies will be well tolerated by the patients. Primary outcome measures include the number of dense cells, assessed by automated cell counting and phthalate density gradients, cellular cation content, cell volume and hemoglobin concentrations. Using the biotin label technique pioneered in Cincinnati, measurements of red cell survival and rate of dense cell formation will be made in six patients in each treatment group, and will shed light on the mechanisms underlying SS RBC dehydration and its postulated inhibition by dipyridamole and Mg.

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Project Title: DNA METHYLATION, CHROMATIN, AND GLOBIN GENE SILENCING Principal Investigator & Institution: Desimone, Joseph; Geneticist; Medicine; University of Illinois at Chicago 310 Aob, M/C 672 Chicago, Il 60612 Timing: Fiscal Year 2005; Project Start 18-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Increased level of fetal hemoglobin (HbF) is clinically beneficial ill patients with sickle cell anemia. Experiments performed in the baboon model demonstrated that HbF levels could be elevated using pharmacologic agents such as 5-aza-2'-deoxycytidine (decitabine), butyrates, and hydroxyurea. The usefulness of these drugs in patients with sickle cell disease was confirmed in a number of clinical trials. The MSH study demonstrated that hydroxyurea therapy reduced the number of pain crises, incidence of acute chest syndrome, and transfusion requirements in patients. A significant number (10-40%) are refractory to treatment as evidenced by minimal changes in HbF levels. Furthermore, because the increased HbF is distributed heterogeneously among red cells, a large percentage of erythrocytes remain unprotected from intracellular polymerization of deoxy-HbS molecules. New and improved agents and therapies must therefore be developed which increase HbF to higher levels in a greater proportion of patients and maximize the number of F cells produced. It is our goal to develop a better therapeutic regimen for patients with sickle cell disease based upon the use of the demethylating drug decitabine, histone deacetylase inhibitors, and growth factors. We intend to investigate the mechanism of action of these agents by determining the role of DNA methylation and histone acetylation in both the development regulation of globin gene expression and the reactivation of HbF expression in the adult. Analysis of the methylation and histone acetylation status of genes in small numbers of highly purified hematopoietic progenitor cells is now possible using FACS, bisulfite sequencing and immunoprecipitation of formaldehydefixed chromatin fragments (CHIP) in combination with PCR. We propose to follow changes in gamma-globin gene expression, DNA methylation, and histone acetylation during fetal development and normal erythroid differentiation, and following augmentation of HbF production induced by administration of decitabine and histone deactylase inhibitors. We will use an in vitro culture system and an in vivo baboon model system that we have used for the past 20 years to study these mechanisms. These studies will define the mechanisms of gamma-globin gene silencing, and will aid in the development of new procedures to augment HbF production in patients with sickle cell disease.

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Project Title: DRED REPRESSION OF EMBRYONIC/FETAL GLOBIN GENE TRANSCRIPTION* Principal Investigator & Institution: Engel, James Douglas.; Professor and Chair; Cell and Developmental Biology; University of Michigan at Ann Arbor 3003 South State Street, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2005; Project Start 01-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): One attractive, efficacious strategy for reducing both the pain and morbidity associated with sickle cell disease (SCD) would be to induce fetal gamma-globin synthesis in adult erythroid cells. Such a strategy could be executed, in theory, either by forcing fetal gene-specific transcriptional activators to be inappropriately activated during adult erythropoiesis or by inhibiting the activity of adult stage fetal globin gene repressors. Using a combination of molecular genetics and biochemistry, we recently identified a potential definitive stage gamma-globin gene repressor (which we named DRED, for direct repeat erythroid-definitive). We cloned the

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DNA binding subunits of the repressor by purifying them from adult murine erythroid tissue culture cells, and the summary of our current evidence suggests that the large DRED repressor complex binds to direct repeat (DR1) sites in the epsilon- and gammaglobin gene promoters using two nuclear orphan receptors, TR2 and TR4, as the molecular scaffold upon which the larger DRED complex is assembled. Since TR2/TR4 heterodimers have been shown to repress other cellular genes, DRED could constitute an excellent target for therapeutic intervention in the treatment of SCD. Here we experimentally address five questions that will either confirm or refute the hypothesis that DRED might be an appropriate target for therapeutic intervention in the treatment of SCD and/or Cooley's anemia (beta-thalassemia). First, can we provide further evidence, using modified transgenic human beta-globinYACs, that the DR1 element in the gamma-globin gene promoter is the direct target of DRED repression? Second, can we provide additional biochemical evidence that the TR2/TR4 heterodimer is the basis for that repression? Third, will tissue-specific gain of function experiments (forced transgenic expression of TR2 and TR4 in erythroid cells) lead to precocious silencing of the endogenous murine or transgenic human embryonic/ fetal globin genes? Fourth, will conditional, erythroid tissue-specific loss of function of TR2 and TR4 (by either germ line inactivation or dominant negative repression) lead to ectopic synthesis of embryonic/fetal globin genes in definitive erythroid cells? Fifth, what are the components, other than TR2 and TR4, that constitute the 0.5 MDa DRED repression complex. •

Project Title: ENU MUTAGENESIS OF GAMMA GLOBIN SILENCERS Principal Investigator & Institution: Ryan, Thomas M.; Biochem & Molecular Genetics; University of Alabama at Birmingham 1530 3Rd Avenue South Birmingham, Al 35294 Timing: Fiscal Year 2005; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Gamma globin silencer gene(s) will be identified in an animal model of sickle cell disease (SCD) after global mutagenesis. N-ethyI-Nnitrosourea (ENU) will be used to induce point mutations that will inactivate or alter random sets of genes throughout the mouse genome in individual embryonic stem (ES) cells. Mice that are cloned from these cells will be screened for dominant and recessive mutations that affect gamma globin gene silencing by quantifying the persistent expression and synthesis of fetal hemoglobin in the founder animals and their progeny. This phenotype driven approach will utilize a knockout-transgenic mouse model of SCD that reproduces most if not alt of the pathology of the disorder (Science 278: 873-876). The model was created by targeted deletion of the adult mouse alpha and beta globin genes followed by introduction of human alpha, gamma, and beta sickle globin transgenes into the germline. During fetal and adult life these animals synthesize only human hemoglobin in their red blood cells. Similar to man, these SCD mice switch from human fetal hemoglobin, HbF, to adult sickle hemoglobin, HbS, at the time of birth. SCD mouse ES cell lines will be established from developing blastocysts isolated from sickle cell females that were mated with sickle males. Sickle ES cells will be treated with ENU and thousands of individual subclones established. Hundreds of SCD founder mice will be produced annually from these randomly mutated ES cell subclones by tetraploid embryo complementation. Alterations of heterocelluiar gamma globin chain levels in circulating erythrocytes will be assessed in founder animals and their offspring to discover potential cell lines containing gamma globin silencer mutations. Microsatellite linkage analysis of mutant offspring outcrossed to congenic SCD mice and direct sequence comparison to the routine genome will allow the positional cloning of gamma globin silencer genes. Finally, putative silencing factors will be positively confirmed by replicating the exact germline modification discovered during the ENU

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screen into SCD and beta thalassemic ES cells, followed by direct examination of the phenotype in mice generated from the modified cells by cloning. Successful completion of these studies will define the gene(s) responsible for gamma globin silencing. By experimental design, the in vivo therapeutic benefits associated with increasing HbF levels due to modification of these gone(s) on the pathophysioiogy of sickle cell anemia and Cootey's anemia will be tested directly in animal models of these disorders. •

Project Title: GENE POLYMORPHISM IN CHRONIC SICKLE CELL LUNG DISEASE Principal Investigator & Institution: Klings, Elizabeth S.; Assistant Professor of Medicine; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 021182394 Timing: Fiscal Year 2005; Project Start 01-JAN-2005; Project End 31-DEC-2009 Summary: Although patients with sickle cell disease (SCD) share a common hemoglobin (Hb) mutation; their clinical presentation is quite variable suggesting a role for extraerythrocytic genetic and environmental factors in the modulation of the disease process. Chronic pulmonary disease characterized by pulmonary hypertension (PH) and rightsided congestive heart failure (cor pulmonale) is an under-appreciated complication. Although it may be present in up to 40%, it is often asymptomatic. Determination of etiological factors responsible for the development of PH in SCD is important as PH represents an independent risk factor for death in this population. Our laboratory has determined that nitric oxide (NO) metabolism is altered in the acute chest syndrome (ACS) of SCD, with the preferential formation of powerful oxidative metabolites such as peroxynitrite and resultant decreased NO bioavailability. As recurrent episodes of ACS may be a risk factor for the development of PH in SCD patients, similarities in pathogenesis may exist. We hypothesize that extra-erythrocytic genetic polymorphisms are an important pre-disposing risk factor for the development of PH in SCD patients and that these polymorphisms are associated with decreases in NO bioavailability. Reductions in functional NO act within the endothelium to produce a pro-constrictive, pro-adhesive phenotype which likely plays an important role in the development of PH of SCD. To investigate these hypotheses, we will: 1) Determine the prevalence and clinical outcome of PH in a clinic population of SCD patients; 2) Determine the role of altered nitric oxide bioavailability in the development of PH of SCD; and 3) Correlate the presence of single nucleotide polymorphisms in endothelial cell-expressed genes in the NO pathway with the presence of PH of SCD. The goal of this application is to establish a cohort of patients with PH related to SCD so that they may be studied biochemically and genetically to gain great insight into the pathogenesis of pulmonary vascular disease in these patients.

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Project Title: GENE TRANSFER INTO STEM CELLS BY FOAMY VIRUS VECTORS Principal Investigator & Institution: Josephson, Neil C.; Puget Sound Blood Center 921 Terry Ave Seattle, Wa 98104 Timing: Fiscal Year 2005; Project Start 01-APR-2001; Project End 31-DEC-2005 Summary: (adapted from the application) This research project is designed to provide the applicant, Neil Josephson, with training in the areas of retroviral vector development and gene transfer into hematopoietic stem cells. Dr. Josephson is a board certified hematologist with an interest in stem cell disorders and gene therapy. Stem cell gene therapy offers the promise of treating hereditary disorders such as sickle cell anemia and thalassemia. It also may play a role in the therapy of acquired diseases such as cancer and HIV. This promising technology has not yet yielded clinical results

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because current retroviral vectors do not efficiently transfer genes into hematopoietic stem cells. The work proposed in this application will develop and test a new retroviral gene transfer system based on the human foamy virus (HFV). HFV vectors have many qualities that make them good candidates for use in stem cell gene transfer. They are non-pathogenic, have a wide host range, and can transduce quiescent cells. Aim 1 focuses on vector development. Using currently available HFV vector backbones, new constructs will be generated with a variety of different internal promoters and reporter genes. Current HFV vector production methods rely on transient transfection of vector constructs and yield a crude stock contaminated with toxins. Density centrifugation techniques for purifying HFV stocks will be investigated. To allow for easier and more pure vector production an HFV packaging line will be developed. Aim 2 looks at the ability of HFV vectors to transduce human hematopoietic cells. The impact of multiplicity of infection and length of exposure to vector stock on hematopoietic cell transduction will be explored. The role of cell cycle in transduction efficiency will also be explored. Conditions that are found to most efficiently transduce progenitor cells will be applied to marking studies of human pluripotent repopulating cells in the NOD/SCID xenotransplantation model. Aim 3 outlines work that will take the best HFV vectors produced in aim 1 and the optimal transduction protocols from work in aim 2 and apply them to a pre-clinical marking study of nonhuman primates. Nonhuman primates are the most biologically similar animal model to humans. Therefore, it is essential to use this model for testing the efficacy and safety of HFV vectors before applying them to clinical studies. Most primates kept in captivity are infected with the simian foamy virus (SFV) which is very similar to HFV. The presence of SFV in HFV vector transduced animals could complicate the interpretation of marking and toxicity results. Therefore, in vitro analysis of HFV effects on SFV will be explored. Transduction protocols from studies in aim 2 will be applied to marking studies of non-human primate hematopoietic progenitor cells. Once optimal transduction protocols have been determined, in vivo transplantation and marking studies will be performed. Marked animals will be followed for the presence of transduced cells by evaluation of reporter gene expression and proviral copy numbers. Animals will be evaluated for any potential toxic effects of the transduction and transplantation. •

Project Title: GENETIC ANALYSIS USING SPERM TYPING Principal Investigator & Institution: Arnheim, Norman; Professor; Biological Sciences; University of Southern California Department of Contracts and Grants Los Angeles, Ca 90033 Timing: Fiscal Year 2006; Project Start 01-SEP-1985; Project End 31-AUG-2010 Summary: (provided by applicant): Project Summary: In humans, there is a sizable burden of inherited mutations that contributes to ill health throughout the world. This includes vast numbers of people with common hemoglobinopathies caused by a single gene alteration (sickle cell anemia, alpha- and beta-thalassemia) and genetic variants that contribute to the burden of "common" diseases present in all populations such as cardiovascular disease, cancer, and diabetes. The bulk of this morbidity and mortality arises from transmission of mutant genes from affected or carrier parents to their children. Some affected individuals also arise each generation as a result of inheriting a de novo germline mutation from unaffected parents. Although this is relatively rare, new germline mutations are the sole source of the heritable genetic variation that contributes not only to the "genetic load" of our species but also to the raw materials for adaptive evolution. Our proposal is focused on studying new mutations that occur in the human male germline using a new set of molecular tools to analyze sperm DNA. We plan to study two dominantly inherited conditions, achondroplasia, and Apert

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syndrome. Our goal is to help explain why the chance of a father having an affected child with a new mutation increases with his age and whether fathers of sporadic cases have the same susceptibility to mutation as men in the general population. In addition, we will test the hypothesis that germline stem cells heterozygous for one of these mutations may have a selective advantage over wild type cells thereby explaining the unexpectedly high mutation frequency typical of both conditions. Relevance: The illness and death due to human genetic disease results from the transmission of mutant genes from affected or carrier parents to their children and the inheritance each generation of new mutations. Our proposal is focused on studying the frequency of new mutations that occur in human sperm using a new set of molecular tools. We plan to study achondroplasia and Apert syndrome with the goal of understanding why the chance of a father transmitting a new mutation to his child increases with his age. •

Project Title: GENETIC DETERMINANTS OF ERYTHROCYTE HYDRATION Principal Investigator & Institution: Brugnara, Carlo; Professor of Pathology; Children's Hospital Boston 300 Longwood Ave Boston, Ma 021155737 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-MAR-2010 Summary: (provided by applicant): Changes in the function of transporters embedded into the cell membrane have been associated with erythrocyte dehydration in sickle cell anemia, Hb CC and SC diseases, hereditary spherocytosis and xerocytosis. Dehydrated cells are the most likely to sickle and produce vaso-occlusion; thus, specific therapies are being developed to diminish dehydration in vivo. The physiologically important regulators/determinants of activity of these pathways are not known, thus impeding the identification of subsets of patients more likely to experience cell dehydration and vaso-occlusion. We propose to identify physiologically important genes affecting the function of ion transport pathways and cell hydration in mouse and eventually human erythrocytes. We will use inbred mouse strains to identify quantitative tract loci (QTLs) and ultimately individual genes that modulate red cell hydration and transport. We have already identified inbred mouse strains with large differences in cell hydration: from the appropriate crosses, QTL analysis will be performed to focus on areas of the genome associated with the different phenotype, and identify the gene(s) involved. We also propose a detailed phenotypic characterization of the erythrocyte ion content and transport properties, focused on three pathways known to mediate dehydration (Gardos channel, K-CI cotransport, and Na-K pump), in 11 normal inbred mouse strains. These strains are widely used, with abundantly available genetic and phenotypic information. We will set-up informative crosses to identify specific QTLs associated with meaningful differences in transport activities. Definition of the genes influencing erythrocyte hydration and ion transport in the mouse will enlighten explorations in the sickle mouse model, and will allow testing of candidate genes using knock in/out experiments. The ultimate intent is to validate in future studies the mouse candidate genes with appropriate association studies in patients. We anticipate that these studies will lead to identification of novel genes relevant to pathophysiology of sickle cell syndromes and other anemias, and of potential new therapeutic targets, markers of disease severity, and indicators of susceptibility to specific therapies.

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Project Title: GENETIC DISSECTION OF SICKLE CELL ANEMIA PHENOTYPES Principal Investigator & Institution: Sebastiani, Paola; Associate Professor in Biostatistics & b; Biostatistics; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 021182394 Timing: Fiscal Year 2005; Project Start 01-JUN-2005; Project End 31-MAY-2007

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Summary: (provided by applicant): Sickle cell anemia is a paradigmatic single gene disorder caused by homozygosity for a unique mutation on the beta-globin locus producing the abnormal sickle hemoglobin (HbS). Phenotypically, sickle cell anemia is a complex disease with different clinical courses ranging from early childhood mortality to virtually unrecognized conditions. Damaged red cells initiate hemolysis, vasoocclusion and the vascular pathology of sickle cell disease. Vaso-occlusion injures vital tissues causing pain and impairing function. Death is premature and life can be oppressive. Supported by the NIH/NHLBI R01 HL68970 "Genetic modulation of sickle cell anemia", in 2001 Dr Steinberg initiated a genome scan study to understand the genetic basis of the major sickle cell anemia phenotypes. This study has led so far to the discovery of several genes that are associated with individual phenotypes of sickle cell anemia, and more than one phenotype appears to be associated with the same genetic variants. These findings support the hypotheses that clinical heterogeneity in sickle cell disease, as in other "single gene" Mendelian disorders, must be caused by the genetic variability in genes that influence the occurrence of defined phenotypes. This variability may be also modulated by other clinical conditions, and some of the sub-phenotypes of sickle cell anemia may have common genetics bases. To model these relationships and to allow ultimately the use of these discoveries as prognostic and therapeutic models, we are developing new computational methods for learning about simultaneous genephenotypes associations based on multivariate dependency models. In this project, we propose to use these new modeling techniques for the simultaneous discovery of the genetic basis of several sickle cell anemia phenotypes, and to use the discovered associations for prognosis of the risk of complications in sickle cell anemia patients. •

Project Title: GENETIC MODIFERS OF SICKLE CELL DISEASE Principal Investigator & Institution: Townes, Tim M.; Professor and Chairman; Biochem & Molecular Genetics; University of Alabama at Birmingham 1530 3Rd Avenue South Birmingham, Al 35294 Timing: Fiscal Year 2005; Project Start 30-SEP-2001; Project End 31-JUL-2007 Summary: (provided by applicant): Microarray based expression profiling and positional cloning will be utilized to define genes that modify the severity of sickle cell disease. Initial experiments will be performed in a mouse model of sickle cell disease that reproduces most if not all of the pathology of the disorder (Science 278: 873- 876). The model was created by targeted deletion of the: mouse alpha and beta globin genes followed by introduction of human alpha, gamma and beta sickle globin transgenes" into the germline. These animals synthesize only human hemoglobin in adult red blood cells. Interestingly, as observed, in humans, the range of disease severity in these outbred sickle mice is dramatic. Genes that modify disease severity will be defined by comparing the gene expression profiles of mice that are severely anemic with animals that are less' severely anemic. Initial experiments will define expression profiles of blood and kidney for 50 animals that have a broad range of disease severity. Hierarchical cluster analysis of expression data will define groups of animals, and these groups will be correlated with disease severity. A major goal is to define expression profiles that predict severe disease. Therefore, the genotypes of multiple, severely affected animals will be fixed by cloning; that is, primary fibroblasts will be cultured from all 50 animals in the study and nuclear transfers into enucleated eggs will be performed for animals that develop severe disease and for non-severely affected controls. Expression profiles will then be determined at 10, 20 and 30 days of age to define profiles that precede anemia and kidney pathology. This analysis will define a profile(s), that predicts severe disease. Comparison of the phenotypes of cloned siblings will also reveal the relative contributions' of genetic and environmental/ stochastic influences on disease

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progression and severity. Linkage analysis of anemia with SNPs will also be used to map genes that modify the disease. Sickle mice that are backcrossed onto the C57B]/6;1 background uniformly develop severe anemia. These animals will be bred with sickle animals that are backcrossed! I onto a strain that results in less severe anemia. Linkage analysis will be performed on F2 animals to define SNPS linked, to severe disease. Candidate modifying genes that are linked to the SNPs will be identified in the public and private, databases and the functional significance of these genes will be examined by modification in ES cells derived from the sickle mice. Expression profiles will also be determined for blood of human sickle patients. A "SickleChip" which contains the human homologues of modifier genes identified in the mouse will be produced. These SickleChips will be probed with blood RNA collected from three to six month old sickle patients after parental consent. Expression profiles I will be determined and disease progression will be followed longitudinally. Profiles that predict severe disease will1i provide important information for early intervention. •

Project Title: GENETIC MODIFIERS OF SEVERITY IN SICKLE CELL ANEMIA Principal Investigator & Institution: Platt, Orah S.; Associate Professor of Pediatrics; Children's Hospital Boston 300 Longwood Ave Boston, Ma 021155737 Timing: Fiscal Year 2005; Project Start 30-SEP-2001; Project End 31-JUL-2007 Summary: (provided by applicant): Despite the fact that all individuals with sickle cell anemia (SS) have the identical genetic defect (homozygous beta 6 glu to val), there is a wide variation in clinical severity. While clinicians have long been aware of this variability, it was the epidemiologic data amassed by the NHLBI's Cooperative Study of Sickle Cell Disease (CSSCD) that allowed objective measurement of this variability and identification of key risk factors for severity. In this proposal we focus on one of the key risk factors for severity identified by the CSSCD - baseline white blood cell count (baseline WBC). This initially unanticipated risk factor is becoming more obviously relevant as new investigations into the pathophysiology of the disease increasingly emphasize the importance of white cells and inflammation. At the same time, baseline WBC and other markers of inflammation are emerging as risk factors for mortality in the general population, making the exploration of genetic determinants of baseline WBC of interest not only to the SS population, but also to the population at large. Our strategy for locating the genes that are responsible for the variability in baseline WBC involves three unique populations: inbred strains of mice (Jackson Labs, Bar Harbor), baboon pedigrees (Southwest Foundation for Biomedical Research, San Antonio), and nuclear and extended families of ~300 probands with SS (Boston, Creteil). The animals will be useful in determining quantitative trait loci (QTLs) and ultimately individual genes that influence baseline WBC. The SS probands and their families will allow quantification of the relative importance of genetic and environmental modifiers of baseline WBC in the probands (SS), as well as their normal heterozygous (AS) and unaffected (AA) relatives. Genotyping, and phenotyping using baseline WBC and more specific markers of inflammation (e.g. cytokines, adhesion molecules, hematopoietic growth factors) in these families will allow not only QTL mapping and gene identification, but also an analysis of how genetically interrelated the inflammatory markers are. We anticipate that these studies will provide new insights into the genetics of inflammation that will be of benefit to patients with SS as well as the general population of African heritage. In addition, the data and sample resource we will create is designed to continue to answer questions well beyond the inflammation issue that we focus on in this proposal.

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Project Title: GENETIC MODULATION OF SICKLE CELL ANEMIA Principal Investigator & Institution: Steinberg, Martin H.; Professor of Medicine and Pediatrics; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 021182394 Timing: Fiscal Year 2005; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant): Endothelial cell genes are likely to be differentially expressed among patients with sickle cell disease. Variable expression of selected genes may, by modulating the response of the endothelium to sickle cells, leukocytes, growth factors, chemokines, cytokines, adhesion molecules and hemostasis, account for some heterogeneity of vasoocclusive disease. In addition, polymorphisms in genes expressed in endothelial cells and other tissues may alter gene expression or the gene product. Single nucleotide polymorphisms (SNPs) that segregate with selected features of the disease may mark important genes for further study. We plan a twofold approach to the question of genetic modulation of defined phenotypes of sickle cell disease. First, using microarrays containing cDNA of human microvascular endothelial cell expressed genes, we will profile the pattern of gene expression in endothelial cells obtained from patients with sickle cell anemia and HbSC disease who have defined phenotypes; we will also ascertain if there is enhanced responsiveness of their endothelial cells to biological stimuli such as TNF , IL1 or LPS. Second, using genomic DNA, we will search for SNPs in genes we hypothesize could play a role in phenotypic heterogeneity of sickle cell anemia and in genes whose endothelial cell expression differs in patients with and without designated phenotypes. In the first phase of our SNP studies, we will use banked DNA from more than 2000 patients with sickle cell disease who participated in the NHLBI-supported Cooperative Study of Sickle Cell Disease and study pooled DNA from patients with defined phenotypes to establish an association between a SNP and a phenotype. In a second phase, we will confirm positive findings in individual samples from these pools. A third phase will involve a search for SNPs in an independent population of family triads with a sickle cell disease proband having a defined phenotype to establish association and linkage of a SNP and phenotype. Our prime objectives are to learn if endothelial cell gene expression or polymorphisms in endothelial cell-expressed genes correlate with phenotypes of sickle cell disease and discover SNPs that segregate with defined phenotypes of sickle cell anemia. We hope to develop insights into the relationships of endothelial-expressed genes and clinical features of sickle cell disease and find SNPs that mark modifiers of disease severity.

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Project Title: GLOBIN GENE TRANSFER FOR THERAPY OF SICKLE CELL ANEMIA Principal Investigator & Institution: Sadelain, Michel; Member; Sloan-Kettering Institute for Cancer Res 1275 York Ave New York, Ny 100216007 Timing: Fiscal Year 2004; Project Start 30-SEP-1996; Project End 31-MAY-2007 Summary: (Applicant's Description Verbatim): Sickle cell anemia is one of the commonest inherited diseases in humans, characterized by a severe chronic hemolytic anemia with an unpredictable course. While current forms of chemotherapy do not represent a radical treatment, the use of bone marrow replacement is limited by complications of allogeneic transplantation and the need for aggressive conditioning regimens. Thus, the goal of this proposal is to develop a treatment for severe hemoglobinopathies that integrates a genetic correction in autologous hematopoietic stem cells (HSC) with a reasonable transplantation strategy. The approach we propose is based on efficient lentiviral-mediated transfer of a wild-type globin gene in cord blood or peripheral blood stem cells, together with a selection for genetically modified cells

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that is applied in vivo after transplantation. In vivo selection is useful for two purposes: (1) to increase the relative representation of genetically corrected blood cells and (2) to decrease the toxicity associated with the transplantation conditioning regimen. Our recent results establish that efficient gene transfer of a modified beta-globin gene and large elements of the beta-globin LCR can be achieved using recombinant lentiviruses. We have demonstrated that (1) a large LCR greatly increases mean globin expression compared to the core elements of the LCR that were previously investigated and (2) incorporation of an insulator element into a retroviral vector increases the probability of expression at random integration sites and decreases vector silencing. The major goals of this project are: (a) to improve erythroid-specific gene expression from a virally encoded beta-globin transcription unit; (b) to compare the betaAand gammaAglobin genes in terms of their level of expression in bone marrow chimeras and their therapeutic activity in mouse models of sickle cell disease; (c) to confer a competitive advantage to the transduced HSC for repopulation of the host marrow using resistance to methotrexate as a model. We propose a detailed analysis of the function of the LCR and of the chicken globin insulator in stringent in vitro and in vivo assays that are relevant to the critical evaluation of their therapeutic potential. These studies are based on investigations in murine models of sickle cell disease and in primary human CD34+ cells of normal subjects and patients. To analyze globin gene expression and the effectiveness of drug resistance in selecting out corrected cells that express therapeutic levels of the globin transgene, we will capitalize on our ability to efficiently derive erythroid progeny from long-term cultured CD34+ cells and our mouse/human xenochimeras based on NODscid/scidmice. We ultimately aim to establish by direct experimental evidence that expression of the lentivirus-encoded human globin gene is sustained over time in murine and human cells in vivo and that expression of the mutant dihydrofolate reductase permits efficient in vivo selection with methotrexate/trimetrexate. •

Project Title: HBF INDUCTION BY PROLYL HYDROXYLASE INHIBITORS Principal Investigator & Institution: Klaus, Stephen J.; Senior Director; Fibrogen, Inc. 225 Gateway Blvd South San Francisco, Ca 94080 Timing: Fiscal Year 2006; Project Start 13-APR-2004; Project End 31-MAY-2008 Summary: (provided by applicant): Beta-hemoglobinopathies are diseases characterized by defective or insufficient expression of the beta-chain of adult hemoglobin, and lead to the anemia associated with sickle cell disease (SCD) and beta-thalassemia. One approach to treat beta-hemoglobinopathies, and in particular SCD, involves the elevation of fetal hemoglobin (HbF) expression in patients. The rationale for this approach came from observations that patients with SCD that also harbor secondary genetic mutations for persistent HbF expression into adulthood exhibit reduced pathophysiological symptoms associated with SCD. Hydroxyurea (HU) is currently the only FDA-approved therapy for SCD and reduces the number of clinical crisis and incidence of episodic pain. However, the use of HU therapy is hindered by dose-limiting toxicity and poor response rate of many patients with SCD, highlighting an unmet medical need for better therapeutic options to treat this disease. The work proposed within this application leverages FibroGen's technology platform aimed at therapeutic HIF stabilization, and in our anemia program we have developed a series of orally bioavailable HIF prolyl hydroxylases inhibitors (PHI) that elevate circulating, endogenous EPO levels and potently stimulate erythropoiesis with repeated intermittent dosing. In the phase I SBIR program, we demonstrated that erythropoietic PHI are also capable of inducing HbF in human bone marrow-derived CD34+ cells undergoing erythroid expansion ex vivo. The primary goal of the proposed phase 2 SBIR plan is to obtain proof-of- concept that orally bioavailable, erythropoietic PHI can elevate HbF protein expression in anemic non-

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human primates, either alone or in combination with HU. Enhancing HbF expression is long recognized as an important protective mechanism against SCD. The ability to activate the HbF expression program by PHI may prove to be a powerful approach in the therapeutic treatment of SCD and beta-hemoglobinopathies. •

Project Title: HBF VARIANTS FOR GENE THERAPY OF SICKLE CELL DISEASE Principal Investigator & Institution: Adachi, Kazuhiko; Children's Hospital of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318 Timing: Fiscal Year 2005; Project Start 01-APR-1998; Project End 31-MAR-2007 Summary: (provided by applicant): Despite extensive research on the Hb molecule, the mechanism by which heme and globin subunits coordinately assemble and how misfolded and unstable unassembled globin chains are removed from erythrocytes are not known. In addition, the basic mechanism by which Hb F inhibits polymerization and ameliorates the clinical course of SCD is not completely understood. Elucidating such mechanisms can contribute to the development of strategies for gene therapy in the treatment of diseases of altered globin chains or those associated with decreased globin synthesis. In this proposal we aim (1) gamma-chain assembly with a chains to form functional human fetal Hb, (2) Ubiquitin-mediated degradation of excess non-alpha globin chains in vivo, and (3) Engineered Hb F variants having low oxygen affinity and inhibitory properties on Rb S polymerization. The long-range goal is to identify and design optimal Rb F variants for use in gene therapy of sickle cell disease (SCD) andthalassemia. In Specific Aims (1) we will test two related hypotheses; (i) Folded alpha-globin chains assemble with intermediately folded nascent gamma-chains prior to or soon after the release from polyribosomes. (ii) The amino acids at G-10, 14 and 18, which have been shown by x-ray crystallographic analysis to be at the alpha1gamma1 interaction sites on the G helix, are critical for assembly of alpha- and gamma-globin chains in vivo as well as in vitro. In Specific Aim (2), we hypothesize that purified nonalpha chain tetramers, like Hb hetero-tetramers, are not substrates for ubiquitination since Beta4 and gamma4 structures are very similar to the alpha2Beta2 heterotetramer structure. Using a rabbit reticulocyte cell free system, we will measure degradation of non-alpha chain in the absence of a chain during translation in the presence of ubiquitin. In specific Aim (3), we will continue to investigate the inhibitory mechanism of Hb S polymerization by Hb F. We hypothesize that Hb F variants (e.g., Hb F gamma 73 His, Rb F gamma 6Val & 73 His) can be engineered that have inhibitory properties exceeding those of Hb F and we will seek such variants. We will also continue to seek Rb F variants with lower oxygen affinity than Hb S through not only enhancement of 2,3-BPG interaction but also amino acid substitution at the alyl interaction sites on the G helix. Because of their lower oxygen affinity, these hemoglobin variants in addition to having anti-nucleation properties would effectively inhibit sickling at lower levels than would native Rb F, such as about 10 percent vs. 20 percent. The understanding of the assembly of gamma and alpha chain and the mechanism of degradation of excess globin will provide a basis for determining the most appropriate gamma chain mutant for gene therapy, which should be one that can be introduced by viral vectors at significantly lower levels than native Rb F. Furthermore, these studies will be of general interest to researchers who study protein biosynthesis and will help identify why some mutant globin chains are incorporated into hemoglobin more or less efficiently than wild type chains as well as how separately translated alpha and non-alpha chain are quality controlled during hemoglobin formation to preserve functional erythrocytes.

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Project Title: HDL DYSFUNCTION AND VASCULAR INFLAMMATION Principal Investigator & Institution: Pritchard, Kirkwood A.; Professor & Vice Chair of Research; Surgery; Medical College of Wisconsin 8701 Watertown Plank Rd Milwaukee, Wi 532260509 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-MAR-2011 Summary: (provided by applicant): The overall goal of this application is to determine the mechanisms by which vascular inflammation impairs vasodilation. Recent reports from this laboratory demonstrate that an apoA-l mimetic, 4F, dramatically improves endothelium-and eNOS-dependent vasodilation in two distinct murine models of vascular disease-hypercholesterolemia and sickle cell disease (SCD). On the basis that apoA-l mimetics were designed to improve HDL function, we hypothesize that oxidative stress and inflammation induce HDL dysfunction, which in turn impairs vasodilation. In this application, we will test this hypothesis in a disease state and a murine model whose vascular dysfunction is more closely associated with inflammation than hyperlipidemia, sickle cell disease (SCD). Although SCD is primarily a genetic disease, many consider the chronic state of inflammation to play a role in the mechanisms by which SCD impairs vasodilation. This application investigates the concept that inflammation plays a central role in impairing vascular dysfunction by determining how the sickling red cell raises up new "partner in crime" to induce vascular disease. The objectives of this application are to determine the interactions between inflammation, HDL function and proinflammatory lipids in hopes of identifying other down-stream "partner(s)" who team up with the sickling red cell to impair vasodilation. We will investigate the role of acute phase proteins, proinflammatory HDL, proinflammatory lipids and xanthine oxidase on vascular function in transgenic SCD mice. Bioassays of plasma from severe and non-severe SCD patients and control subjects will be used to identify and rank potential partners that impair vasodilation and shift the balance of nitric oxide (-NO) and superoxide anion (O2.-) generation in the vessel wall. Mechanisms will be investigated at the vascular level to determine how SCD induces endothelial cell dysfunction. Hematopoietic stem cell transplantation (HSCT) of SCD into genetically engineered mice will be used to test alternative hypotheses that low-density lipoprotein contributes to impaired vasodilation in SCD. HSCT of SCD into an apoA-l knockout mouse that expresses apoA-l-deficient HDL will be used to test the alternative hypothesis that D-4F does not improve HDL function to restore vasodilation. The utility of D-4F in improving outcomes will be tested at the level of survival, mechanisms of ischemic injury, organ pathobiology and proteomics of HDL interactions with other inflammatory mediators. On the basis that D4F improves vasodilation in other systems, our data suggest that targeting HDL may be an effective means of protecting vascular function in diseases characterized by chronic states of inflammation. Through these studies, new treatment modalities may be realized for preventing vascular dysfunction in a variety of diseases characterized by increases in oxidative stress and inflammation.

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Project Title: HOMOCYSTEINE AND COAGULATION IN SICKLE CELL DISEASE Principal Investigator & Institution: Balasa, Vinod; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2003; Project Start 11-JUL-2003; Project End 31-MAR-2008 Summary: The coagulation system and endothelial cells are believed to contribute to the vascular pathology of sickle cell disease (SCD). Elevated plasma homocysteine (Hcy) is associated with vascular disease and thrombosis in the general population and is believed to induce endothelial cell dysfunction and activate the coagulation system.

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Patients with SCD exhibit activation of coagulation and an increase in activated circulating endothelial cells (CEC). Preliminary data demonstrate that hyperhomocysteinemia (HHcy) is present in 38% of patients with SCD and that a majority (62%) of these individuals have pyridoxine deficiency, compared to race and age-matched controls. It is hypothesized that HHcy is associated with activation of coagulation and CEC in SCD and that a lowering of Hcy with pyridoxine supplementation will reduce this activation. Therefore, the aims of this study are to determine the following in patients with SCD: (1) prevalence of HHcy and its association with vitamin cofactor deficiencies (2) correlation of HHcy with activation of CEC and coagulation (3) responsiveness of HHcy to pyridoxine supplementation (4) correlation of a decrease in Hcy levels with reduction in the activation of CEC and coagulation. The following laboratory determinations will be made in patients with SCD and in race and age-matched controls: fasting and post-methionine load Hcy, levels of red cell folate, serum vitamin B12, pyridoxal 5'-phosphate, the C677T MTHFR genotype; markers of activation of coagulation (prothrombin fragment 1.2, thrombin:antithrombin complexes), and fibrinolysis (plasmin:antiplasmin complexes, D-dimer); enumeration of CECs and the presence of activation markers VCAM-1 and tissue factor on CECs. SCD patients with HHcy will be randomized to receive a 6-week trial of pyridoxine supplementation or placebo and levels of Hcy, pyridoxine, and determination of markers of activation of coagulation and CECs will be repeated. This study is a collaborative trial open to all the sickle cell centers and at least 248 SCD patients and 248 controls will be recruited. Hey levels will be regressed on age in the controls and 95% confidence intervals will be determined. The chi-square statistic will be used to test the difference. Linear regression will be used to determine the relationship between Hcy and the activation markers. Paired t-tests will be used to test the other hypotheses. Pyridoxine supplementation is a simple therapy with the potential to reduce thrombotic complications of sickle cell disease. •

Project Title: HOWARD UNIVERSITY RESEARCH SCIENTIST AWARD Principal Investigator & Institution: Gordeuk, Victor R.; Professor; Administration; Howard University 2400 6Th St Nw Washington, Dc 20059 Timing: Fiscal Year 2005; Project Start 30-SEP-1996; Project End 31-AUG-2010 Summary: (provided by applicant): The goal of this competitive renewal Research Scientist proposal is to expand a successful investigative program in hemoglobinopathies and other hematological diseases that will build the research capacity of Howard University and increase the number of minority individuals involved in biomedical research. The underlying themes of the research we now envision are to reduce health disparities and to enhance excellence in research into heart, lung and blood diseases at Howard University. An integral part of the program will be to obtain additional research support from the NIH and other sources. Scientific Specific Aims: 1. Disordered iron metabolism in sickle cell disease and HIV infectionelucidate the role of altered iron metabolism in the pathogenesis of sickle cell disease and HIV disease. 2. The hypoxic response and sickle cell disease, congenital polycythemia, and HIV- clarify the role of the hypoxic response in the complications of sickle cell disease by comparing patients with sickle cell disease and congenital polycythemia at the clinical and molecular levels. Examine the effect of the hypoxic response on HIV transcription. 3. Immune response and anemia in malaria and HIV disease- determine whether alterations in the immune response and in iron metabolism are related to the degree of anemia in malaria and HIV disease. Educational Specific Aims: 1. Developmental research projects- provide pilot projects for faculty and junior investigators of Howard University and help them develop independent research

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support. 2. Laboratory research training activities- provide laboratory experience to undergraduate, MS and PhD students at Howard University. 3. Research collaborations with other institutions nationally and internationally- develop new and expand existing collaborations. 4. Organize research seminars at Howard University- bring leading investigators from these collaborating institutions for seminars at Howard University. •

Project Title: INDUCTION OF STABLE CHIMERISM FOR SICKLE CELL ANEMIA Principal Investigator & Institution: Walters, Mark C.; Director; Children's Hospital & Res Ctr at Oakland 747 52Nd St Oakland, Ca 946091809 Timing: Fiscal Year 2004; Project Start 25-AUG-2001; Project End 31-JUL-2007 Summary: Hematopoietic cell transplantation (HCT) has curative potential for individuals with sickle cell disease. While the results of conventional HCT have been good, this treatment carries risks of significant short- term and longterm toxicities. For this reason, HCT has been reserved for children who have experienced severe symptoms that predict a poor outcome. Of interest, some patients developed stable donor-host hematopoietic chimerism after conventional HCT. Due to a natural enrichment of donor erythrocytes in the blood, those who developed stable chimerism had a significant clinical benefit, even when there was a minority of donor cells. These observations have paralleled efforts to develop less-toxic, non-myeloablative preparative regiments for transplantation, proved first in a canine model of transplantation, and subsequently translated successfully in a clinical trial for older adults with hematological malignancies. Thus, this proposal, based on these supporting pre-clinical and clinical investigations, aims to investigate a modified transplant procedure for sickle cell disease that significantly reduces the toxicity of HCT, yet retains its therapeutic benefit. This is a novel approach, conducted in the outpatient setting, which will rely upon the ability to establish and maintain donorhost chimerism. It will be achieved by combining less toxic, non-myeloablative pre-transplant therapy with modulated post-grafting immuno-suppression aimed at controlling host-versusgraft and graft-versus-host reactions. This investigation will employ an existing network of collaborative sickle cell and transplant centers to identify and enroll eligible patients. The primary endpoint of stable donor cell engraftment will be determined and secondary endpoints to measure the impact on sickle cell-related symptoms and endorgan damage will be followed. If successful, this novel approach will expand the availability of HCT for patients with clinically significant hemoglobinopathies.

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Project Title: INFLAMMATION IN SICKLE DISEASE Principal Investigator & Institution: Vercellotti, Gregory M.; Senior Associate Dean for Education; Medicine; University of Minnesota Twin Cities 450 Mcnamara Alumni Center Minneapolis, Mn 554552070 Timing: Fiscal Year 2006; Project Start 01-APR-2001; Project End 31-JUL-2010 Summary: (provided by applicant): Sickle cell disease (SCD) is a devastating hemolytic disease characterized by recurring episodes of painful vaso-occlusion, leading to ischemia-reperfusion injury and organ damage. Despite significant advances in the knowledge of sickle hemoglobin and red blood cells, we still lack a clear understanding of the pathophysiology and treatment of vaso-occlusion. It is now understood that oxidative stress is a trigger for vascular inflammation which promotes vaso-occlusion. Recently the critical roles of endothelial cell activation and inflammation in vasoocclusion have been recognized, in part due to the development of transgenic murine models of SCD. However, a critical gap exists in explaining how does the sickle patient defend or adapt to excessive hemolysis with the release of hemoglobin/heme/iron into

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the vasculature and the exuberant production of reactive oxygen species. To remove this heme burden and lessen the oxidative stress, the vasculature increases the expression of heme oxygenase-1 (HO-1). HO-1 is a highly adaptable anti-inflammatory defense against excessive heme burdens. We hypothesize that HO-1, an adaptive, antiinflammatory gene, plays a critical role in the inhibition and resolution of vaso-occlusion in SCD. In Specific Aim 1, we will test whether HO-1 and its downstream products, including carbon monoxide, biliverdin/bilirubin and ferritin, manipulated pharmacologically or with gene therapy, will prevent hypoxia/reoxygenation-induced stasis, ameliorate organ pathology and prolong life span in transgenic sickle mice. In Specific Aim 2, we will identify the mechanisms whereby HO-1 modulates SCD in SCD by examining the effects of HO-1 and its products on oxidative stress, NF-kB activation and endothelial cell adhesion molecule expression. We will demonstrate that adaptative increases in HO-1 activity in SCD are inadequate to handle the excessive heme burden. We expect that further upregulation of HO-1 activity and/or its downstream products will be important strategies to develop innovative new therapies to prevent and treat vaso-occlusion in SCD. This research on inflammation using mouse models of sickle cell anemia wilt identify new targets for drug therapies to alleviate the complications of SCD. These new treatments should decrease sickle crises, prevent organ damage, improve quality and length of lives of sickle cell anemia patients. •

Project Title: INFLAMMATORY CONTROL OF ERYTHROPOIESIS IN SICKLE DISEASE Principal Investigator & Institution: Means, Robert T.; Internal Medicine; University of Kentucky 109 Kinkead Hall Lexington, Ky 405060057 Timing: Fiscal Year 2004; Project Start 30-SEP-2001; Project End 31-JUL-2007 Summary: (provided by applicant): The anemia of chronic disease (ACD) is one of the most common hematologic syndromes encountered in clinical medicine. Over the last decade, studies have clearly established that ACD is a consequence of the cytokines which mediate the immune and inflammatory process. In contrast, sickle cell anemia is the result of a genetic defect producing a single amino acid change which alters the solubility of deoxygenated hemoglobin. Over the same period of time, it has become recognized that the clinical manifestations of the sickle syndromes result from a constellation of processes, including activation of inflammation. A heightened inflammatory state with consequent cytokine production can be demonstrated in patients with sickle cell disease. However, the unique characteristics of the sickle erythrocyte (including the persistent expression of CD36) alter the characteristics of the erythroid response to cytokines. Review of the literature suggests that CD36 persistence at high levels is unique to sickle erythrocytes, and contributes to their adhesive properties. In our preliminary data, we have demonstrated that CD36 is a positive regulator of erythropoiesis. As discussed above, the cytokine mediators of the inflammatory response produce ACD, and similar mechanisms can be implicated in sickle disease. Based on data in the literature and on our preliminary results reported below, it is hypothesized that CD36 expression protects sickle erythroid progenitors against cytokine suppression, and that those progenitors which persistently express CD36 have a selective growth advantage in the presence of inhibitory cytokines. This would result in the preferential production of CD36-expressing erythrocytes, which are then more likely to participate in intravascular adhesion. The cytokines involved in the inflammatory response would therefore enhance the frequency of vascular sickling events by increasing the frequency of potentially adherent erythrocytes. This hypothesis will be tested through the following Specific Aims: Specific Aim 1 will identify the differences in CD36 expression between progenitors from sickle cell patients and

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precursors, and those from controls. In Specific Aim 2, the differences in sensitivity to cytokine inhibition between sickle and control CFU-E, and the extent to which these differences can be attributed to differences in CD36 expression, will be defined. In Specific Aim 3, FA6-152will be used to characterize the response of CFU-E from sickle patients to CD36 activation, and to determine how CD36 activation alters the pattern of progenitor suppression by inhibitory cytokines, as well as the contribution of rhEPO to these processes; and Specific Aim 4 will characterize local cytokine production in the marrow of sickle cell patients, and how it relates to erythroid CD36 expression and to clinical phenotype. •

Project Title: INHIBITION OF INTESTINAL HEME IRON ABSORPTION Principal Investigator & Institution: Bommer, Jc C.; Frontier Scientific, Inc. 195 South 700 West Logan, Ut 84321 Timing: Fiscal Year 2005; Project Start 29-SEP-2000; Project End 31-JAN-2008 Summary: (provided by applicant): Iron overload syndromes (attributable to transfusions / dietary uptake) are a significant cause of the morbidity and mortality associated with hemochromatosis, thalasemia, and sickle cell anemia. In the developed world, 2/3 of absorbed iron is derived from heme (organic iron) rather than inorganic iron. While the mechanism by which inorganic iron is absorbed is partially understood, the mechanism by which heme iron is absorbed is not understood. Present treatments for iron overload syndromes include phlebotomy (in non-anemic cases) and subcutaneous continuous infusions of deferoxamine. The latter treatment would be rendered more effective or unnecessary if intestinal iron absorption could be halted. We have developed, in a Phase I SBIR study, an inhibitor of heme-iron uptake that is effective in tissue culture cells and in the rat duodenal loop model. These models provide a good approximation of the human physiology. The inhibitor is a soluble metalloporphyrin (Cr-TMP) that inhibits the uptake of iron from heme at about 4 mu/M in tissue cultured cells and appears non-toxic to tissue culture cells. It is active in vivo at less than 200 nanomole/kg and is poorly absorbed by the intestinal mucosa. In Phase II, (A) we will develop a synthesis capable of producing large amounts of the compound, institute quality control and GMP protocols, and stabilize and appropriately formulate the drug for delivery. (B) We will further assess toxicity in tissue culture cells. (C) We will discover the optimal concentration required to inhibit the uptake of heme iron in the rat duodenum, explore the effects of food and other potential interactions on the drug's action, and conduct long-term toxicity studies in rats. (D) SRI will assess genetic and other toxicity. (E) We will explore the drug's mechanism of action. (F) We will induce iron deficiency anemia in dogs by use of the inhibitor. These studies should provide a basis for a partnership with biotechnology companies for a Phase III pursuit of an IND and appropriate studies in humans. A business plan to accomplish these goals appears in the Phase II application.

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Project Title: INTRACELLLAR PATHWAYS THAT SILENCE THE FETAL GLOBIN GENE Principal Investigator & Institution: Ikuta, Tohru; Associate Professor; Medicine; Medical College of Georgia (Mcg) 1120 15Th St Augusta, Ga 30912 Timing: Fiscal Year 2005; Project Start 07-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Considerable concerns and efforts have been directed to the development of new fetal hemoglobin (Hb F) inducers. Hydroxyurea (HU) is being used for treating sickle cell anemia (SCA), but the magnitude of response to HU significantly varies between SCA patients. The clinical efficacy of HU for beta-

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thalassemia remains unclear. Rather than studying cis-acting regulatory elements, our research has been focusing on clarifying intracellular pathways that regulate globin gene expression. We recently showed that an intracellular pathway comprising soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase (PKG) plays an important role in gamma-globin gene expression in primary erythroblasts. Our hypothesis that the sGC-PKG pathway plays an important role in Hb F expression was recently substantiated by a discovery of Italian brothers who have no mutations in beta-globin locus but express 25 to 30 % Hb F. They were found to have high levels of protoporphyrin IX, which is a strong activator of sGC. To study "with fresh eyes" the molecular mechanisms for gamma-globin gene silencing, we were concerned with a phenomenon that expression of the gamma- and beta-globin genes is regulated "in a reciprocal manner" at the perinatal period. This has led us to speculate that the gammaglobin gene is silenced in the adult stage by the mechanisms required for activating the beta-globin gene. We will test this hypothesis in this application. Our preliminary studies suggested that 1) cAMP-dependent protein kinase (PKA) activity is necessary for the induction of the beta-globin gene in adult erythroid cells such as MEL cells and primary erythroblasts, that 2) expression of the gamma-globin gene is decreased by activating cAMP-dependent pathways in K562 cells, and that 3) activity of HS2 and a gamma-globin gene promoter is markedly increased by suppressing PKA activity. These results suggest that cAMP-dependent pathways might play a negative role in gammaglobin gene expression. This application has three specific aims. In the first aim, we will characterize intracellular pathways that are required for activating beta-globin gene expression. The second aim will focus on the molecular mechanisms by which intracellular pathways for beta-globin gene expression silence the gamma-globin gene, In the third aim, we will examine whether expression of the gamma-globin gene is induced in primary erythroblasts of the beta-globin disorders and adult mice which have low activities of intracellular pathways for beta-globin gene expression. This application should not only shed much light on the mechanisms that silence the gammaglobin gene, but also provide a clue to the mechanisms underlying the developmental regulation of beta-like globin genes. Furthermore, important information to develop novel Hb F inducers will be disclosed by this study. •

Project Title: LUNG ENDOTHELIUM IN VASO-OCCLUSION Principal Investigator & Institution: Wu, Songwei; Center for Lung Biology; University of South Alabama 307 N University Blvd. Ad200 Mobile, Al 366880002 Timing: Fiscal Year 2005; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: The acute chest syndrome is initiated by lung inflammation that induces increased adhesion of sickled red blood cells to pulmonary microvascular endothelium. Emerging evidence indicates the interaction between red blood cells and endothelium is dynamic. While in the non-inflamed state perfusion is facilitated by anti-adhesive proteins expressed on the endothelial surface, in the inflamed state vaso-occlusion is partly caused by upregulation of adhesive proteins such as P-selectin and release of von Willebrand factor (v W f) from microvascular endothelium. The secretory organelle in endothelium is the WeibeI-Palade body, a structure unique to this cell type. In the inflamed circulation thrombin and other Gq-linked neurohumoral inflammatory mediators increase endothelial cell cytosolic calcium, and this rise in cytosolic calcium is sufficient to cause rapid translocation of WeibeI-Palade bodies to the plasmalemma for v W f secretion and P-selectin up-regulation. Specific calcium entry pathways that stimulate v W f secretion and P-selectin up-regulation remain incompletely understood, particularly in microvascular endothelial cells obtained from the prominent site of vasoocclusion. Preliminary studies suggest that lung microvascular endothelial cells express

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T-type, voltage-activated calcium channels which promote a pro-coagulant endothelial phenotype during inflammation. In this proposal, we will test the overall HYPOTHESIS that calcium entry through T-type calcium channels is an important amplification step in release of vWf and up-regulation of P-selectin from lung microvascular endothelium that promotes the retention of sickled red blood cells. The hypothesis will be explored using lung microvascular endothelial cells in culture and an isolated rat lung model, in which the role of the T channel to red blood cell retention can be assessed under flow conditions. The SPECIFIC AIMS test the hypotheses that: [1] Lung microvascular endothelial cells express a T-type calcium channel that is activated by Gq-linked neurohumoral inflammatory mediators, and [2] Activation of T-type calcium channels promotes the release of v W f and up-regulation of P-selectin from lung microvascular endothelial cells important for vaso-occlusion. It is hoped completion of these studies will improve our understanding of mechanisms that regulate erythrocyte-endothelial adherence so that effective therapies can be developed for treatment of sickle cell anemia, as well as other vascular thrombosis disorders. •

Project Title: MARIAN ANDERSON SICKLE CELL CENTER - SICKLE CELL DISEASE Principal Investigator & Institution: Dampier, Carlton; Director, Ped. Sickle Cell Prog.; Pediatrics; Drexel University Office of Research Philadelphia, Pa 19104 Timing: Fiscal Year 2006; Project Start 01-JUN-2006; Project End 31-MAR-2011 Summary: (provided by applicant): This Clinical Center will provide support for stateof-the-art clinical research activities for 962 SCD patients at St. Christopher's Hospital for Children (SCHC), Thomas Jefferson University Hospital (TJUH), Kosair Children's Hospital (KCH), and duPont Children's Hospital (DCH). Three of these sites (SCHC, KCH, TJUH) are currently part of the Marian Anderson Comprehensive (MAC) Sickle Cell Center and currently lead enrollment in several of the phase l/ll/lll Inter-Center studies sponsored by the Comprehensive Centers, also under the direction of Dr. Dampier and Ms. Rockstein through the MAC Center's Clinical Core. The Center PI and Center Chief Clinical coordinator at St. Christopher's Hospital are both credentialed by the Association of Clinical Research Professionals (Clinical Trial Investigator, and CRA certifications respectively) and have a several year record of successful coordination and supervision of research activities at the various Center sites. The proposed network clinical trials address important issues in clinical care of SCD patients. The first study is a phase IV of headache management that will build on descriptive and epidemiologic data being gathered as part of the C-data project of the Comprehensive Center's Network. This study proposes a 4 month placebo controlled RCT of prophylactic therapy (amitryptline with or without CBT training) in children aged 7- 17 years with >/= 2 headaches per month in the preceding 3 months, while a companion study will evaluate the effectiveness of amitriptyline or divalproex ER in reducing the number of days of recurrent headaches in a 4 month double blind, parallel treatment, placebocontrolled trial of adults with >/= 2 migraine headaches per month. The second clinical trial will examine the efficacy of two alternative morphine PCA dosing regimens in comparison to a standard PCA therapy. It will also determine whether variations in morphine pharmacokinetics, in morphine pharmacodynamics as determined by pharmacogenetics, or subject psychosocial factors, alter the efficacy of the various PCA regimens. An Outcomes Core is also proposed which will focus on developing a variety of outcome measures and descriptive clinical information to support the appropriate, conduct of high quality clinical trials of therapies for sickle cell-related pain. The performance of these studies will advance the clinical understanding of sickle cell-

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related pain and its consequences. Their results will stimulate the development of innovative clinical trials of sickle pain. (End of abstract) •

Project Title: MECHANISMS FOR STAT 3-MEDIATED GAMMA-GLOBIN GENE SILENC* Principal Investigator & Institution: Pace, Betty S.; Professor; Molecular and Cell Biology; University of Texas Dallas 2601 North Floyd Road Richardson, Tx 750801407 Timing: Fiscal Year 2005; Project Start 11-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): This application is aimed at validating a regulatory function for an array of cis-acting elements in the 5'untranslated region of the gamma globin gene and cognate transcription factors including Stat3beta in gamma globin silencing. The collection of cis elements includes three Stat3 DNA elements at -14, +9 and +26, one GATA-1 element at +26 previously assigned a negative regulatory function, and a putative HoxB2 binding AT-rich element at +26. We have recently demonstrated by site directed mutagenesis and co-transfecfion analysis that the +9 ciselement is required for Stat3beta-mediated repression of the gamma globin promoter. Furthermore, subsequent experiments presented as preliminary data in this application show recombinant Stat3 binding to the +9 and +26 cis elements in vitro. We next explored the possibility that Stat3beta inhibits gamma globin promoter via proteinprotein interactions with other transcription factors such as HoxB2, a known inhibitor of gamma promoter activity. We found potential interactions between Stat3 with HoxB2, GATA-1 and CBP. This suggests that inhibition of the gamma globin by Stat3beta may involve synergy with HoxB2 and functional antagonism with GATA-1. Based on these preliminary observations we hypothesize that "a Stat3-containing multi-protein complex interacts through a putative gamma-globin silencing domain to repress the gamma gene". This hypothesis will be tested in four specific aims, 1) Determine the functional significance of cis elements within a putative gamma-globin silencing domain by mutation analysis in chromosomally integrated g promoters. 2) Demonstrate in vivo Stat3 binding to the putative gamma-globin silencing domain and identify components of the Stat3 repressor complex by chromatin immunoprecipitation and mass spectrometry. 3) Develop methods to inhibit Stat3-mediated gamma globin repression as a therapeutic strategy for inducing HbF production by two approaches. The first approach will test the ability of Stat3cz to functionally inhibit Stat3 gamma. Secondly we will test the ability of novel anti-Stat3 binding peptides to de-repress the y gene promoter. 4) Finally we will test the efficacy of combined treatment with activated Stat3 blocking peptides and novel short chain fatty acids to augment g gene expression. This project thus offers a systematic analysis of gamma globin silencing that offers a unique opportunity to develop a novel gene-based therapy to increase HbF expression in Sickle cell disease and Cooley's anemia.

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Project Title: METABOLIC CONSEQUENCES OF SICKLE CELL ANEMIA Principal Investigator & Institution: Buchowski, Maciej S.; Associate Professor; None; Meharry Medical College 1005 D. B. Todd Boulevard Nashville, Tn 37208 Timing: Fiscal Year 2005; Project Start 01-AUG-2001; Project End 31-JUL-2007 Summary: (Applicant?s abstract) Homozygous sickle cell disease (HbSS), known also as sickle cell anemia, results from inheritance of the sickle cell Betas-globin gene from both parents and is characterized usually by marked clinical severity. Many children with HbSS have delayed growth and sexual development. The reason for the delayed growth and associated poor weight gain is not well understood but it might be associated with the increased requirement for energy. The underlying physiological mechanism of this

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increase could be in part explained by the accelerated synthesis of new red blood cells (RBCs) and the altered catabolism of irreversibly sickled RBCs. However, how these metabolic events develop and progress during the accelerated growth occurring in HbSS adolescents is unknown. The central hypothesis of this application is that increased whole-body protein turnover and increased cardiac output, resulting in increased energy expenditure for basal needs and physical activity, divert energy and protein from normal growth pathways in HbSS adolescents. The rationale for the proposed research is that quantifying energy and protein needs ad finding the underlying mechanism(s) for stunting will lead us to establishing nutritional recommendations and designing specific supplementation for HbSS children and adolescents. The specific aims are: 1) to determine how much energy and protein is needed for optimal growth in adolescents with HbSS; 2) to explain how growth rate in HbSS adolescents is altered by increased demands for energy caused by higher whole-body protein turnover, and increased cardiac output; and 3) to quantify how much energy and protein is required for daily physical activity in adolescents with HbSS. In the proposed longitudinal study of HbSS adolescents, energy and protein balance will be measured in a controlled environment and assessed in free living. At regular intervals, all components of energy expenditure and the total 24-h energy balance will be measured continuously inside a whole-room indirect calorimeter while using stable isotopes techniques for assessing protein kinetics. Healthy (HbAA) adolescents matched initially for Tanner stage of sexual development, gender, and race will serve as controls in all experiments. The proposed research is significant, because it is expected to result in new guidelines for nutritional management of adolescents with HbSS that will significantly improve their growth rate and attendant weight gains. In addition, what is learned from this research will contribute to broader understanding of how HbSS affects energy and protein metabolism, how these changes alter growth in HbSS adolescents, and what underlying physiological mechanism(s) are involved. •

Project Title: MOLECULAR CONTROL OF FETAL G-GLOBIN GENE EXPRESSION Principal Investigator & Institution: Peterson, Kenneth R.; Professor and Vice-Chairman; Biochem and Molecular Biology; University of Kansas Medical Center Msn 1039 Kansas City, Ks 66160 Timing: Fiscal Year 2004; Project Start 30-SEP-2001; Project End 31-MAY-2007 Summary: (provided by applicant) Developmental regulation of human beta-like globin gene switching is controlled by several parameters, primarily the trans-acting transcriptional milieu and cis-acting DNA elements. Molecular control of globin gene switching provides a paradigm for understanding the dynamics of mammalian gene expression during ontogeny. Unraveling the mechanisms underlying beta-like globin gene switching, particularly those involved in fetal hemoglobin F (Hb F) induction, will have enormous benefit to patients suffering from a variety of hemoglobinopathies, since the general consensus within the scientific community is that sustained expression of the gamma-globin genes in adults will be palliative to these diseases. Transactivation of fetal gamma-globin gene expression has important therapeutic application for the treatment of sickle cell anemia and Cooley's anemia, as well as certain betathalassemias. The Specific Aims of this research are to (1) validate the fetal specificity of already identified trans-acting proteins that activate fetal globin synthesis using novel erythroid cell lines derived from human beta-globin locus yeast artificial chromosome (beta-YAC) transgenic mice, (2) verify the fetal specificity of the same transactivators during development in an animal model by over-expression of these proteins in betaYAC transgenic mice, (3) develop an assay system to identify new, or test existing, pharmacologic compounds that induct fetal gamma-globin gene expression without

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Sickle Cell Anemia

activating adult beta-globin gene expression using simultaneous measurement of both globin gene products, and (4) clone new transcriptional activators of gamma- globin gene expression from human fetal liver or GM 979 cell cDNA libraries. •

Project Title: MOLECULAR MECHANISM OF HUMAN G-GLOBIN GENE SILENCING Principal Investigator & Institution: Li, Qiliang; Medicine; University of Washington Office of Sponsored Programs Seattle, Wa 98105 Timing: Fiscal Year 2005; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): The goals of this research application are a) to test the hypothesis that the variable human gamma-globin gene silencing in the adult is the consequence of a dynamic equilibrium between euchromatin originating in the LCR and heterochromatin originating in the gamma gene promoter, b) to identify gamma-globin gene specific repressors and corepressors. Our specific aims are i) To test the hypothesis that the gamma gene silencing in the adult is the consequence of a dynamic balance between euchromatin originating in the LCR and heterochromatin originating in the gamma gene promoter. This will be tested in transgenic mice carrying the human betaglobin locus yeast artificial chromosome (betaYAC) and various mutated betaYACs by examining changes of the histone code specific for heterochromatin and euchromatin. This hypothesis can be validated if changes of the histone code are correlated with the phenotypes induced by the various mutations, ii) To test whether the gammaCACCC box causes heterochromatinization in the gamma gene promoter in the adult. This will be done by relocating the gammaCACCC box in the different locations in the betaglobin locus and examining formation of heterochromatin induced by the gammaCACCC box. iii) To develop an oligonucleotide-mediated chromatin immunoprecipitation approach and using this approach to search for gamma gene specific repressors/corepressors. It is expected that these studies will lead to a unifying model explaining variable silencing of human gamma-globin gene in the adult, and will identify gamma gene specific repressors/corepressors. These studies will facilitate designing of a feasible strategy for human gamma-globin gene reactivation. Such a development will have important consequences for the treatment of patients with sickle cell disease or beta thalassemia syndromes.

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Project Title: MOLECULAR MECHANISM OF TRANSDUCING CARDIAC ISCHEMIC PAIN Principal Investigator & Institution: Mc Cleskey, Edwin W.; Senior Scientist; None; Oregon Health & Science University 3181 Sw Sam Jackson Pk Rd Portland, or 972393098 Timing: Fiscal Year 2005; Project Start 01-JUN-2001; Project End 31-MAY-2007 Summary: provided by applicant) Sensory neurons that innervate the heart (cardiac afferents) detect cardiac ischemia, the condition when the heart receives insufficient oxygen. They trigger chest pain-either the acute pain of a heart attack or angina, an intermittent pain caused by coronary artery disease. They also contribute to damaging cardiac reflexes that accompany artery disease. Although it is clear that cardiac afferents transduce cardiac pain, the molecular mechanism(s) is uncertain. The driving hypothesis of this proposal is that cardiac ischemia releases a set of chemical mediators that activate ion channels and receptors on cardiac afferents, thereby triggering pain. The proposal relies heavily on a novel method we developed to fluorescently tag cardiac afferents so they can be distinguished from other kinds of sensory neurons. This is an essential step for identifying molecules that are necessary for cardiac pain but not for other sensations. Our initial work fmds that cardiac afferents have a unique molecular fmgerprint: they

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express an extremely Sensitive acid-sensing ion channel at grossly high levels. The result underscores the importance of protons created during ischemia as a mediator of cardiac pain. Our specific aims will: 1) definitively identify the particular clone of acid-sensing ion channel used by cardiac afferents; 2) fmd whether other putative mediators of cardiac pain act by modulating this channel; 3) explore why there is different expression of channels in the two different populations of cardiac afferents. The experimental methods are single cell electrophysiology and immunocytochemistry. The clinical significance of the project lies in the suppression of angina, which is suffered by some 6 million Americans, is debilitating in some, and which triggers damaging cardiac reflexes in all. The results might also be relevant to other forms of vaso-oclusive pain, notably that of sickle cell anemia. We will identify molecules that trigger cardiac pain, thereby providing new pharmaceutical targets for its treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NON-MYELOABLATIVE THERAPY FOR SICKLE CELL DISEASE Principal Investigator & Institution: Rizzieri, David A.; Duke University 2424 Erwin Rd. Durham, Nc 27705 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAR-2008 Summary: Ablative AIIogeneic transplantation is used to treat diseases, though the potential severe toxicitiesof the procedure have precluded its broad use for adults with severe effects from sickle cell disease. The long-term objectives of this project are to reduce the toxicity and improve the overall survival following non-myeloablative allogeneic transplantation for sickle cell disease. The central hypothesis of this project is that allogeneic stem cells infused after a less toxic, non- myeloablative regimen will induce a stable donor hematopoietic state. Two complementary strategies will be pursued in order to test this hypothesis. First, persons with severe illness from sickle cell disease will be transplanted with HLA matched sibling donor peripheral blood stem cells (PBSC) using a less toxic non-myeloablative regimen. The primary purpose of this clinical trial is to assess the feasibility in terms of toxicity and engraftment of a less toxic, nonablative conditioning regimen of in vivo alemtuzumab (anti-CD52) monoclonal antibody, moderate dose fludarabine, and cyclophosphamide for patients with sickle cell disease. Early stoppping rules for toxicity and failure of donor engraftment are an important part of the IRB approved trial. Clinical outcomes, quality of life, and cost efficiency of the nonmyeloablative transplant will be evaluated. Secondary purposes of this study are to investigate recipient immune reconstitution to ensure a robust recovery of immune function in these patients with sickle cell disease. The second approach will rely on in vitro measurements to define the kinetics of immune reconstitution in transplant recipients. These measurements will consist of general, antigen specific, and alloreactive immune responses to define the dynamics of immune reconstitution following allogeneic transplantation in this patient population. Results of these investigtions will lead to future trials of efficacy of this approach with adults with severe sickle cell disease and ensure recovery of a strong immune system such that we do not simply trade one illness (sickle cell disease) for another (chronic immunosuppression).

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Project Title: NORTHERN CALIFORNIA COMPREHENSIVE SICKLE CELL CENTERS Principal Investigator & Institution: Vichinksy, Elliott P.; Children's Hospital & Res Ctr at Oakland 747 52Nd St Oakland, Ca 946091809 Timing: Fiscal Year 2005; Project Start 01-JUL-2003; Project End 31-MAR-2008

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Summary: The objectives of the Northern California Comprehensive Sickle Cell Center (NCCSCC) are:1) to facilitate hemoglobinopathy research in the areas of basic research, clinical science, psychosocial aspects of the disease; and to initiate multicenter collaborative research projects 2) to provide hemoglobinopathy detection, counseling, education and care to affected populations. To pursue these objectives, we have developed interdependent basic research programs at Childrens' Hospital Oakland Research Institute (CHORI) and University of California at San Francisco (UCSF). These basic programs are complemented by core clinical research programs in the West Bay (UCSF/San Francisco General Hospital) and in the East Bay (Childrens' Hospital Oakland]. These programs provide hemoglobinopathy detection, counseling, education and comprehensive care needed to maintain a stable, well characterized group of over 700 patients with sickle cell disease (SCD) who participate in NCCSCC research projects. Clinical, basic and collaborative network research projects aims are: A) To initiate a phase lla, randomized, trial to determine if LY315920 [anti PLA 2 inhibitor] can be safely used to prevent impending ACS and to characterize the mechanisms by which it prevents damage. B) To determine the extent of neurocognitve and neuromimaging abnormalities in neurologically asymtomatic adult SCD patients. C) To understand the mechanisms that result in phospholipid asymmetry in red cell membranes and to determine their in vivo significance in SCD patients by studying physiological processes. D) To construct sickle cell mice utilizing BAC's to isolate the beta-globin clusters from patients with the four sickle haplotypes: Benin, CAR, Senegal and Saudi Arabia, and to study their pathophysiology and rheology. E) Our network project's aim is to test hypothesis that a non-myeloablative conditioning regimen in young adults with symptomatic SCD a can induce stable donor host hematopoietic chimerism after stem cell transplantation from HLA identical sibling donors. •

Project Title: NOVEL FUNCTIONS OF RED CELL PROTEINS LU AND LW Principal Investigator & Institution: Chasis, Joel A.; Staff Scientist; Division of Life Sciences; University of Calif-Lawrenc Berkeley Lab C/O Sponsored Projects Office Berkeley, Ca 94720 Timing: Fiscal Year 2005; Project Start 01-SEP-2000; Project End 31-JUL-2009 Summary: (provided by applicant): Erythrocyte adhesion proteins Lu and LW (now termed ICAM-4) are well-defined blood groups, but little is known regarding their membrane function. During erythropoiesis, erythroblasts differentiate within erythroblastic islands surrounding a macrophage. We hypothesize that ICAM-4 mediates interactions between erythroblasts via ICAM-4/alpha4beta1 binding and regulates adhesion of erythroblasts to macrophages via ICAM-4/alphaV binding. Peptides corresponding to areas of ICAM-4 that interact with alphaV and beta1 inhibit erythroblastic island formation. Additionally, we identified a secreted isoform of ICAM4, which may modulate binding. We and others have shown that ICAM-4 also binds integrins present on endothelial cells, neutrophils and platelets. Hence, we will explore the contribution of ICAM-4 to vascular pathology of sickle cell disease. Lu binds laminins containing the alpha5 chain (laminins 10/11) with high affinity. Importantly, cultured erythroblasts increasingly bind laminin 10/11 from day 6 onwards and the level of binding paralleled increasing expression of Lu. We hypothesize that Lu-laminin adhesion functions during enucleation and/or marrow egress, since alpha5 laminin localizes to subendothelial basement membranes of bone marrow sinusoids. To test our hypotheses we propose to: 1) Examine ICAM-4 function by identifying regions of ICAM-4 involved in alpha4beta1 binding employing site directed mutagenesis and in vitro binding assays; characterize the effect of blocking reagents on formation and dissociation of erythroblastic islands; assess interactions between cells within islands in

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the presence and absence of blocking reagents using micropipette techniques; measure single adhesion bond strength by dynamic force spectroscopy; and study erythroblastic islands in ICAM-4 knockout mice. 2) Determine function of the Lu-laminin receptor complex by identifying the laminin binding region on Lu; developing blocking antibodies and peptides and testing their effects on nuclear extrusion and reticulocyte generation in vitro laminin 10/11; and by analyzing apoptosis, enucleation, and reticulocytosis in Lu knockout mice. 3) Explore contributions of ICAM-4 to vascular pathology in sickle cell disease by studying effects on vascular blood flow of infusing transgenic/knockout sickle mice with peptides and antibodies directed against ICAM-4 which block adhesion of sickle red cells to endothelial cells. Successful accomplishment of these aims will further our goals of developing a mechanistic understanding of normal erythropoiesis and the pathophysiology of sickle cell disease which could lead to novel therapeutic modalities. •

Project Title: NOVEL GLOBIN GENE MODULATORS Principal Investigator & Institution: Perrine, Susan P.; Associate Professor of Medicine; Cancer Research Center; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 021182394 Timing: Fiscal Year 2005; Project Start 01-JUN-1998; Project End 31-MAY-2008 Summary: (provided by applicant): The beta hemoglobinopathies do not become manifest until fetal globin (Hb F) is suppressed in infancy, and renewed production of fetal (5') globin decreases complications of these diseases. The need for additional therapeutics which stimulate high proportions of Hb F-containing red blood cells (Fcells) has been recently cited as an unmet priority. Short chain fatty acids (SCFAs) induce beta globin experimentally and in some patients. However, most SCFAs also inhibit erythroid cell growth, which limits the pool of cells in which fetal globin can be induced. Further, the need for IV infusions or large doses, due to rapid metabolism, has made the first SCFA therapies difficult for patient use. We have identified unusual SCFA derivatives, which induce fetal globin in transgenic mice and nonhuman primates, and also stimulate, rather than inhibit, hematopoietic cell proliferation. We hypothesize that mitogenic SCFAs which can be given more often, without dose limitations to prevent cell growth arrest, should induce higher levels of F-cells and beta globin than the growth-inhibitory SCFAs. Five SCFAD candidates with favorable oral PK profiles in baboons have been identified. The aims of this proposal are: 1) to determine which lead SCFA maximally induces F-cells and beta globin in nonhuman primates long-term, and whether there is additive activity between the novel SCFADs and hydroxyurea; 2) to identify additional T globin-inducing compounds using a computer-modeled pharmacophore, and to determine if any have greater potency, 3) to perform rational selection for preclinical development of candidates for the therapeutic induction of beta globin, and 4) to determine molecular mechanisms of cellular growth stimulation by the mitogenic SCFADs.

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Project Title: TRANSPORT

NOVEL MECHANISM

OF ERYTHROCYTE

NITRIC OXIDE

Principal Investigator & Institution: Pawloski, John R.; Assistant Professor of Medicine; Medicine; Duke University 2424 Erwin Rd. Durham, Nc 27705 Timing: Fiscal Year 2005; Project Start 08-APR-2002; Project End 31-MAR-2007 Summary: Circulating red blood cells (RBC) constitute the largest pool of biologically available nitric oxide (NO) in the mammalian organism. It has now been shown that NO-related bioactivity is released form human RBCs in an oxygen-dependent manner.

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The mechanism of NO export seems to involve a novel system whereby Snitrosohemoglobin (SNO- Hb) transnitrosylates cysteine thiols in the cytoplasmic domain of the membrane RBC anion-exchanger 1 protein (AE1). The details of this novel RBC function stand to be elucidated. To characterize this system, the following specific aims have been formulated. 1) To identify the chemical nature of released NO species and to specific the target thiols in the cytoplasmic domain of AE1. 2) Determine the effects of S-nitrosylation AE1 function. 3) Characterize the NO exporter in sickle cell RBCs, a prototypical disease model fo hemoglobin dysfunction. 4) Develop a transgenic murine model with site-directed mutagenesis of AE1 cytoplasmic domain thiols transnitrosylated SNOHb. The abiding goals of this project are to gain a greater understanding of mechanisms in the RBC in both normal and disease states. The results of these studies underscore the potential but largely unexplored role of Hb- membrane interactions in the pathogenesis of the thrombotic diathesis, ischemic syndromes, oxidative disorders and hypertensive states that are associated with altered hematocrit, hemoglobinopathies (like sickle cell disease), and RBC membrane defects. •

Project Title: OPIOID ACTIVITY IN ENDOTHELIUM IN SICKLE CELL DISEASE Principal Investigator & Institution: Gupta, Kalpna; Assistant Professor; Medicine; University of Minnesota Twin Cities 450 Mcnamara Alumni Center Minneapolis, Mn 554552070 Timing: Fiscal Year 2005; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by the applicant): Our preliminary data show that opioid drugs, administered to sickle patients promote growth of microvascular endothelial cells. This opioid effect on endothelium is accompanied by MAPK/ERK activation and promotion of in vitro (tube formation) and in vivo (in Matrigel implants in mice) angiogenesis. We hypothesize that administration of opioids to sickle patients may increase their risk for retinopathy by pro-angiogenic signaling of opioids in endothelium. We will test this via 4 Specific Aims. I Aim#1 Characterize opioid induced endothelial proliferation, by testing specific hypotheses that endothelial growth response to opioids is, [a] exaggerated for human dermal microvascular endothelial cells (HDMEC) and retinal EC vs. HUVEC, [b] influenced by pro-inflammatory cytokines and VEOF, [c] accompanied by EC activation, cell adhesion molecule and NOS expression, Ed] caused by both a stimulation of growth and inhibition of apoptosis. Aim#2 Identify mechanism of endothelial growth stimulation by opioids via 4 specific hypotheses, that [a] opioid stimulated growth involves specific opioid receptors in both presence and absence of pro-inflammatory cytokines, [b] pro-inflammatory cytokines and growth factors regulate mu opioid receptor (MOR) expression on human microvascular EC, [c] opioid signaling in endothelium involves MAPK/ERK phosphorylation via Gi coupled receptors and NO, Ed] opioid induced proliferation is I dependent upon above signaling pathway. Aim#3 Determine if pro-inflammatory cytokine induced MOR. expression and opioid-induced endothelial growth actually promotes angiogenesis in vitro (tube formation in Matrigel) and in vivo (in Matrigel implants in mice). Aim #4 Use sickle mice to determine if opioids exert biologically important effects in vivo, by testing specific hypotheses that administration of opioids to sickle mice [a) causes increased endothelial activation and cell adhesion molecule and NOS expression, [b] accelerates and/or exaggerates development of retinopathy, [c] improves rate of healing of skin wounds; (longer-term goal). Mostly HDMEC and some retinal microvascular EC will be used, since it is critical for angiogenesis studies to use microvascular not large vessel EC. If our hypotheses are true, this Project may lead to several implications of opioid signaling, resulting in altered, clinical decision making and perhaps even to development of novel therapeutics.

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Project Title: OUTCOME MODIFYING GENES IN SICKLE CELL DISEASE Principal Investigator & Institution: Telen, Marilyn J.; Chief, Division of Hematology; Medicine; Duke University 2424 Erwin Rd. Durham, Nc 27705 Timing: Fiscal Year 2005; Project Start 30-SEP-2001; Project End 31-JUL-2007 Summary: (provided by applicant): Sickle cell disease (SCD) is caused by homozygosity for a single mutation of the beta hemoglobin gene. Despite the constancy of this genetic abnormality, the clinical course of patients with SCD is remarkably variable. SCD can affect the function and cause the failure of multiple organ systems through the process of vaso-occlusion. However, we as yet do not understand why the clinical course of SCD and the organs affected are so variable among patients. The process of vaso-occlusion itself appears both complex, involving multiple pathophysiological processes, as well as possibly variable from one organ system to another. This study, therefore, is designed to identify genetic factors that predispose SCD patients to develop specific end-organ complications and to experience more or less severe clinical courses. We will0 enroll 1000 patients with Hb SS and Hb S-beta thalassemia being followed at three regional institutions (Duke University Medical Center, University of North Carolina Medical Center, and Emory University Medical Center). Medical information obtained will identify the presence or absence of specific targeted outcomes (overall disease severity as well as specific types of end organ damage). All clinical data will be managed and stored on the PEDIGENE system and will include medical status (history, physical examination, and laboratory results) and information regarding potentially confounding environmental factors. We will also obtain blood for DNA analysis, and plasma samples potentially useful for later correlative studies (e.g. of cytokine levels or coagulation activation) will also be stored. Information on sample quality and quantity will be stored in the PEDIGENE system and linked to the clinical data obtained. Identification and development of SNPs for the candidate target genes will be performed, and the DNA samples will be analyzed for these, with results entered into the PEDIGENE system. State-of-the-art statistical methods will be used to examine the relationship between specific clinical outcomes with the SNPs, to determine which genetic characteristics predispose patients with SCD to a more or less severe overall clinical course as well as to individual organ-specific complications. Identification of such genetic factors will reveal new targets for development of therapy individualized to specific complications of SCD, thus leading eventually to improved outcomes and increased life expectancy for patients with SCD.

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Project Title: OXYHEMOGLOBIN DESATURATION AND VASCULOPATHY IN SCD Principal Investigator & Institution: Ohene-Frempong, Kwaku; Director; Children's Hospital of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318 Timing: Fiscal Year 2005; Project Start 15-AUG-2005; Project End 31-JUL-2009 Summary: (provided by applicant): The overall goal of this proposal is to investigate the significance of oxyhemoglobin desaturation in pulmonary complications and vasculopathy in sickle cell disease (SCD). A multidisciplinary approach will involve collaborations among hematology, radiology, neuroradiology, pulmonary science, and biochemistry and utilize state-of-the-art techniques within each discipline. Studied will be SCD-SS patients between the ages of 2 and 18 years. Nearly 500 patients with SCD-SS receive treatment at the Children's Hospital of Philadelphia. The proposal has 4 specific aims. The first is directed toward answering the question of whether children with SCD have a higher prevalence of oxyhemoglobin desaturation than the normal population. This will be a cross-sectional study with a prospective component. Three clinical

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categories are expected to emerge: persistent desaturation (OHD), intermittent sleeprelated desaturation, and normal oxyhemoglobin desaturation. Specific Aim 2 will investigate mechanisms leading to OHD and intermittent oxyhemoglobin desaturation in SCD. Pulmonary consequences will be addressed, as will the hypothesis that sleeprelated intermittent desaturation results from obstructive sleep apnea due to anatomical and/or functional mechanisms. Anatomical factors may include overgrowth of adenoid and tonsils as a result of functional asplenia known to occur in this population. The third aim concerns determination of anatomical or functional evidence for vascular pathology, including that in the lung and brain, in children with SCD and oxyhemoglobin desaturation. In addition to imaging studies, assays for biomarkers for vasculopathy, including but not limited to markers of oxidative stress, endothelial injury, RBC flexibility and morphology, will be performed. Aim 4 will examine the effects of intervention for persistent and intermittent OHD on health, vascular manifestations and peripheral biomarkers. Interventions will include clinically-indicated adenotonsillectomy, positive pressure oxygen administration, and nocturnal oxygen supplementation. •

Project Title: PLEIOTROPIC AND EPISTATIC EFFECTS IN SICKLE CELL ANEMIA Principal Investigator & Institution: Nagel, Ronald L.; Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2005; Project Start 30-SEP-2001; Project End 31-JUL-2007 Summary: (provided by applicant): Sickle cell anemia (SCA) is the paradigmatic monogenic disease, but the sickle mutation is not sufficient to define the phenotype. Pleiotropic effects influence complications. Secondly, SCA exhibits an intense interindividual variability, which is likely to be the effect of epistatic genes, since heritability of major determinants of severity exhibit high concordance in monozygote twins (89%). The aim of this project is to define the epistatic/pleiotropic genes involved in sickle-cell mediated vaso-occlusion in different organs, building on our years of working on the genetics and pathophysiology of this problem in mice and men. We will engage in the detection of genes involved in sickle cell-mediated vaso-occlusion in animal models, in the detection of genes involved in sickle cell-mediated vaso-occlusion in patients with sickle cell anemia and in the detection of genes involved in vaso-occlusive and vasoproliferative processes in sickle cell retina and choroid and in cerebrovascular complications in sickle cell anemia, which our previous work has defined as a special case. The experimental design is the following: Approach 1: Appropriate tissues in sickle transgenic mice and other animal models -+ RNA -+ expression chips -> select the higher express genes and the lower expressing genes vs control -+ BLAST --> the selected human genes will be analyzed for potential epistatic effects by SNP arrays and by sequencing to define polymorphism in appropriately defined human sickle cell anemia DNA samples. Approach 2: In the complications without animal models, but candidate genes based on human pathophysiological data, SNPs and sequencing analyzes will be performed in sickle cell anemia patients with a particular complication vs sickle cell anemia patients without it. Of course, appropriate matching age groups will be selected to assure that the complication is no longer possible in the control group. Genes defined by these two approaches will be followed in animal models when available (KO or over expression, or generated for further confirmation. Members of this proposal have special expertise in retinal, cerebro-vascular problems and statistical analysis. Our institution has well established expertise in transgenic mice, microcirculatory preparations, hemopoiesis and patient follow-up, as a well as experienced SNP, sequencing and CHIP expression facilities.

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Project Title: POTASSIUM CHLORIDE COTRANSPORTER GENE EXPRESSION Principal Investigator & Institution: Anderson, Kathleen P.; Associate Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2003; Project Start 11-JUL-2003; Project End 31-MAR-2008 Summary: HbS polymerization is the basis for sickle cell pathophysiology, but disease severity and clinical course are influenced by other factors, including cellular dehydration, which markedly accelerates HbS polymer formation. The KCI cotransporter (KCC) normally regulates cation and water content in reticulocytes. However, in sickle red blood cells (SS RBC), high expression of KCC and abnormal response to cell volume may both contribute to SS reticulocyte dehydration. Thus, KCC plays a role in sickle cell pathology, and a potential therapeutic strategy is to reduce KCC activity to improve RBC hydration. One approach to this end would be the genetic manipulation of KCC expression. A comprehensive understanding of the regulated expression of the KCC gene in RBC is the focus of the three specific aims of this project. Recent data indicates that the KCCl isoform and several splicing isotypes are present in erythroid cells. The goal of Specific Aim 1 is to characterize the temporal sequence and level of expression of KCCl and its isotypes during erythroid differentiation, comparing AA and SS cells. Bone marrow samples from AA and SS patients will be analyzed using in situ hybridization teehrdques to assess KCCI mRNA levels in various erythroid precursors. Parallel studies will examine KCCl mRNA levels by RT-PCR and RNase protection assays in differentiating erythroid cells in culture. Protein levels will also be assessed by immunocytochemistry and Western blot analysis. Studies in Specific Aim 2 will determine the critical cis elements regulating transcription of the human gene encoding KCC isoform 1. We have identified at least one functional promoter for this gene, with preliminary evidence suggesting a second promoter as well. These studies will involve transient and stable transfections of erythroid and control cell lines with various reporter gene constructs derived from these promoter regions. Experiments in Specific Aim 3 will characterize the trans-acting factors that bind the genetic elements identified in aim 2. These studies will include electrophoretic mobility shift assays, antibody supershifts to confirm known factors, and protein purification of uncharacterized factors. Together, these experiments will produce a clearer understanding of the mechanisms of KCC gene regulation and its possible abnormalities in sickle cell disease, with the ultimate goal of developing new therapies for altering red cell hydration to augment the treatment of sickle cell disease.

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Project Title: PRIAPISM IN BOYS AND YOUNG MEN: INCIDENCE AND PREVALENCE Principal Investigator & Institution: Redding-Lallinger, Rupa C.; Duke University 2424 Erwin Rd. Durham, Nc 27705 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAR-2008 Summary: The primary goal of this study is to conduct a comprehensive investigation of priapism in boys and young men with sickle cell disease (SCD). As such, it represents the initial step toward defining an effective way to manage priapism, and to reduce the frequency of impotence that is its major complication in adult males with SCD. The aims of this proposal are: 1) to conduct a Iongitudinal cohort study in order to define the incidence of priapism in relationship to the physical and hormonal developmental stages of puberty and early maturity, to explore the relationship between priapism and psychological adjustment; and 2) to conduct a pilot, placebo-controlled intervention trial in which the ability of pseudoephedrine to prevent priapism will be evaluated. The first stage of this proposal involves an observational study that will be open to all boys and

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young men with SCD between the ages of 7 -29 years. They will keep daily records of the occurrence of priapism, and will be admitted every 6 months for an intensive evaluation of physical growth, genital pubertal stage, body composition, bone age, gonadotropins, testosterone, insulin-like growth factor and nocturnal penile tumescence. During these admissions, the participants will also complete several psychological assessments. Data from this phase will be used to identify the association (if any) between priapism and pubertal stage, gonadotropin levels, and testosterone concentration. The data will also determine if there is a relationship between priapism and psychological adjustment. The second stage of this proposal will seek to enroll those individuals who are found to have qualifying episodes of priapism on to a randomized, double-blinded, placebo-controlled clinical trial of pseudoephedrine. The purpose of this pilot study is to determine whether pseudoephedrine is able to prevent episodes of priapism. During this trial, each participant will continue to keep the same daily journal. In addition, each participant will be admitted at the beginning and end of the trial to complete the same physical, hormonal and psychological assessments as were performed in the observational phase. The outcome measures of the prevention trial will be the occurrence of priapism, duration of priapism and the interval between episodes of priapism. In addition, physical growth, secondary sexual development, body composition and psychological adjustment will be compared between the treatment arms. The data collected will establish the feasibility of certain key methods, and will provide estimates of rates, standard deviations, median time-to-event. These results, which are absolutely essential before a large scale treatment trial can be planned, will provide the biological and statistical background for future work in this field. •

Project Title: PROJECT HEALTHCARE

FOR

TEACHING

CULTURAL

COMPETENCE

IN

Principal Investigator & Institution: Degannes, Christopher N.; Assistant Professor; Office of Medical Education; Howard University 2400 6Th St Nw Washington, Dc 20059 Timing: Fiscal Year 2005; Project Start 05-SEP-2005; Project End 31-AUG-2010 Summary: (provided by applicant): Existing health disparities and increasing social diversity, underscore the need for strategies to eliminate these disparities among racial and ethnic groups. While eradication of disparities will require multilevel interventions targeting social, healthcare and economic factors, one important strategy is increasing the skills of healthcare professionals in the areas of health disparities and cultural competency. Building on its existing work in cultural competency and addressing health disparities through the training of physicians from disadvantaged backgrounds, Howard University proposes the "Project to Teach Cultural Competency in Healthcare". We propose to develop a curriculum in health disparities and cultural competency for medical students, residents, and practicing physicians, that will be implemented through the Howard University College of Medicine in conjunction with the Center to Improve Child Health Disparities that was funded by the National Center for Minority Health at Howard University, Department of Pediatrics, in 2002. We propose a multidisciplinary approach to curriculum development involving researchers in cultural competency and health disparities from Psychology, Communications, Social Work, and Medicine, as well as community representatives, curriculum specialists and program evaluators. Data from community focus groups on causes of health disparities will augment the curriculum development process. Diseases with the greatest disparities based on race and ethnicity-asthma, hypertension, obesity and sickle cell - will be emphasized. We will collaborate with the National Medical Association (NMA) to expand outreach to practicing physicians and award Continuing Medical Education credit. Program evaluation will include both process-oriented assessments and outcome

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variables that measure the impact on knowledge, skills, and attitudes of learners. This proposal describes plans to develop and implement the curriculum components, methods of instruction, and evaluation strategies over the five year grant. Included are plans to be a coordinating center. •

Project Title: PSYCHOBIOLOGICAL REACTIVITY IN SICKLE CELL DISEASE Principal Investigator & Institution: Treadwell, Marsha J.; Director; Children's Hospital & Res Ctr at Oakland 747 52Nd St Oakland, Ca 946091809 Timing: Fiscal Year 2005; Project Start 01-AUG-2005; Project End 31-JUL-2010 Summary: (provided by applicant): This application describes a five-year plan of training and development for the candidate who will refocus her clinical psychology career from service and program administration to patient-oriented bio-behavioral research in sickle cell disease. This transition will occur under the primary mentorship of Dr. Tom Boyce, a highly-regarded expert in psychobiological reactivity and health outcomes. Dr. Lori Styles, an accomplished basic and clinical researcher in sickle cell disease, will serve as co-mentor. Both sponsors have mentored a number of scientists who have gone on to independent careers in biomedical research. The training program will integrate resources from the University of California-Berkeley and Children's Hospital and Research Center at Oakland, as well as diverse concepts and methods from the fields of medicine and psychology. The candidate's collaborators will supplement her training by lending their expertise in autonomic reactivity, biomedical science and psychiatry. An advisory committee of clinical scientists with distinguished contributions to psychological and medical research in sickle cell disease will provide guidance to the candidate as she broadens her focus to an academic research career. The research plan will focus on psychobiological reactivity in response to laboratory challenge, a novel individual difference variable that integrates physiological and psychological factors, for a cohort of pediatric patients with sickle cell disease. In our pilot study, a measure of autonomic reactivity was the only variable among those studied that bore a strong association with clinical disease severity for young children with sickle cell disease. The aims of the proposed research are to: (1) evaluate psycho-biological reactivity as a robust predictor of sickle pain, defined as rate of painful episodes and daily pain frequency and intensity, for children ages five to twelve with sickle cell disease; and (2) to evaluate the independent and combined influences of physiological and psychological factors on outcomes for children with sickle cell disease. This study will offer new insight into predictors of outcomes for SCD that can in turn inform the design of more effective interventions. The strengths of the institutions and the candidate combined will maximize the candidate's potential for the successful transition into a career as an independent biobehavioral scientist. (End of Abstract)

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Project Title: QUALITY OF LIFE CHILDREN WITH SICKLE CELL DISEASE Principal Investigator & Institution: Panepinto, Julie A.; Pediatrics; Medical College of Wisconsin 8701 Watertown Plank Rd Milwaukee, Wi 532260509 Timing: Fiscal Year 2005; Project Start 28-SEP-2005; Project End 31-AUG-2010 Summary: (provided by applicant): This investigator is a pediatric hematologist whose long-term objective is to become an independent clinical investigator in health outcomes in sickle cell disease with a primary focus on the study of health-related quality of life (QOL). The overall goal of this project is, not only to understand the impact of common disease complications on the health status and health-related QOL of the child, but also to increase the applicability of health-related QOL instruments in children with sickle cell disease. Under the mentorship of well established investigators in the fields of

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hematology, sickle cell disease, and health-related QOL, the candidate proposes a tailored career development program that addresses the long-term objective above. The proposed didactic coursework will provide training in theory and fundamental skills specific to the candidate's short-term goals to 1) increase content knowledge in the QOL research field, 2) increase pertinent methodological skills related to QOL research and the study of health outcomes in sickle cell disease, 3) effectively communicate research ideas and findings to colleagues, patients, families and lay public, and 4) effectively manage the candidate's research career. This application proposes to validate a commonly used generic measure of health-related QOL and compare it to another widely used generic measure. In addition, the health-related QOL of children with overt stroke will be examined and compared to the health-related QOL of those with silent stroke and no cerebral infarction. The impact of family factors on the health-related QOL of the child will be determined. The assessment of health-related quality of life for these children will provide a critically important tool for the expanded assessment of treatment outcomes and contribute to a refined determination of the utilities of currently used therapies such as hydroxyurea and new, high-risk experimental treatment, such as alternative donor bone marrow transplantation. •

Project Title: RBC ION TRANSPORTERS AS HEMOGLOBINOPATHY RISK MODIFIERS Principal Investigator & Institution: Alper, Seth L.; Professor; Beth Israel Deaconess Medical Center 330 Brookline Avenue, Br 264 Boston, Ma 02215 Timing: Fiscal Year 2006; Project Start 15-JUN-2006; Project End 31-MAY-2010 Description (provided by applicant): Sickle cell disease and thalassemia are characterized by pathological red cell dehydration. The mean corpuscular hemoglobin concentration of sickle erythrocytes critically determines the lag time preceding the rapid phase of deoxygenation-induced polymerization of hemoglobin S. Several erythroid ion transporters and channels are believed on the basis of pharmacological and physiological studies to regulate red cell hemoglobin concentration secondary to regulation of red cell volume. Among these activities already studied as therapeutic targets in sickle cell disease are the KCNN/IK1/SK4 Ca2+-activated K+ channel of intermediate conductance (Gardos channel), several types of KCC K-CI cotransporters, at least two types of erythroid CI- conductance, and at least one type of Ca2+permeable cation conductance. The K-CI cotransporters have also been tested as therapeutic targets for thalassemia. The genes encoding these ion-transporting polypeptides are strong candidate risk modifier genes for the hemoglobinopathies. This application proposes the general hypothesis that genetic modulation of these transporter and channel activities will modulate disease severity in mouse models of hemoglobinopathies. This general hypothesis will be tested by experiments designed to pursue the following Specific Aims: Aim 1. We will test the hypothesis that genetic deficiency of the erythroid IK1/Gardos channel will decrease pathologic red cell dehydration and will ameliorate clinical severity in mouse models of sickle cell disease. Aim 2. We will test the hypothesis that genetic deficiency of erythroid KCC K-CI cotransporters will decrease pathologic red cell dehydration and will ameliorate clinical severity in mouse models of sickle cell disease and of beta-thalassemia intermedia. Aim 3. We will test the hypothesis that combined genetic deficiency of erythroid IK1/Gardos channel and of erythroid KCC K-CI cotransporters will further ameliorate clinical severity in mouse models of sickle cell disease. The proposed experiments will increase understanding of sickle cell disease and thalassemia by providing mouse models for genetic tests of new drug therapies under development for near-term clinical testing.

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Project Title: REGULATION AND FUNCTION OF A HUMAN EMBRYONIC GLOBIN Principal Investigator & Institution: Russell, J Eric.; Assistant Professor; Medicine; University of Pennsylvania Office of Research Services Philadelphia, Pa 19104 Timing: Fiscal Year 2005; Project Start 01-APR-1999; Project End 31-MAR-2008 Summary: (provided by applicant): This proposal extends an ongoing research program that is committed to defining the latent therapeutic value of epsilon-globin gene reactivation in adults with disorders in beta-globin expression. The potential benefit of epsilon-globin in these individuals derives from its incorporation into Hb heterotetramers that display physiologically appropriate O2-binding and antisickling properties. As post-transcriptional mechanisms play essential roles in the regulated expression of other globin genes, it is likely that similar processes affecting the stability and translational efficiency of epsilon-globin mRNA are equally important to its expression. Pilot studies carried out in intact animals and in vitro implicate specific cis sequences and defined trans-acting factors as participants in regulated epsilon-globin mRNA stability, several of which are highly similar to well-described determinants of adult-stage beta-globin mRNA stability. The current proposal extends these pilot studies in three Specific Aims that investigate independent aspects of regulated epsilon-globin mRNA stability. The Aims utilize well-established techniques that draw upon the applicant's experience, as well as several novel methods that have been validated in preliminary studies. Aim I will define specific cis-acting elements that dictate the stability of epsilon-globin mRNA, through novel cell culture analysis of epsilon-globin mRNA variants containing defined site-specific 3'UTR mutations. The physiological importance of these determinants will subsequently be validated in a well-established transgenic mouse model system. Aim II will identify the specific cytoplasmic factors that effect the characteristic stability of epsilon-globin mRNA and may also participate in coregulating the stabilities of beta- and gamma-globin mRNAs. These experiments will be carried out in vitro and in vivo using familiar analytical methods. Aim III will investigate the effect of regulated epsilon-globin mRNA stability on crucial physiological and molecular processes, including its developmental stage-restricted expression and its translational efficiency in definitive erythroid cells. These experiments will capitalize on several unusual but highly informative methods that have been developed for this specific purpose in the applicant's laboratory. The results from all three Aims will integrate to provide a solid understanding of the fundamental molecular processes regulating the stability of epsilon-globin mRNA, the manner in which these processes may affect the stability of other globin mRNAs, and the physiological consequences--both desirable and undesirable--that result from their targeted dysregulation. The proposed research comprises a crucial step in evaluating the promise of developmentally silenced globin genes for individuals with beta-thalassemia and sickle cell anemia.

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Project Title: REGULATION OF THE MURINE BETA-GLOBIN LOCUS Principal Investigator & Institution: Fiering, Steven N.; Associate Professor; Microbiology and Immunology; Dartmouth College Office of Sponsored Projects Hanover, Nh 03755 Timing: Fiscal Year 2005; Project Start 12-SEP-1997; Project End 31-MAY-2007 Summary: (provided by applicant): Transcriptional regulation of the beta-globin locus is a historically important system for the study of tissue and developmentally regulated transcription in mammals. In addition to its importance for fundamental insights into mammalian transcription, understanding how this locus is regulated holds the potential

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for developing novel therapies for sickle cell anemia and beta-thalassemia, two very common human genetic disorders. Regulation of the beta-globin locus is analyzed predominantly in transgenic mice that carry transgenes from the human beta-globin locus. This system has been productive but suffers from problems that are inherent to studying human transgenes in mice, where the randomly generated integration site has powerful effects and the murine transcription factors have not coevolved with the cis regulatory elements of the transgene. Results from human locus transgenes have been complemented and clarified by analysis of the murine beta-like globin locus through mutation of the murine locus using homologous recombination in ES cells. Comparisons of the human transgene studies and the murine locus studies have formed a baseline of definitive studies that underlies general conclusions concerning the regulation of this locus regardless of species. This proposal continues with the mutational analysis of the routine beta-like globin locus and definitively tests the following hypotheses that have been suggested by studies of human beta-globin locus transgenes in transgenic mice: Aim l tests the hypothesis that expression of one gene at the locus quantitatively suppresses expression of another gene at the locus which is expressed at the same developmental stage. This will clarify specific aspects of models of how the locus control region influences gene expression. Aim 2 tests the hypothesis that expression of the embryonic genes suppresses expression of the fetal/adult genes in the embryo. This will prove or disprove the consensus hypothesis concerning the mechanism by which the genes expressed later in development are kept silent early in development. Aim 3 tests the hypothesis that deletion of the core part of a hypersensitive site in the locus control region will have stronger suppressive effects than deletion of the entire site. Unexpected findings using human transgenes have suggested this hypothesis and the experiments proposed in aim 3 will demonstrate the generality of this hypothesis and develop a facile system to dissect the effect if it is also seen in the murine locus. •

Project Title: RESPONSE TO MORPHINE IN CHILDREN WITH SC DISEASE Principal Investigator & Institution: Jacob, Eufemia; Assistant Professor; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2005; Project Start 15-AUG-2005; Project End 31-MAY-2008 Summary: (provided by applicant): Sickle cell disease (SCD) is an inherited disease characterized by chronic hemolytic anemia with acute and chronic complications. The painful episode that results from tissue ischemia due to vaso-occlusion is the most common reason for admission in children with SCD. Painful vaso-occlusive episodes (VOE) account for a significant number of emergency department and hospital admissions. Morphine via patient controlled analgesia is widely used in hospital settings to manage severe pain in SCD. However, the opioid dose required to achieve pain relief varies considerably within each painful episode, from one episode to another, and between individual patients, and some patients do not receive adequate relief. Our hypothesis is that children with sickle cell disease do not achieve plasma concentrations of morphine at therapeutic levels. We propose to examine whether the lack of response to morphine is related to subtherapeutic morphine concentrations or other factors. Pharmacokinetic parameters of morphine will be compared with known population values during acute painful states. One of the blood samples will be used for genotyping genes (UGT2B7, MOR1, COMT) that may affect response to morphine. Response to morphine will be assessed using pain intensity and pain relief scores, pain location and pain quality, and side effects such as sedation/drowsiness, nausea, itching, hypoventilation (oxygen saturation, respiratory rate), or hypotension (blood pressure). Data from this career development award K23 will be used to design optimal pain management strategies and clinical protocols that aim to minimize the short and long

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term consequences resulting from untreated or inadequately managed pain during acute vaso-occlusive episodes in children with sickle cell disease. These advancements in pain management will lead Dr. Jacob to her long term career goal as an independent clinical researcher. •

Project Title: REVERSAL OF EPIGENETIC SILENCING OF THE G-GLOBIN GENE Principal Investigator & Institution: Atweh, George F.; Professor; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 100296574 Timing: Fiscal Year 2005; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): The discovery that fetal hemoglobin can ameliorate the clinical severity of sickle cell disease generated considerable interest in the reactivation of the silenced gamma-globin genes in adult life as a potential therapeutic approach in patients with this disease. Intensive investigation of the molecular bases of the genetic disorders that are characterized by the persistence of fetal hemoglobin production in adult life has not translated into effective therapies. In contrast, the study of epigenetic modifications (e.g. DNA methylation and histone acetylation) in the developmental silencing of the gamma-globin genes spurred the development of a number of therapeutic agents that can induce fetal hemoglobin and ameliorate the severity of sickle cell disease. For the past 8 years, we have been conducting clinical trials of butyrate and hydroxyurea in sickle cell disease. In the course of these studies, we made a number of important and at times unexpected clinical observations that raised new questions about the mechanism(s) of induction of fetal hemoglobin by these agents. The major aim of this application is to study the potential role of the epigenetic state of the beta-globin gene cluster in the variable silencing of the gamma-globin genes and in the reactivation of fetal hemoglobin by butyrate and hydroxyurea. The specific aims are to: 1) Compare the state of histone acetylation and DNA methylation in the gamma-globin gene cluster of patients with variable silencing (i.e. either complete or partial silencing) of the beta-globin genes; 2) Investigate the effects of butyrate and hydroxyurea on histone acetylation and DNA methylation in the beta-globin gene cluster; 3) Investigate the potential roles of histone acetylation and DNA methylation in butyrate resistance and the reversal of this resistance by pre-treatment with hydroxyurea; 4) Investigate the heritability of the induction of gamma-globin gene expression by butyrate and nonbutyrate inhibitors of histone deacetylases; 5) Investigate the effects of butyrate and other inhibitors of histone deacetylase on the translational efficiency of gamma-globin mRNA. We believe these studies will shed important light on the normal mechanisms of silencing of the gamma-globin genes and their reversal by pharmacological therapies.

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Project Title: RHEOLOGIC VASOOCCLUSION

&

VASCULAR

MODULATORS

IN

SICKLE

Principal Investigator & Institution: Kaul, Dhananjay K.; Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2005; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): We hypothesize that in sickle cell anemia, the source of hemodynamic abnormalities is not only abnormal red cell rheology (sickling and adhesion to endothelium), but a derangement of microvascular controls secondary to endothelial dysfunction. This proposal focuses on two potential modulators of microvascular flow and vasoocclusion in sickle cell anemia. First, endothelial dysfunction in response to hypoxia, mechanical injury (red cell sickling and adhesion), and oxidative stress (secondary to transient ischemic episodes) would affect the ability

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of microvasculature to respond to rheological challenge. Second, abnormal adherence of red cells to vascular endothelium would not only result in endothelial injury, but also in a prosickling environment. The objective of this revised proposal is to examine the relationship between abnormal rheology, oxidative stress and vascular tone under in vivo conditions in the sickle context, using transgenic and knockout sickle mouse lines. We will test the following specific hypotheses: 1) Test the hypothesis that sickling and attendant flow abnormalities (e.g., transient vasoocclusive events) will cause oxidative stress, microvascular injury and vascular tone abnormalities. To test this hypothesis, we will investigate the effect of enhanced sickling (hypoxia), examine the effect of arginine supplementation, and evaluate the effect of selected anti-oxidants; 2) Test the hypothesis that genetic and experimental modulations of red cell density and polymer formation will impact endothelium and thereby microvascular function. To test this aspect, we will determine the effects of anti-sickling fetal hemoglobin and experimental modulations of red cell density; 3) Test the hypothesis that red cell adhesion in vivo not only contributes to endothelial injury but plays a crucial role in microvascular obstruction. To test this hypothesis, we will focus on the role of endothelial activation, specific adhesion molecules, hypoxia, NO, anti-oxidants, and use DNA microarray technology to identify genes regulated by adhesion inducing factors. The proposed research involves participation of scientists with expertise in microcirculation, hematology, biochemistry, cell biology and molecular biology. These studies are expected to elucidate new mechanisms with relevance to human sickle cell disease and with potential therapeutic implications. •

Project Title: RIBOZYME-MEDIATED REPAIR OF SICKLE BETA-GLOBIN RNA AND DNA Principal Investigator & Institution: Sullenger, Bruce Alan.; Professor & Vice Chair; Duke University 2424 Erwin Rd. Durham, Nc 27705 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAR-2008 Summary: The overall goal of this proposal is to explore the ability of group I and group II introns to repair mutant beta-globin genes and transcripts and assess the potential utility of these molecules in human cells. These introns have been of great scientific interest because they are able to perform catalysis and because a subclass of these RNA enzymes can act as mobile genetic elements. Moreover, their ability to modify RNA and DNA sequences through forward and reverse-splicing reactions makes these introns of particular interest to translational researchers. Previously, we demonstrated that transsplicing group I ribozymes can convert sickle beta-globin encoding mRNAs into gamma-globin encoding transcripts following transient transfection of the ribozyme into erythrocyte precursors derived from patients with sickle cell disease. In addition, we have demonstrated that such RNA repair can proceed with low to moderate efficiency (up to 50% repair) in 293 cells cotransfected with ribozyme and sickle beta-globin expression cassettes. More recently, we have demonstrated that the Lactococcus lactis group II intron can reverse-splice and site specificallv insert itself into desired DNA target sequences in transfected human cells. These proof of concept studies suggest that such catalytic RNAs may represent molecules that can be employed to modify genetic instructions for therapeutic ends to treat sickle cell disease and other genetic disorders. These studies also underscore the necessity for further evaluation and optimization of these catalytic RNAs if they are to become therapeutically useful. Here we propose to perform more detailed analyses of group I and group II intron activity in human ceils focusing upon repair of mutant beta-globin transcripts and genes. The completion of these studies will establish the needed experimental foundation from which the logical

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development of therapeutic group I and group II ribozymes for the treatment of sickle cell disease and other genetic disorders can proceed. •

Project Title: ROLE OF PLACENTA GROWTH FACTOR IN SICKLE ACS Principal Investigator & Institution: Punam, Malik; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 900276062 Timing: Fiscal Year 2005; Project Start 15-JUN-2005; Project End 31-MAY-2009 Summary: (provided by applicant): Acute chest syndrome (ACS), a devastating complication of sickle cell disease (SCD), is the most common cause of disease-related mortality. Nonetheless, little is known about its pathophysiology, it is diagnosed and treated only after the disease process is well underway. Work from our laboratory suggests a novel insight into the underlying pathophysiology of ACS. We show that an erythroid-cell derived angiogenic growth factor, placental growth factor (PIGF) promotes a strong inflammatory response in SCD: it increases expression of VEGF, IL1beta, IL-8, MCP-1, TNF alpha and tissue factor (TF) from monocytes via binding to VEGFR1/Flt-1. PIGF levels are increased in SCD plasma and correlate with disease severity. PIGF is inducible by hypoxia and erythropoietin (Epo), factors elevated in SCD. PIGF was recently found to strongly predict a) death or nonfatal myocardial infarction in patients presenting with chest pain and b) development and severity of bronchopulmonary dysplasia in newborns. We show that PIGF initiates downstream signaling events resulting in activation of early growth response-1 (Egr-1). Downstream targets of Egr-1 include VEGF, IL-1beta, MCP-1, TNFalpha, TF and 5-lipoxygenase (5LO), all of which increase leukocyte chemotaxis and inflammation; 5LO initiates the cascade that produces leukotrienes (LT). We show that SCD patients have evidence of reactive airway disease at baseline; PIGF increases expression of 5LO and 5LO activator protein from human pulmonary endothelial cells; and that PIGF-/- mice have a reduced inflammatory response to acute lung injury. ACS often follows an acute event, associated with a drop in hemoglobin. The latter would increase hypoxia, Epo and erythropoiesis, all of which increase PIGF production. We hypothesize that elevated PIGF, via its effect on inflammatory cytochemokines and leukotrienes results in increased inflammation and reactive airway disease at baseline in patients with SCD. Further elevations in PIGF levels during acute sickle events amplify the inflammation and reactive airway disease and contribute significantly to the cascade of events that result in ACS. Aim1: Knock out the PIGF gene in transgenic sickle mice and study their disease severity and response to acute lung injury. Aim 2: Determine whether elevated PIGF levels will predict ACS in SCD patients hospitalized for an acute event and that PLGF levels and LT levels will predict the magnitude of airway reactivity and obstructive lung disease in patients with SCD. Together, these aims are a focused approach combining basic science and clinical investigation to elucidate a mechanism that likely contributes to ACS, in order to enable early intervention in patients at high risk for ACS and target therapy at the underlying disease process. VEGFR-antagonists are in clinical trials and leukotriene blockers are FDA approved and in clinical use for asthma and could be candidates for an ACS prevention trial.

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Project Title: SELF-MANAGEMENT OF SICKLE CELL DISEASE Principal Investigator & Institution: Mccauley, Stephen Ryan.; Phys Med and Rehabilitation; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2006; Project Start 15-FEB-2006; Project End 31-JAN-2008 Summary: (provided by applicant): Project Summary: The main goal of this 2-year pilot project (in response to PA 03-159) is to apply the Children's Health Belief Model

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(CHBM) to predict self-management behaviors in children age 6-13 years of age with sickle cell disease (SCO). As these children grow older, they become increasingly more responsible for the management of their disease. This may involve both preventative actions and medications. Models to predict medical self-management and adherence outcome in children have largely focused on specific environmental and psychosocial factors (such as motivation, perceived threat, risk-taking behavior, socioeconomic status, etc.), but have not used a more complete modeling of these factors in combination to specifically address children with chronic medical illness, including SCO Furthermore, no models thus far have included a neurocognitive component, often an important consideration in chronic illnesses that may result in compromise of central nervous system functioning. Although the CHBM has been used to predict medication use in children with common, minor ailments, it has never been applied to a chronic pediatric illness. In addition to applying this health belief model, we propose to include a neurocognitive factor to account for varying degrees of CMS compromise demonstrated in children with SCO. The neurocognitive factor will consist of measures of prospective memory (remembering to perform actions in the future) and sustained attention (vigilance) as these cognitive processes are hypothesized to be important in performing self-management behaviors. The plan is to test the addition of this neurocognitive factor to a subsection of the full CHBM including only the statistically significant major pathways found to be important in medication use (which is a subset of selfmanagement behaviors). We hypothesize that the subsection of the causal model will account for a significant portion of the variance in self-management behaviors. Further, the addition of the neurocognitive factor (primarily focusing on prospective memory) will significantly improve the variance accounted for in self-management. These data will allow for the testing of the full CHBM model in a future study with a larger sample of children with SCO, and provide guidance as to which pathways would be most amenable to intervention directed at improving self-management behaviors, and ultimately improving the quality of life for children with SCO. Relevance: This project will help identify behaviors, mental abilities, and beliefs that contribute to how well a child performs SCO self-manage behaviors to maintain optimal health. The model being tested will help identify areas (behaviors and health beliefs) that could be targeted through intervention programs to help children self-manage their SCO more effectively to maintain optimal health. •

Project Title: SICKLE-CELL DISEASE: NEUROIMAGING AND COGNITIVE DECLINE Principal Investigator & Institution: Rule, Randall R.; Radiology; University of California San Francisco 3333 California St., Ste. 315 San Francisco, Ca 941430962 Timing: Fiscal Year 2005; Project Start 20-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The overall goal of this neuroimaging project is to determine the anatomical basis of reduced cognition in sickle cell disease (SCD). Specifically to test the hypothesis that impaired cognition is closely associated with decreased cortical gray matter and hippocampal volumes, and is less associated with the extent of subcortical ischemia/infarction. This will be accomplished by quantitative magnetic resonance imaging (MRI), long TE proton magnetic resonance spectroscopic imaging (1H MRSI), and neuropsychological testing that will include test of executive function and memory. These tests will include the California Card Sorting Task (CCST), the Self Ordered Pointing Task, tests of written and verbal fluency and the this study will focus on adult SCD patients with Wechsler Memory Scale (WMS). no history of overt clinical stroke. Overt infarcts are known to be associated with cognitive deficits. However, SCD patients with no history of CVAs are known suffer from impairment of

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memory and executive function. This study is designed to test whether cortical and hippocampal degeneration subsequent to subcortical ischemia is a marker of cognitive decline in these patients with no history of stroke. The ischemia that can occur in subcortical ischemic vascular disease (SIVD) is similar to the silent infarcts seen in SCD. In SIVD it has been determined that cognitive decline is associated with decreased cortical gray matter and hippocampal volumes. This project is designed to look for similar relationships in SCD. The primary hypotheses are: 1.) Gray matter volume and gray matter NAA are significantly decreased in SCD versus control subjects. 2.) Comical gray matter and hippocampal volume and NAA will correlate highly with cognition while white matter lesions, lacunars infarcts, and white matter NAA will be less correlated with cognition. Secondary hypotheses are: 1.) Gray matter volume and NAA reductions in SCD compared with controls will be greater in the frontal lobe than in posterior areas. 2) Hippocampal volume will correlate with memory function. And frontal cortical gray matter volume will correlate with executive function. •

Project Title: SIGNALING PATHWAYS ACTIVATING ADHESION IN SICKLE CELLS Principal Investigator & Institution: Parise, Leslie V.; Professor and Vice Chair; Pharmacology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2005; Project Start 01-JUL-2002; Project End 31-MAY-2007 Summary: (provided by applicant): Agonist-induced signaling is a primary mechanism regulating adhesiveness of platelets, leukocytes and other cells. However, RBCs are generally considered to be inert to agonist-stimulated enhancement of adhesion; thus signaling in sickle (SS) RBCs by any agonist to directly activate SS RBC adhesiveness is relatively unexplored. Thrombospondin (TSP) is an adhesive protein that is abnormally elevated in the plasma of sickle cell patients. While TSP has known agonist properties towards other cells, it has been proposed in sickle cell disease to function purely as an adhesive molecule, by bridging adherent SS RBCs to the endothelium and subendothelial matrix. Here we establish that SS RBCs, in contrast to normal (AA) RBCs, respond to agonist stimulation by TSP to become significantly more adhesive. We also identify a site within TSP, which when immobilized can support SS RBC adhesion, or when soluble, can activate SS RBC adhesion. We further establish a previously unappreciated role for integrin-associated protein (TAP or CD47) on SS RBCs as both a basal adhesion receptor for immobilized TSP and a signal-transducing receptor in response to soluble TSP, and detect a potential physical difference in TAP on SS RBC that may contribute to the higher adhesion of SS versus AA RBCs. Evidence is also provided for a unique synergy between TAP-mediated signaling and shear stressinduced signaling, involving activation of large G-proteins and tyrosine kinases, to ultimately activate an a4B1 integrin-dependent increase in SS RBC adhesion. We therefore propose to: 1) identify proximal events in the activation of a4B1-mediated SS RBC adhesion, 2) define the basis for the apparent physical difference in sickle cell TAP and ask whether that difference contributes to the enhanced basal and stimulated sickle cell adhesion, 3) delineate the specific signaling pathway(s) induced by stimulation of lAP that results in increased SS RBC adhesiveness, 4) determine the role and mechanism of TAP-mediated SS RBC activation in SS RBC adhesion to endothelial cells, and 5) test the hypothesis that TAP contributes to SS RBC adhesion and pathology in vivo in studies of human sickle cell flow through a rat cremaster muscle model system. These data therefore provide new fundamental models of sickle cell adhesion and identify multiple potential therapeutic targets for down-regulating sickle cell adhesiveness and potentially preventing vaso-occlusive crises.

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Project Title: SINGLE MOLECULE ANALYSIS OF ERYTHROCYTE ADHESION IN SICKLE CELL DISEASE Principal Investigator & Institution: Golan, David E.; Professor; Boston Medical Center One Boston Medical Center Place Boston, Ma 02118 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAR-2008 Summary: Adhesive interactions involving sickle erythrocytes are critically important in the pathophysiology of vaso-occlusive crisis, hemolytic anemia, and other clinical manifestations of sickle cell disease. These interactions appear to be mediated by the abnormal expression and/or function of adhesion molecules on the surface of sickle erythrocytes. Recent studies in model membranes and intact biological systems have begun to elucidate the biochemical and biophysical properties of adhesion molecules that are necessary for stable adhesion; these properties include adhesion molecule expression, size, lateral mobility, surface density, surface distribution, and affinity for the molecule's cognate ligand. Although a number of molecular interactions involved in sickle lerythrocyte adhesion to vascular endothelial cells and T lymphocytes have been identified, the properties of these molecular interactions that are important for stable adhesion remain to be characterized. We have developed a unique set of biophysical and imaging techniques to study, at the level of individual adhesion molecules, the molecular interactions involved in cell-cell adhesion. The methods include fluorescence photobleaching recovery, polarized fluorescence depletion, single particle tracking, laser optical tweezers, glass-supported planar bilayer membranes, fluorescence resonance energy transfer, and dynamic in vitro and in vivo (intravital) adhesion assays. Here we propose to apply these methods to the study of (1) membrane protein iand lipid dynamics in sickle erythrocytes, (2) adhesive interactions between sickle erythrocytes and activated vascular endotheliai cells, and (3) adhesive interactions between sickle erythrocytes and activated T lymphocytes. We shall use these methods to study adhesive interactions involving the adhesion molecules VLA-4 (alpha4beta1integrin), CD36, and CD2 on sickle erythrocytes, VCAM-1 and alpha-v, beta3 integrin on activated vascular endothelial cells, CD58 on activated T lymphocytes, and the adhesive plasma protein thrombospondin. Results from these studies are expected to lead to a quantitative understanding of important molecular and cellular events in the pathophysiology of sickle cell disease, and, ideally, to point the way to targeted therapies that interrupt the most critical aspects of these molecular and cellular events.

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Project Title: STATISTICS AND DATA MANAGEMENT CENTER-CSCC Principal Investigator & Institution: Lieff, Susan; Rho Federal Systems Division, Inc. 6330 Quadrangle Dr, Ste 500 Chapel Hill, Nc 27517 Timing: Fiscal Year 2005; Project Start 01-JUL-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Rho Federal Systems Division, Inc. (RhoFED), located in Chapel Hill, North Carolina, proposes to continue to serve as the Statistics and Data Management Center (SDMC) for the Comprehensive Sickle Cell Centers (CSCC) program. The SDMC will act as a coordinating center in support of collaborative clinical studies, local basic and clinical research, and activities to promote optimal communication among CSCC participants and the NHLBI Project Office. These studies will focus on the most promising therapeutic modalities for sickle cell disease. The primary goals of the coordinating center are to act as central point of communication for the day-to-day activities of the study group, provide epidemiological and statistical collaboration in the scientific elements, and provide the tools and support to ensure that the data generated by the clinical sites are of highest quality. RhoFED considers the following four aims to be essential in meeting the operational and scientific

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requirements of the project: a) Provide data management, statistical leadership, and clinical operations management support for common clinical protocols for the CSCC program; b) provide statistical support for all research projects within the CSCC program; c) develop, implement, and maintain web-based information technology to facilitate communication across facilities within the CSCC program and secure data entry and data management for the collaborative clinical studies; d) maintain, expand, and improve the existing CSCC program common patient database with particular emphasis on incorporating data on the social and financial burden of living with sickle cell disease and data related to health services utilization, health outcomes, and quality of life. •

Project Title: STROKE WITH TRANSFUSIONS CHANGING TO HYDROXYUREA (SWITCH) TRIAL DATA COORDINATING Principal Investigator & Institution: Helms, Ronald W.; Director of Statistics; Rho Federal Systems Division, Inc. 6330 Quadrangle Dr, Ste 500 Chapel Hill, Nc 27517 Timing: Fiscal Year 2005; Project Start 01-AUG-2005; Project End 31-JUL-2010 Summary: (provided by applicant): Stroke occurs in 10% of children with sickle cell anemia (SCA) and has a very high risk of recurrence without therapy. Affected children receive chronic erythrocyte transfusions to prevent a secondary stroke, which are effective but have limited long-term utility due to transmission of infectious agents, erythrocyte alloantibody and autoantibody formation, and iron overload. Transfusion acquired iron overload has morbidity and mortality, including chronic organ damage with hepatic fibrosis and cirrhosis, poor growth and development, cardiac arrhythmias, and early sudden death. Deferoxamine chelation therapy is difficult to tolerate. Our pilot data indicate that hydroxyurea (HU) is an effective alternative to transfusions for secondary stroke prevention that also addresses the issue of transfusion acquired iron overload, and can prevent acute vaso-occlusive events in SCA, after transfusions are discontinued, serial phlebotomy reduces iron burden. We propose a Phase III randomized clinical trial for children with SCA, named Stroke with Transfusions Changing to Hydroxyurea (SWITCH) to demonstrate that hydroxyurea and phlebotomy can maintain an acceptable stroke recurrence and significantly reduce the hepatic iron burden, both in comparison to transfusion plus chelation. This is one of two companion proposals: a proposal to fund the SWiTCH Medical Coordinating Center concurrently submitted by Russell Ware, Duke Univ., and this proposal to fund the SWiTCH Data Coordinating Center (DCC). The DCC will provide very high quality coordinating center services, including study design and planning, co-authoring study documents (Protocol, manuals of operation, statistical analysis plan, etc.), central interactive patient registration and randomization system, remote data entry facilities, centralized data management, the complete range of statistical design and analysis services, design and generation of progress and DSMB reports, DSMB administrative support, participation in SWiTCH committees, and collaboration in the preparation of SWiTCH publications and presentations.

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Project Title: UNIV OF TX SOUTHWESTERN COMPREHENSIVE MED SICKLE CELL CT Principal Investigator & Institution: Buchanan, George R.; Professor of Pediatrics; Pediatrics; University of Texas Sw Med Ctr/Dallas 5323 Harry Hines Blvd. Dallas, Tx 753909105 Timing: Fiscal Year 2005; Project Start 01-JUL-2003; Project End 31-MAR-2008

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Summary: In recent years, treatments for Sickle Cell Disease (SCD) have significantly decreased the frequency and duration of sickle cell crises and significantly lengthened the life expectancy of patients. These improvements have been due to clinical, genetic and molecular advances that have revealed basic aspects of the pathophysiology of SCD. In spite of these advances, SCD remains associated with significant mortality and morbidity. The large body of data for autologous stem cell bone marrow transplantation has shown it to be effective for a minority of patients with SCD, but early mortality, the availability of suitable donors and factors involved in patient selection remain limiting factors. As an alternative, genetic correction of SCD offers hope as a potential curative approach for the majority of patients. Recent progress in the development of mouse models of hemoglobin disorders and in lentivirus-based vector design have provided strong rationale and impetus for preclinical implementation of gene therapy approaches for SCD. In this proposal, we address three important challenges to the successful genetic correction of SCD. First, we develop lentivirus-based vectors for the transduction of human gamma-globin genes. These vectors include regulatory elements that are critical for high-level single copy gene expression and are evaluated both in transgenic mice and model cell lines. Second, we evaluate their transduction efficiency into bone marrow-derived hematopoietic stem cells from SCD patients. And third, we evaluate these transduced cells in vivo using a human/mouse xenograft model of bone marrow transplantation. The preclinical data obtained from these experiments will serve as the rational basis for the implementation of future clinical gene therapy protocols aimed at the genetic correction of SCD. •

Project Title: VACCINE EFFICACY IN CHILDREN WITH SICKLE CELL DISEASE Principal Investigator & Institution: Adamkiewicz, Thomas V.; Research Assistant Professor; Family Medicine; Morehouse School of Medicine 720 Westview Dr., Sw Atlanta, Ga 30310 Timing: Fiscal Year 2006; Project Start 12-JUL-2000; Project End 31-OCT-2007 Summary: The applicant proposes a comprehensive program for development as a clinical investigator, reflecting his interest and expertise in pediatric infectious diseases and pediatric hematology. Under the mentorship of Dr Jim Eckman, a senior Nationally recognized investigator in the area of Sickle Cell Disease, and co- mentorship of two investigator in pediatric infectious disease at Emory University, the applicant will pursue a focused clinical research project and will receive formal and practical instruction in all aspects of clinical investigation. The rich academic environment, including the Emory University School of Medicine and School of Public Health (SPH), the Centers for Disease Control and Prevention (CDC), one of the country's largest comprehensive pediatric SCD clinics and the Emory Vaccine Center, is a remarkable resource for the applicant's optimal development as a pediatric clinical investigator. The applicant is interested in developing more effective prevention strategies of Streptococcus pneumoniae infections in children with sickle cell disease (SCD), inasmuch as these infections remain a major cause of morbidity and mortality in these children. In a recent prospective multicenter survey, the applicant has shown that over 40 percent of S. pneumoniae isolates in children with SCD are now no longer susceptible to penicillin. This rapid increase in penicillin resistance warrants evaluation of more effective prophylaxis of S. pneumoniae infections, to be used in addition to or possibly instead of penicillin prophylaxis. The hypothesis of the applicant project is that protein conjugated vaccines will offer effective protective immunity to children with SCD against S. pneumoniae infections. To test this hypothesis the applicant will conduct a prospective study of the efficacy of this protein conjugate vaccine in pediatric SCD patients. To facilitate this project, the applicant has organized a collaborative network of

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several major pediatric SCD centers and enlisted the collaboration of senior pediatric clinical investigators who direct those centers. The specific aims of this project are to estimate the conjugate vaccine efficacy in children with SCD by comparing rates of S. pneumoniae infections occurring before and after vaccine introduction in the general population (expected licensure in 2000). In this once in a life time "natural" experiment, the applicant will characterize the specific S. pneumoniae isolates, including serotype distribution and antibiograms. The applicant will also evaluate immunity by laboratory assays (ELISA, functional, and T and B cell memory) following vaccination in children with SCD. This project will be conducted within the framework of a recently formed and CDC funded Emory Consortium (PI: Dr Harry Keyserling). Results from these studies will provide the foundation for future clinical care recommendations to prevent this most lethal complication of childhood SCD. Through the course of this trial, the applicant will enhance and develop clinical research expertise by interactions with colleagues at the CDC and the National Institutes of Health, and with vaccine trial researchers and members of the pharmaceutical industry. To complement his stewardship of a focused clinical research project, he will participate in didactic coursework offered by the Emory University SPH, including biostatistics, epidemiology, clinical trial design, and information systems/database management. Practical instruction in the ethics of informed consent and evaluation of clinical trial design and methods will be obtained through an internship at the Human Investigations Committee of Emory University. A motivated and creative applicant, dedicated mentorship, formal educational opportunities, and an innovative clinical study are factors that indicate the tremendous potential for the applicant's successful career development as a thoughtful, well-trained pediatric clinical investigator. •

Project Title: VASCULAR PATHOBIOLOGY OF SICKLE CELL DISEASE Principal Investigator & Institution: Hebbel, Robert P.; Professor and Vice-Chairman; Medicine; University of Minnesota Twin Cities 450 Mcnamara Alumni Center Minneapolis, Mn 554552070 Timing: Fiscal Year 2005; Project Start 30-SEP-1995; Project End 31-MAR-2007 Summary: This abstract is not available.

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Project Title: VASO-OCCLUSIVE PROCESSES IN SICKLE CELL RETINOPATHY Principal Investigator & Institution: Lutty, Gerard A.; Professor; Ophthalmology; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2005; Project Start 30-SEP-1990; Project End 31-MAR-2007 Summary: (provided by applicant): Sickle cell disease has the highest incidence for a population at risk of any genetically-derived disease. Three in every 1000 African Americans born have sickle cell anemia (SS disease). Vaso-occlusions from sickling of erythrocytes (RBCs) occur in most organs and are the initiating event in sickle cell retinopathy, which occurs in 15-30% of African Americans (depending on genotype) with sickle cell disease. We have identified three possible mechanisms of vaso-occlusion in the sickle cell retina in our prior studies with a rat model for sickle erythrocyte (RBC)mediated vaso-occlusion: 1) tumor necrosis factor alpha (TNFa) stimulated adherence of sickle reticulocytes to vascular endothelium; 2) retention of dense sickled RBCs in hypoxic conditions; and 3) transient retention of sickled RBCs in normal rats as observed with the Rodenstock Scanning Laser Ophthalmoscope (SLO). Retention of sickled RBCs by Mechanism 1 was inhibited by antagonists of VLA-4, an integrin present on some sickled reticulocytes, and by antibodies against fibronectin administered intravenously. One of the proposed studies will determine the effect of TNFa on endothelial cells that

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stimulates reticulocyte adherence using parallel flow chambers, confocal microscopy, and scanning electron microscopy. Nitric oxide will be evaluated as a therapy for dense, irreversibly sickled cells mediated occlusions (Mechanism 2). The Proposal will also evaluate sites of sickled RBC-mediated vaso-occlusions for injury to endothelial cells, changes in the retinal milieu, and production of cytokines in the retina. Finally, all three mechanisms will be investigated in real time using the Rodenstock SLO. Therapies for prevention of vaso-occlusion or disruption of formed vaso-occlusions will be evaluated for their ability to shorten retention time or eliminate retention of sickled RBCs in real time using the SLO. In summary, this proposal will further investigate the mechanisms of vaso-occlusion in sickle cell retinopathy and will suggest strategies to prevent this initiating event in sickle cell retinopathy and necrosis in other organ systems. •

Project Title: DISEASE

VIRGINIA

COMMONWEALTH

UNIVERSITY

SICKLE

CELL

Principal Investigator & Institution: Smith, Wally R.; Internal Medicine; Virginia Commonwealth University Po Box 980568 Richmond, Va 232980568 Timing: Fiscal Year 2006; Project Start 17-APR-2006; Project End 31-MAR-2011 Summary: (provided by applicant): VCU proposes a strong team to as a member of the NIH Sickle Cell Clinical Research Network. All investigators on the team have extensive experience in the management of sickle cell disease. Full-service adult and pediatric sickle cell clinical programs are in place. The Principal Investigator has cared for adults with sickle cell almost exclusively since 1986. A Co-Investigator co-directs the Adult Sickle Cell Program. Three pediatric hematologist/oncologists with 20 years of experience caring for sickle cell patients and experience with pediatric bone marrow transplantation are listed in the project or available to the project. The medical director of Transfusion Medicine is part of the team, as well as an Intensivist and Emergency Department physician with special concentration in shock and sickle cell disease. Investigators bring experience from the Cooperative Study of Sickle Cell Disease, Multicenter Study of Hydroxyurea in Sickle Cell Anemia, Gardos Channel Inhibitor ICA-17043 Phase II, Phase II Followup, Phase III Studies, an Oral Iron Chelation Phase II Study, and VCU shock research related to sickle cell disease. Besides the proposed trials related to Zometa for bone pain and simple vs. exchange transfusion for acute chest syndrome, potential trials that could be mounted include trials of Perfluorocarbons, Blood substitutes (synthetic hemoglobins), Implantable Drug Delivery Devices for Sickle Cell Pain, and bone marrow transplantation. Extensive clinical trial expertise, new drug development expertise, and human subjects expertise are resident in the team. Approximately 1000 patients are available to approach for involvement in a clinical trial. Over 300 VCU sickle cell patients have been enrolled into clinical studies in the past 5 years, and VCU has been the top or second highest enroller in two sickle cell studies. Five FTE, including 2 full-time sickle cell-only nurse practitioners (one adult and one pediatric) giving clinical care, one full-time sickle cell-only clinical coordinator, and two full-time coordinators partly devoted to sickle cell research, are available to identify and recruit patients. Two clinical trials are proposed: Zometa (Zoledronic acid, or ZA) for Bone Pain in Sickle Cell disease, and a Randomized Trial To Compare Length Of Stay For Simple Transfusion And Exchange Transfusion For The Treatment Of Acute Chest Syndrome In Patients With Sickle Cell Disease. (End of Abstract) CLINICAL CENTER

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NTIS (National Technical Information Service) The NTIS (www.ntis.gov), a service of the U.S. Department of Commerce, has published the following information on sponsored studies related to sickle cell anemia: •

"ELSI Bibliography: Ethical, legal and social implications of the Human Genome Project. 1994 Supplement. - Bibliography," published in September 1994. Sponsored by: Department of Energy, Washington, DC. Office of Energy Research. Written by: M. S. Yesley and P. N. Ossorio. Abstract: This report updates and expands the second edition of the ELSI Bibliography, published in 1993. The Bibliography and Supplement provides a comprehensive resource for identifying publications on the major topics related to the ethical, legal and social issues (ELSI) of the Human Genome Project. The Bibliography and Supplement are extracted from a database compiled at Los Alamos National Laboratory with the support of the Office of Energy Research, US Department of Energy. The second edition of the ELSI Bibliography was dated May 1993 but included publications added to the database until fall 1993. This Supplement reflects approximately 1,000 entries added to the database during the past year, bringing the total to approximately 7,000 entries. More than half of the new entries were published in the last year, and the remainder are earlier publications not previously included in the database. Most of the new entries were published in the academic and professional literature. The remainder are press reports from newspapers of record and scientific journals. The topical listing of the second edition has been followed in the Supplement, with a few changes. The topics of Cystic Fibrosis, Huntington's Disease, and Sickle cell anemia have been combined in a single topic, Disorders. Also, all the entries published in the past year are included in a new topic, Publications: September 1993--September 1994, which provides a comprehensive view of recent reporting and commentary on the science and ELSI of genetics.

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"Sickle Cell Disease: Screening, Diagnosis, Management, and Counseling in Newborns and Infants. Clinical Practice Guideline Number 6; Sickle Cell Disease: Comprehensive Screening and Management in Newborns and Infants. Quick Reference Guide for Clinicians Number 6; Sickle Cell Disease in Newborns and Infants. A Guide for Parents," published in April 1993. Abstract: The clinical practice guideline sets forth a comprehensive program for identifying, diagnosing, and treating newborns and infants with sickle cell disease and recommends education and counseling strategies for their parents. Sickle cell disease is a term for a group of genetic disorders characterized by production of hemoglobin S(Hb S), anemia, and acute and chronic tissue damage secondary to the blockage of blood flow produced by abnormally shaped red blood cells. Sickle cell anemia is the most common form of the disease and is estimated to affect more than 50,000 Americans. A clinical practice guideline and quick reference guide provide background information and recommendations for clinicians, and a parent's guide explains sickle cell disease, usual treatments and complications, and the signs and symptoms which indicate that a child with sickle cell disease needs immediate medical attention; the parent's guide also includes a list of resources for further information.

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

A C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism and G20210A mutation in the prothrombin gene of sickle cell anemia patients from Northeast Brazil. Author(s): Couto FD, Boas WV, Lyra I, Zanette A, Dupuit MF, Almeida MN, Reis MG, Goncalves MS. Source: Hemoglobin. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15481892&query_hl=18&itool=pubmed_docsum

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A comparative study of academic achievement of children with sickle cell anemia and their healthy siblings. Author(s): Ogunfowora OB, Olanrewaju DM, Akenzua GI. Source: Journal of the National Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15779507&query_hl=18&itool=pubmed_docsum

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A genetic strategy to treat sickle cell anemia by coregulating globin transgene expression and RNA interference. Author(s): Samakoglu S, Lisowski L, Budak-Alpdogan T, Usachenko Y, Acuto S, Di Marzo R, Maggio A, Zhu P, Tisdale JF, Riviere I, Sadelain M. Source: Nature Biotechnology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16378095&query_hl=18&itool=pubmed_docsum

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A journey from sickle cell anemia to ADAMTS13. Author(s): Tsai HM. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15333022&query_hl=18&itool=pubmed_docsum

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

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A randomized, controlled pilot trial of a school intervention for children with sickle cell anemia. Author(s): Koontz K, Short AD, Kalinyak K, Noll RB. Source: Journal of Pediatric Psychology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14747361&query_hl=18&itool=pubmed_docsum

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Abnormal pulmonary function in adults with sickle cell anemia. Author(s): Klings ES, Wyszynski DF, Nolan VG, Steinberg MH. Source: American Journal of Respiratory and Critical Care Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16556694&query_hl=18&itool=pubmed_docsum

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Acquisition of mutans streptococci and caries prevalence in pediatric sickle cell anemia patients receiving long-term antibiotic therapy. Author(s): Fukuda JT, Sonis AL, Platt OS, Kurth S. Source: Pediatr Dent. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16173221&query_hl=18&itool=pubmed_docsum

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Acute myocardial infarction in sickle cell anemia. Author(s): Assanasen C, Quinton RA, Buchanan GR. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14663284&query_hl=18&itool=pubmed_docsum

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Acute splenic rupture in an adult with homozygous sickle cell anemia treated with chronic transfusions. Author(s): Shoemaker MT, Pitney AC, Harford DJ, Barker JA. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15591912&query_hl=18&itool=pubmed_docsum

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Albuterol-induced myocardial ischemia in sickle cell anemia after hemolysis from ceftriaxone administration. Author(s): Corso M, Ravindranath TM. Source: Pediatric Emergency Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15699818&query_hl=18&itool=pubmed_docsum

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alpha-thalassemia in Bantu population from Congo-Brazzaville: its interaction with sickle cell anemia. Author(s): Mouele R, Pambou O, Feingold J, Galacteros F. Source: Human Heredity. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10799970&query_hl=18&itool=pubmed_docsum

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Angiotensinogen gene associated polymorphisms and risk of stroke in sickle cell anemia: Additional data supporting an association. Author(s): Romana M, Diara JP, Doumbo L, Muralitharan S, Ramasawmy R, Keclard L, Tarer V, Chaar V, Elion J, Krishnamoorthy R, Clayton J. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15224377&query_hl=18&itool=pubmed_docsum

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Anti-beta s-ribozyme reduces beta s mRNA levels in transgenic mice: potential application to the gene therapy of sickle cell anemia. Author(s): Alami R, Gilman JG, Feng YQ, Marmorato A, Rochlin I, Suzuka SM, Fabry ME, Nagel RL, Bouhassira EE. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10389593&query_hl=18&itool=pubmed_docsum

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Anti-s antibody-associated delayed hemolytic transfusion reaction in patients with sickle cell anemia. Author(s): Kalyanaraman M, Heidemann SM, Sarnaik AP, Meert KL, Sarnaik SA. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10029818&query_hl=18&itool=pubmed_docsum

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Association of polymorphisms of IGF1R and genes in the transforming growth factorbeta /bone morphogenetic protein pathway with bacteremia in sickle cell anemia. Author(s): Adewoye AH, Nolan VG, Ma Q, Baldwin C, Wyszynski DF, Farrell JJ, Farrer LA, Steinberg MH. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16886151&query_hl=18&itool=pubmed_docsum

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Association of sickle cell anemia and glycogen storage disease type 1a. Author(s): Al-Dabbagh AA, Sayes FM. Source: Saudi Med J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15711703&query_hl=18&itool=pubmed_docsum

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Association of the G-463A myeloperoxidase polymorphism with infection in sickle cell anemia. Author(s): Costa RN, Conran N, Albuquerque DM, Soares PH, Saad ST, Costa FF. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15996936&query_hl=18&itool=pubmed_docsum

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Association of UGT1A1 polymorphism with prevalence and age at onset of cholelithiasis in sickle cell anemia. Author(s): Chaar V, Keclard L, Diara JP, Leturdu C, Elion J, Krishnamoorthy R, Clayton J, Romana M. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15710570&query_hl=18&itool=pubmed_docsum

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Asthma is associated with acute chest syndrome and pain in children with sickle cell anemia. Author(s): Boyd JH, Macklin EA, Strunk RC, DeBaun MR. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16690969&query_hl=18&itool=pubmed_docsum

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Avascular necrosis of the mandibular condyle causing fibrous ankylosis of the temporomandibular joint in sickle cell anemia. Author(s): Baykul T, Aydin MA, Nasir S. Source: The Journal of Craniofacial Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15547404&query_hl=18&itool=pubmed_docsum

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Babesiosis in a patient with sickle cell anemia. Author(s): Klein P, McMeeking A, Goldenberg A. Source: The American Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9217625&query_hl=18&itool=pubmed_docsum

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Beta S-gene-cluster haplotypes in sickle cell anemia patients from two regions of Brazil. Author(s): Costa FF, Arruda VR, Goncalves MG, Miranda SR, Carvalho MH, Sonati MF, Saad SO, Gesteira F, Fernandes D, Nascimento ML, et al. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8250018&query_hl=18&itool=pubmed_docsum

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Beta-S gene cluster haplotypes modulate hematologic and hemorheologic expression in sickle cell anemia. Use in predicting clinical severity. Author(s): Powars DR, Meiselman HJ, Fisher TC, Hiti A, Johnson C. Source: Am J Pediatr Hematol Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7508688&query_hl=18&itool=pubmed_docsum

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BetaS-haplotypes in sickle cell anemia patients from Salvador, Bahia, Northeastern Brazil. Author(s): Goncalves MS, Bomfim GC, Maciel E, Cerqueira I, Lyra I, Zanette A, Bomfim G, Adorno EV, Albuquerque AL, Pontes A, Dupuit MF, Fernandes GB, dos Reis MG. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14502357&query_hl=18&itool=pubmed_docsum

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Biliary scintigraphy in children with sickle cell anemia and acute abdominal pain. Author(s): D'Alonzo WA Jr, Heyman S. Source: Pediatric Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=4058965&query_hl=18&itool=pubmed_docsum

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Biologically active CD40 ligand is elevated in sickle cell anemia: potential role for platelet-mediated inflammation. Author(s): Lee SP, Ataga KI, Orringer EP, Phillips DR, Parise LV. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16601237&query_hl=18&itool=pubmed_docsum

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Blood transfusions and immunophenotypic alterations of lymphocyte subsets in sickle cell anemia. The Transfusion Safety Study Group. Author(s): Wong WY, Powars DR, Operskalski EA, Hassett J, Parker JW, Sarnaik S, Pegelow CH, Hilgartner MW, Johnson CS, Zhou Y, et al. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7718880&query_hl=18&itool=pubmed_docsum

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Bone marrow transplantation corrects the splenic reticuloendothelial dysfunction in sickle cell anemia. Author(s): Ferster A, Bujan W, Corazza F, Devalck C, Fondu P, Toppet M, Verhas M, Sariban E. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8427992&query_hl=18&itool=pubmed_docsum

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Bone marrow transplantation for sickle cell anemia. Author(s): Abboud MR, Jackson SM, Barredo J, Beatty J, Laver J. Source: Am J Pediatr Hematol Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8311178&query_hl=18&itool=pubmed_docsum

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Bone marrow transplantation for sickle cell anemia. Author(s): Vermylen C, Cornu G, Ferster A, Sariban E. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8301449&query_hl=18&itool=pubmed_docsum

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Bone marrow transplantation for sickle cell anemia: is it the right choice? Author(s): Gupta P. Source: Indian Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9332129&query_hl=18&itool=pubmed_docsum

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Bone marrow transplantation for sickle cell anemia: progress and prospects. Author(s): Iannone R, Ohene-Frempong K, Fuchs EJ, Casella JF, Chen AR. Source: Pediatric Blood & Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15390273&query_hl=18&itool=pubmed_docsum

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Bone marrow transplantation in a young child with sickle cell anemia. Author(s): Kalinyak KA, Morris C, Ball WS, Ris MD, Harris R, Rucknagel D. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7717375&query_hl=18&itool=pubmed_docsum

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Bone marrow transplantation in sickle cell anemia. Author(s): Hoppe CC, Walters MC. Source: Current Opinion in Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11224704&query_hl=18&itool=pubmed_docsum

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Bone marrow transplantation in the treatment of sickle cell anemia. Author(s): Johnson FL. Source: Am J Pediatr Hematol Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3934995&query_hl=18&itool=pubmed_docsum

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Bone mineral density in children with sickle cell anemia. Author(s): Lal A, Fung EB, Pakbaz Z, Hackney-Stephens E, Vichinsky EP. Source: Pediatric Blood & Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16317761&query_hl=18&itool=pubmed_docsum

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Bone mineral density of the lumbar spine and proximal femur is decreased in children with sickle cell anemia. Author(s): Brinker MR, Thomas KA, Meyers SJ, Texada T, Humbert JR, Cook SD, Gitter R. Source: Am J Orthop. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9452835&query_hl=18&itool=pubmed_docsum

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Bordetella holmesii isolated from a patient with sickle cell anemia: analysis and comparison with other Bordetella holmesii isolates. Author(s): Njamkepo E, Delisle F, Hagege I, Gerbaud G, Guiso N. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11168088&query_hl=18&itool=pubmed_docsum

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Bronchial stricture and hemoptysis in a woman with sickle cell anemia. Author(s): Robinson KJ, Cury JD, Laos LF. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14769762&query_hl=18&itool=pubmed_docsum

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Can exchange transfusions treat postoperative intrahepatic colestasis in patients with sickle cell anemia? Author(s): Delis SG, Touloumis Z, Bourli A, Madariaga J, Dervenis C. Source: Transplantation Proceedings. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16797311&query_hl=18&itool=pubmed_docsum

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Can peak systolic velocities be used for prediction of stroke in sickle cell anemia? Author(s): Jones A, Granger S, Brambilla D, Gallagher D, Vichinsky E, Woods G, Berman B, Roach S, Nichols F, Adams RJ. Source: Pediatric Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15517239&query_hl=18&itool=pubmed_docsum

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Can we just say NO to sickle cell anemia? Author(s): Nagel RL. Source: The Journal of Clinical Investigation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10510323&query_hl=18&itool=pubmed_docsum

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Cerebral vasculopathy in sickle cell anemia: diagnostic contribution of positron emission tomography. Author(s): Powars DR, Conti PS, Wong WY, Groncy P, Hyman C, Smith E, Ewing N, Keenan RN, Zee CS, Harold Y, Hiti AL, Teng EL, Chan LS. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9864148&query_hl=18&itool=pubmed_docsum

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Chronic myelogenous leukemia in sickle cell anemia. Author(s): Chen L, Zhuang M, Shah HQ, Lin JH. Source: Archives of Pathology & Laboratory Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15737048&query_hl=18&itool=pubmed_docsum

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Circulating cytokines response and the level of erythropoiesis in sickle cell anemia. Author(s): Croizat H, Nagel RL. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9929101&query_hl=18&itool=pubmed_docsum

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Clinical and laboratory effects of hydroxyurea in children and adolescents with sickle cell anemia: a Portuguese hospital study. Author(s): Braga LB, Ferreira AC, Guimaraes M, Nazario C, Pacheco P, Miranda A, Picanco I, Seixas T, Rosado L, Amaral JM. Source: Hemoglobin. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16114180&query_hl=18&itool=pubmed_docsum

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Clinical presentation of severe anemia in pediatric patients with sickle cell anemia seen in Enugu, Nigeria. Author(s): Juwah AI, Nlemadim A, Kaine W. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12605390&query_hl=18&itool=pubmed_docsum

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Clinical response of patients with sickle cell anemia to cromolyn sodium nasal spray. Author(s): Karimi M, Zekavat OR, Sharifzadeh S, Mosavizadeh K. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16941613&query_hl=18&itool=pubmed_docsum

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Clinical, hematological, and molecular characterization of sickle cell anemia pediatric patients from two different cities in Brazil. Author(s): Lyra IM, Goncalves MS, Braga JA, Gesteira Mde F, Carvalho MH, Saad ST, Figueiredo MS, Costa FF. Source: Cadernos De Saude Publica / Ministerio Da Saude, Fundacao Oswaldo Cruz, Escola Nacional De Saude Publica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16021267&query_hl=18&itool=pubmed_docsum

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Collection of blood stem cells from patients with sickle cell anemia. Author(s): Richard RE, Siritanaratkul N, Jonlin E, Skarpidi E, Heimfeld S, Blau CA. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16125985&query_hl=18&itool=pubmed_docsum

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Comparison of energy prediction equations with measured resting energy expenditure in children with sickle cell anemia. Author(s): Williams R, Olivi S, Mackert P, Fletcher L, Tian GL, Wang W. Source: Journal of the American Dietetic Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12146559&query_hl=18&itool=pubmed_docsum

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Comparison of transcranial Doppler sonography with and without imaging in the evaluation of children with sickle cell anemia. Author(s): McCarville MB, Li C, Xiong X, Wang W. Source: Ajr. American Journal of Roentgenology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15385317&query_hl=18&itool=pubmed_docsum

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Complications of sickle cell anemia in adults: guidelines for effective management. Author(s): Ballas SK. Source: Cleve Clin J Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9926631&query_hl=18&itool=pubmed_docsum

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Concentrations of B vitamins and homocysteine in children with sickle cell anemia. Author(s): Segal JB, Miller ER 3rd, Brereton NH, Resar LM. Source: Southern Medical Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14982264&query_hl=18&itool=pubmed_docsum

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Concern about use of narcotics for pain in sickle cell anemia. Author(s): Johnson NA. Source: American Family Physician. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7810478&query_hl=18&itool=pubmed_docsum

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Coping with sickle cell anemia: additional recommendations for school nurses. Author(s): Javid VR. Source: J Sch Nurs. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10745802&query_hl=18&itool=pubmed_docsum

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Correlation of serum cholylglycine level with hepatic dysfunction in children with sickle cell anemia. Author(s): Sayad AE, Farah RA, Rogers ZR, Heubi JE, Buchanan GR, Squires RH Jr. Source: Clinical Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10349527&query_hl=18&itool=pubmed_docsum

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Daytime pulse oximeter measurements do not predict incidence of pain and acute chest syndrome episodes in sickle cell anemia. Author(s): Uong EC, Boyd JH, DeBaun MR. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17095349&query_hl=18&itool=pubmed_docsum

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Decreased urinary excretion of beta-glucuronidase in sickle cell anemia in Nigeria. Author(s): Yazzie D, Adoga GI, Okolo A, Szlachetka R, Fry D, Glew RH. Source: Renal Failure. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7770645&query_hl=18&itool=pubmed_docsum

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Deficiencies in school readiness skills of children with sickle cell anemia: a preliminary report. Author(s): Chua-Lim C, Moore RB, McCleary G, Shah A, Mankad VN. Source: Southern Medical Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7682015&query_hl=18&itool=pubmed_docsum

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Defining stroke risks in sickle cell anemia. Author(s): Meschia JF, Pankratz VS. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15800645&query_hl=18&itool=pubmed_docsum

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Delayed hemolytic transfusion reaction presenting as a painful crisis in a patient with sickle cell anemia. Author(s): Fabron A Jr, Moreira G Jr, Bordin JO. Source: Sao Paulo Medical Journal = Revista Paulista De Medicina. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10413970&query_hl=18&itool=pubmed_docsum

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Delayed methotrexate clearance in a patient with sickle cell anemia and osteosarcoma. Author(s): Mantadakis E, Rogers ZR, Smith AK, Quigley R, Ratliff AF, Kamen BA. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10206466&query_hl=18&itool=pubmed_docsum

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Detection of nitrosyl hemoglobin in venous blood in the treatment of sickle cell anemia with hydroxyurea. Author(s): Glover RE, Ivy ED, Orringer EP, Maeda H, Mason RP. Source: Molecular Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10347241&query_hl=18&itool=pubmed_docsum

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Determinants of red cell survival and erythropoietic activity in patients with sickle cell anemia in the steady state. Author(s): Ballas SK, Marcolina MJ. Source: Hemoglobin. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11186257&query_hl=18&itool=pubmed_docsum

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Determination of beta-globin gene cluster haplotypes and prevalence of alphathalassemia in sickle cell anemia patients in Venezuela. Author(s): Arends A, Alvarez M, Velazquez D, Bravo M, Salazar R, Guevara JM, Castillo O. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10814985&query_hl=18&itool=pubmed_docsum

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Developing a community for patients with sickle cell anemia at Harbor-UCLA. Author(s): Tucker C, Spencer J, Dowling PT, Allman L. Source: Emphasis Nurs. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7705269&query_hl=18&itool=pubmed_docsum

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Diastolic dysfunction and pulmonary hypertension in sickle cell anemia: is there a role for L-carnitine treatment? Author(s): El-Beshlawy A, Abd El Raouf E, Mostafa F, Talaat M, Isma'eel H, Aoun E, Hoffbrand AV, Taher A. Source: Acta Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16424656&query_hl=18&itool=pubmed_docsum

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Different glomerular pathologies in sickle cell anemia. Author(s): Balal M, Paydas S, Seyrek N, Karayaylali I. Source: Clinical Nephrology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15571189&query_hl=18&itool=pubmed_docsum

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Differential diagnosis and management of an infant presenting in shock with a history of sickle cell anemia and a recent fall. Author(s): Wilhelm GW, Mehaffey M. Source: Tex Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11004904&query_hl=18&itool=pubmed_docsum

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Digital analysis of trabecular pattern in jaws of patients with sickle cell anemia. Author(s): White SC, Cohen JM, Mourshed FA. Source: Dento Maxillo Facial Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10808227&query_hl=18&itool=pubmed_docsum

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Disseminated nontuberculous mycobacterial infections in sickle cell anemia patients. Author(s): Thorell EA, Sharma M, Jackson MA, Selvarangan R, Woods GM. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17023829&query_hl=18&itool=pubmed_docsum

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Distinct HLA associations by stroke subtype in children with sickle cell anemia. Author(s): Hoppe C, Klitz W, Noble J, Vigil L, Vichinsky E, Styles L. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12517810&query_hl=18&itool=pubmed_docsum

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Do automated red cell exchanges relieve priapism in patients with sickle cell anemia? Author(s): McCarthy LJ, Vattuone J, Weidner J, Skipworth E, Fernandez C, Jackson L, Rothenberger S, Waxman D, Miraglia C, Porcu P, Danielson CF. Source: Therapeutic Apheresis : Official Journal of the International Society for Apheresis and the Japanese Society for Apheresis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10910030&query_hl=18&itool=pubmed_docsum

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Doppler echocardiographic study in adolescents and young adults with sickle cell anemia. Author(s): Martins W, Mesquita ET, Cunha DM, Pinheiro LA, Romeo Filho LJ, Pareto Junior RC. Source: Arquivos Brasileiros De Cardiologia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10904267&query_hl=18&itool=pubmed_docsum

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Duration of penicillin prophylaxis in sickle cell anemia: issues and controversies. Author(s): Pai VB, Nahata MC. Source: Pharmacotherapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10641985&query_hl=18&itool=pubmed_docsum

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Effect of a comprehensive clinical care program on disease course in severely ill children with sickle cell anemia in a sub-Saharan African setting. Author(s): Rahimy MC, Gangbo A, Ahouignan G, Adjou R, Deguenon C, Goussanou S, Alihonou E. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12702514&query_hl=18&itool=pubmed_docsum

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Effect of age on testicular function in adult males with sickle cell anemia. Author(s): Modebe O, Ezeh UO. Source: Fertility and Sterility. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7890081&query_hl=18&itool=pubmed_docsum

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Effect of hydroxyurea in sickle cell anemia: a clinical trial in children and teenagers with severe sickle cell anemia and sickle cell beta-thalassemia. Author(s): Koren A, Segal-Kupershmit D, Zalman L, Levin C, Abu Hana M, Palmor H, Luder A, Attias D. Source: Pediatric Hematology and Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10326220&query_hl=18&itool=pubmed_docsum

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Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. Author(s): Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, Orringer E, Bellevue R, Olivieri N, Eckman J, Varma M, Ramirez G, Adler B, Smith W, Carlos T, Ataga K, DeCastro L, Bigelow C, Saunthararajah Y, Telfer M, Vichinsky E, Claster S, Shurin S, Bridges K, Waclawiw M, Bonds D, Terrin M. Source: Jama : the Journal of the American Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12672732&query_hl=18&itool=pubmed_docsum

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Effect of hydroxyurea on the deformability of the red blood cell membrane in patients with sickle cell anemia. Author(s): Athanassiou G, Moutzouri A, Kourakli A, Zoumbos N. Source: Clinical Hemorheology and Microcirculation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16899945&query_hl=18&itool=pubmed_docsum

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Effect of long-term transfusion on growth in children with sickle cell anemia: results of the STOP trial. Author(s): Wang WC, Morales KH, Scher CD, Styles L, Olivieri N, Adams R, Brambilla D; STOP Investigators. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16126058&query_hl=18&itool=pubmed_docsum

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Effects of hydroxyurea in a population of Brazilian patients with sickle cell anemia. Author(s): Vicari P, Barretto de Mello A, Figueiredo MS. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15726590&query_hl=18&itool=pubmed_docsum

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Effects of hydroxyurea on the membrane of erythrocytes and platelets in sickle cell anemia. Author(s): Covas DT, de Lucena Angulo I, Vianna Bonini Palma P, Zago MA. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15020264&query_hl=18&itool=pubmed_docsum

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Effects of red blood cell transfusion on resting energy expenditure in adolescents with sickle cell anemia. Author(s): Harmatz P, Heyman MB, Cunningham J, Lee PD, Styles L, Quirolo K, KoppHoolihan L, Ghiron J, Hintz RL, Vichinsky E. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10435647&query_hl=18&itool=pubmed_docsum

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Elevated resting energy expenditure in adolescents with sickle cell anemia. Author(s): Kopp-Hoolihan LE, van Loan MD, Mentzer WC, Heyman MB. Source: Journal of the American Dietetic Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9972187&query_hl=18&itool=pubmed_docsum

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Endothelial function in patients with sickle cell anemia during and after sickle cell crises. Author(s): Blum A, Yeganeh S, Peleg A, Vigder F, Kryuger K, Khatib A, Khazim K, Dauerman H. Source: Journal of Thrombosis and Thrombolysis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16052296&query_hl=18&itool=pubmed_docsum

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Engraftment of immune-deficient mice with primitive hematopoietic cells from betathalassemia and sickle cell anemia patients: implications for evaluating human gene therapy protocols. Author(s): Larochelle A, Vormoor J, Lapidot T, Sher G, Furukawa T, Li Q, Shultz LD, Olivieri NF, Stamatoyannopoulos G, Dick JE. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7757063&query_hl=18&itool=pubmed_docsum

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Enhanced erythrocyte apoptosis in sickle cell anemia, thalassemia and glucose-6phosphate dehydrogenase deficiency. Author(s): Lang KS, Roll B, Myssina S, Schittenhelm M, Scheel-Walter HG, Kanz L, Fritz J, Lang F, Huber SM, Wieder T. Source: Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12438773&query_hl=18&itool=pubmed_docsum

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Equation to estimate resting energy expenditure in adolescents with sickle cell anemia. Author(s): Buchowski MS, Chen KY, Byrne D, Wang WC. Source: The American Journal of Clinical Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12450901&query_hl=18&itool=pubmed_docsum

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Erythropoiesis and myocardial energy requirements contribute to the hypermetabolism of childhood sickle cell anemia. Author(s): Hibbert JM, Creary MS, Gee BE, Buchanan ID, Quarshie A, Hsu LL. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17130748&query_hl=18&itool=pubmed_docsum

82

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ET-1 and ecNOS gene polymorphisms andsusceptibility to acute chest syndrome and painful vaso-occlusive crises in children with sickle cell anemia. Author(s): Chaar V, Tarer V, Etienne-Julan M, Diara JP, Elion J, Romana M. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16956834&query_hl=18&itool=pubmed_docsum

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Etiology of strokes in children with sickle cell anemia. Author(s): Debaun MR, Derdeyn CP, McKinstry RC 3rd. Source: Mental Retardation and Developmental Disabilities Research Reviews. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17061288&query_hl=18&itool=pubmed_docsum

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Evaluation of left ventricular systolic function in pediatric sickle cell anemia patients using the end-systolic wall stress-velocity of circumferential fiber shortening relationship. Author(s): Lamers L, Ensing G, Pignatelli R, Goldberg C, Bezold L, Ayres N, Gajarski R. Source: Journal of the American College of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16750697&query_hl=18&itool=pubmed_docsum

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Evidence for the molecular heterogeneity of sickle cell anemia chromosomes bearing the betaS/Benin haplotype. Author(s): Patrinos GP, Samperi P, Lo Nigro L, Kollia P, Schiliro G, Papadakis MN. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16138336&query_hl=18&itool=pubmed_docsum

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Exchange blood transfusion compared with simple transfusion for first overt stroke is associated with a lower risk of subsequent stroke: a retrospective cohort study of 137 children with sickle cell anemia. Author(s): Hulbert ML, Scothorn DJ, Panepinto JA, Scott JP, Buchanan GR, Sarnaik S, Fallon R, Chu JY, Wang W, Casella JF, Resar L, Berman B, Adamkiewicz T, Hsu LL, Smith-Whitley K, Mahoney D, Woods G, Watanabe M, DeBaun MR. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17095350&query_hl=18&itool=pubmed_docsum

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F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: a double-blind study. Author(s): Nagel RL, Vichinsky E, Shah M, Johnson R, Spadacino E, Fabry ME, Mangahas L, Abel R, Stamatoyannopoulos G. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8417806&query_hl=18&itool=pubmed_docsum

Studies

83

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Fatal delayed transfusion reaction in a sickle cell anemia patient with Serratia marcescens sepsis. Author(s): Seeyave D, Desai N, Miller S, Rao SP, Piecuch S. Source: Journal of the National Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17052065&query_hl=18&itool=pubmed_docsum

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Fatal hemolysis induced by ceftriaxone in a child with sickle cell anemia. Author(s): Bernini JC, Mustafa MM, Sutor LJ, Buchanan GR. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7752012&query_hl=18&itool=pubmed_docsum

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Femoral head avascular necrosis in sickle cell anemia: MR characteristics. Author(s): Rao VM, Mitchell DG, Steiner RM, Rifkin MD, Burk DL Jr, Levy D, Ballas SK. Source: Magnetic Resonance Imaging. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3210909&query_hl=18&itool=pubmed_docsum

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Fetal hemoglobin concentration predicts disease severity in children with sickle cell anemia. Author(s): Rucknagel DL, Sarniak SA, Whitten CF, Odenheimer DA. Source: Prog Clin Biol Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2448815&query_hl=18&itool=pubmed_docsum

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Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea. Author(s): Steinberg MH, Lu ZH, Barton FB, Terrin ML, Charache S, Dover GJ. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9028341&query_hl=18&itool=pubmed_docsum

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Fetal hemoglobin in sickle cell anemia: examination of phylogenetically conserved sequences within the locus control region but outside the cores of hypersensitive sites 2 and 3. Author(s): Figueiredo MS, Steinberg MH. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9236157&query_hl=18&itool=pubmed_docsum

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Fetal hemoglobin in sickle cell anemia: relation to regulatory sequences cis to the beta-globin gene. Multicenter Study of Hydroxyurea. Author(s): Lu ZH, Steinberg MH. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8608254&query_hl=18&itool=pubmed_docsum

84

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Fetal hemoglobin in sickle cell anemia: relationship to erythrocyte adhesion markers and adhesion. Author(s): Setty BN, Kulkarni S, Dampier CD, Stuart MJ. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11313243&query_hl=18&itool=pubmed_docsum

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Fetal hemoglobin synthesis in sickle cell anemia: some molecular considerations. Author(s): Bhaumik K. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7513493&query_hl=18&itool=pubmed_docsum

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First report of reversal of organ dysfunction in sickle cell anemia by the use of hydroxyurea: splenic regeneration. Author(s): Claster S, Vichinsky E. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8822912&query_hl=18&itool=pubmed_docsum

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First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia. Author(s): Xu K, Shi ZM, Veeck LL, Hughes MR, Rosenwaks Z. Source: Jama : the Journal of the American Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10328069&query_hl=18&itool=pubmed_docsum

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Five-year retrospective study of hospitalization and treatment of patients with sickle cell anemia. Author(s): Tetrault SM, Scott RB. Source: Southern Medical Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=982108&query_hl=18&itool=pubmed_docsum

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Fluidotherapy and exercise in the management of sickle cell anemia. A clinical report. Author(s): Alcorn R, Bowser B, Henley EJ, Holloway V. Source: Physical Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6483980&query_hl=18&itool=pubmed_docsum

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Foetal haemoglobin in sickle cell anemia. Author(s): Jain RC. Source: Transactions of the Royal Society of Tropical Medicine and Hygiene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2440156&query_hl=18&itool=pubmed_docsum

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Fourier analysis reveals increased trabecular spacing in sickle cell anemia. Author(s): Faber TD, Yoon DC, White SC. Source: Journal of Dental Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11876278&query_hl=18&itool=pubmed_docsum

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From a dry bone to a genetic portrait: a case study of sickle cell anemia. Author(s): Faerman M, Nebel A, Filon D, Thomas MG, Bradman N, Ragsdale BD, Schultz M, Oppenheim A. Source: American Journal of Physical Anthropology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10640943&query_hl=18&itool=pubmed_docsum

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Frontal and orbital bone infarctions causing periorbital swelling in patients with sickle cell anemia. Author(s): Garty I, Koren A, Garzozi H. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6237632&query_hl=18&itool=pubmed_docsum

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Fulminant stroke in an adult patient with sickle cell anemia. Author(s): Vicari P, Sampaio Silva G, de Cassia Rosario Cavalheiro R, Massaro AR, Figueiredo MS. Source: Acta Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16809893&query_hl=18&itool=pubmed_docsum

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Gadolinium-DOTA enhanced MRI of painful osseous crises in children with sickle cell anemia. Author(s): Bonnerot V, Sebag G, de Montalembert M, Wioland M, Glorion C, Girot R, Lallemand D. Source: Pediatric Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8078730&query_hl=18&itool=pubmed_docsum

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Gallbladder disease in young Congolese with sickle cell anemia: an ultrasound survey. Author(s): Longo-Mbenza B, Ngiyulu R, Kizunda P, Kaluila M, Bikangi N. Source: Journal of Tropical Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15088794&query_hl=18&itool=pubmed_docsum

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Gallstones in sickle cell anemia. Author(s): Namjoshi SP. Source: Journal of Clinical Ultrasound : Jcu. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10525219&query_hl=18&itool=pubmed_docsum

86

Sickle Cell Anemia

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Gastrointestinal/genitourinary case of the day. Liver infarction in a patient with sickle cell anemia, splenic atrophy, and gallstones. Author(s): Atkinson DS Jr, Fenlon HM, Kuligowska E. Source: Ajr. American Journal of Roentgenology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10470926&query_hl=18&itool=pubmed_docsum

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Gelation kinetics of dilute hemoglobin from sickle cell anemia patients. Author(s): Fasanmade AA. Source: Hemoglobin. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8936467&query_hl=18&itool=pubmed_docsum

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Gender and haplotype effects upon hematological manifestations of adult sickle cell anemia. Author(s): Steinberg MH, Hsu H, Nagel RL, Milner PF, Adams JG, Benjamin L, Fryd S, Gillette P, Gilman J, Josifovska O, et al. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7532353&query_hl=18&itool=pubmed_docsum

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Gene interactions and stroke risk in children with sickle cell anemia. Author(s): Hoppe C, Klitz W, Cheng S, Apple R, Steiner L, Robles L, Girard T, Vichinsky E, Styles L; CSSCD Investigators. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14615367&query_hl=18&itool=pubmed_docsum

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Genetic counseling in sickle cell anemia: experiences with couples at risk. Author(s): Neal-Cooper F, Scott RB. Source: Public Health Reports (Washington, D.C. : 1974). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3128834&query_hl=18&itool=pubmed_docsum

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Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Author(s): Sebastiani P, Ramoni MF, Nolan V, Baldwin CT, Steinberg MH. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15778708&query_hl=18&itool=pubmed_docsum

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Genetic marker of segregation: sickle cell anemia, thalassemia, and racial ideology in American medical writing 1920-1950. Author(s): Wailoo K. Source: History and Philosophy of the Life Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9136281&query_hl=18&itool=pubmed_docsum

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Genetic modulation of sickle cell anemia. Author(s): Steinberg MH. Source: Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7724611&query_hl=18&itool=pubmed_docsum

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Genetics and epidemiology of sickle cell anemia in India. Author(s): Rao VR. Source: Indian Journal of Medical Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2907511&query_hl=18&itool=pubmed_docsum

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Glycosylated hemoglobin levels in a benign form of sickle cell anemia in Saudi Arabia. Author(s): Alayash AI, Dafallah A, Al-Husayni H, Al-Ali AK, Al-Quorain A, Omer AH, Wilson MT, Bonaventura J, Cashon R. Source: Acta Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3092532&query_hl=18&itool=pubmed_docsum

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Glycosylated hemoglobin levels in Sudanese sickle cell anemia patients. Author(s): Atabani GS, Hassan DA, Abdul Rahman AM, Saeed BO. Source: Acta Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2496561&query_hl=18&itool=pubmed_docsum

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Glycosylated hemoglobins in a diabetic patient with sickle cell anemia. Author(s): Abraham EC, Rao KR. Source: Clin Physiol Biochem. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3446434&query_hl=18&itool=pubmed_docsum

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GM-CSF in sickle cell anemia patients with elevated Hb F. Author(s): Haider MZ, Raghupathy R, Azizieh F, Abdelsalam R, D'Souza TM, Adekile AD. Source: Acta Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10692677&query_hl=18&itool=pubmed_docsum

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Gonadal function abnormalities in sickle cell anemia. Studies in adult male patients. Author(s): Abbasi AA, Prasad AS, Ortega J, Congco E, Oberleas D. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=984611&query_hl=18&itool=pubmed_docsum

88

Sickle Cell Anemia

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Gonadotropin-releasing hormone analogues in the treatment of sickle cell anemiaassociated priapism. Author(s): Levine LA, Guss SP. Source: The Journal of Urology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8326584&query_hl=18&itool=pubmed_docsum

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Group A beta-hemolytic streptococcal bacteremia in a patient with sickle cell anemia on penicillin prophylaxis. Author(s): LeBlanc W, Salah H, Khakoo Y. Source: Journal of the National Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7783241&query_hl=18&itool=pubmed_docsum

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Growth hormone and insulin-like growth factor I axis and growth of children with different sickle cell anemia haplotypes. Author(s): Luporini SM, Bendit I, Manhani R, Bracco OL, Manzella L, Giannella-Neto D. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11563770&query_hl=18&itool=pubmed_docsum

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Hb F in sickle cell anemia. Author(s): Adekile AD, Huisman TH. Source: Experientia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7679078&query_hl=18&itool=pubmed_docsum

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Hearing thresholds in sickle cell anemia patients: emerging new trends? Author(s): Aderibigbe A, Ologe FE, Oyejola BA. Source: Journal of the National Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16173329&query_hl=18&itool=pubmed_docsum

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Hematological effects of atypical and Cameroon beta-globin gene haplotypes in adult sickle cell anemia. Author(s): Steinberg MH, Lu ZH, Nagel RL, Venkataramani S, Milner PF, Huey L, Safaya S, Rieder RF. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9766796&query_hl=18&itool=pubmed_docsum

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Hematopoietic stem cell transplantation for sickle cell anemia. Author(s): Vermylen C, Cornu G. Source: Current Opinion in Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9358992&query_hl=18&itool=pubmed_docsum

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High frequency of the CCR5delta32 variant among individuals from an admixed Brazilian population with sickle cell anemia. Author(s): Chies JA, Hutz MH. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12532229&query_hl=18&itool=pubmed_docsum

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Homocysteine levels and sickle cell anemia. Author(s): Rana S, Houston P, Castro OL. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10779039&query_hl=18&itool=pubmed_docsum

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Hospitalizations for painful episodes: association with school absenteeism and academic performance in children and adolescents with sickle cell anemia. Author(s): Eaton ML, Haye JS, Armstrong FD, Pegelow CH, Thomas M. Source: Issues in Comprehensive Pediatric Nursing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8707636&query_hl=18&itool=pubmed_docsum

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Hydroxyurea (HU) for prevention of recurrent stroke in sickle cell anemia (SCA). Author(s): Sumoza A, de Bisotti R, Sumoza D, Fairbanks V. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12410569&query_hl=18&itool=pubmed_docsum

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Hydroxyurea and sickle cell anemia: effect on quality of life. Author(s): Ballas SK, Barton FB, Waclawiw MA, Swerdlow P, Eckman JR, Pegelow CH, Koshy M, Barton BA, Bonds DR. Source: Health and Quality of Life Outcomes [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16942629&query_hl=18&itool=pubmed_docsum

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Hydroxyurea as secondary prevention for stroke in children with sickle cell anemia. Author(s): DeBaun MR. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16227052&query_hl=18&itool=pubmed_docsum

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Hydroxyurea corrects the dysregulated L-selectin expression and increased H(2)O(2) production of polymorphonuclear neutrophils from patients with sickle cell anemia. Author(s): Benkerrou M, Delarche C, Brahimi L, Fay M, Vilmer E, Elion J, GougerotPocidalo MA, Elbim C. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11895759&query_hl=18&itool=pubmed_docsum

90

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Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. Author(s): Platt OS, Orkin SH, Dover G, Beardsley GP, Miller B, Nathan DG. Source: The Journal of Clinical Investigation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6205021&query_hl=18&itool=pubmed_docsum

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Hydroxyurea in two pregnant women with sickle cell anemia. Author(s): Byrd DC, Pitts SR, Alexander CK. Source: Pharmacotherapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10600098&query_hl=18&itool=pubmed_docsum

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Hydroxyurea in very young children with sickle cell anemia is not a cure-all. Author(s): Powars DR. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11743496&query_hl=18&itool=pubmed_docsum

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Hydroxyurea increases fetal hemoglobin in cultured erythroid cells derived from normal individuals and patients with sickle cell anemia or beta-thalassemia. Author(s): Fibach E, Burke LP, Schechter AN, Noguchi CT, Rodgers GP. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7680923&query_hl=18&itool=pubmed_docsum

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Hydroxyurea therapy associated with declining serum levels of magnesium in children with sickle cell anemia. Author(s): Altura RA, Wang WC, Wynn L, Altura BM, Altura BT. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12032523&query_hl=18&itool=pubmed_docsum

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Hydroxyurea treatment in children with sickle cell anemia in Central America and the Caribbean countries. Author(s): Svarch E, Machin S, Nieves RM, Mancia de Reyes AG, Navarrete M, Rodriguez H. Source: Pediatric Blood & Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16550531&query_hl=18&itool=pubmed_docsum

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Hydroxyurea treatment of sickle cell anemia in hospital-based practices. Author(s): Ferguson RP, Arun A, Carter C, Walker SD, Castro O. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12214583&query_hl=18&itool=pubmed_docsum

Studies

91

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Hyperhemolysis during the evolution of uncomplicated acute painful episodes in patients with sickle cell anemia. Author(s): Ballas SK, Marcolina MJ. Source: Transfusion. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16398738&query_hl=18&itool=pubmed_docsum

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Imaging retinal depression sign in sickle cell anemia using optical coherence tomography and the retinal thickness analyzer. Author(s): Shakoor A, Blair NP, Shahidi M. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16157817&query_hl=18&itool=pubmed_docsum

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Immunotactoid glomerulopathy in sickle cell anemia. Author(s): Aviles DH, Craver R, Warrier RP. Source: Pediatric Nephrology (Berlin, Germany). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11198611&query_hl=18&itool=pubmed_docsum

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Impact of bone scintigraphy on the clinical management of a patient with sickle cell anemia and recent chest pain. Author(s): Sisayan R, Elgazzar AH, Webner PJ, Religioso DG. Source: Clinical Nuclear Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8818462&query_hl=18&itool=pubmed_docsum

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Impaired venous hemodynamics in a minority of patients with chronic leg ulcers due to sickle cell anemia. Author(s): Chalchal H, Rodino W, Hussain S, Haq I, Panetta T, Solomon W, Gillette P, Braverman AS. Source: Vasa. Zeitschrift Fur Gefasskrankheiten. Journal for Vascular Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11771212&query_hl=18&itool=pubmed_docsum

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Implementation of the STOP protocol for Stroke Prevention in Sickle Cell Anemia by using duplex power Doppler imaging. Author(s): Malouf AJ Jr, Hamrick-Turner JE, Doherty MC, Dhillon GS, Iyer RV, Smith MG. Source: Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11323457&query_hl=18&itool=pubmed_docsum

92

Sickle Cell Anemia

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Incidence of G20210A mutation in severe vaso-occlusive events complicating sickle cell anemia. Author(s): Favier R, Neonato MG, Maillet F, Feingold J, Cayre Y, Girot R. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10192661&query_hl=18&itool=pubmed_docsum

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Increased bone turnover is associated with protein and energy metabolism in adolescents with sickle cell anemia. Author(s): Buchowski MS, de la Fuente FA, Flakoll PJ, Chen KY, Turner EA. Source: American Journal of Physiology. Endocrinology and Metabolism. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11171608&query_hl=18&itool=pubmed_docsum

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Increased levels of endothelin-1 in plasma of sickle cell anemia patients. Author(s): Rybicki AC, Benjamin LJ. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9746804&query_hl=18&itool=pubmed_docsum

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Increased red cell glutamine availability in sickle cell anemia: demonstration of increased active transport, affinity, and increased glutamate level in intact red cells. Author(s): Niihara Y, Zerez CR, Akiyama DS, Tanaka KR. Source: The Journal of Laboratory and Clinical Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9242370&query_hl=18&itool=pubmed_docsum

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Increased response of erythroid progenitors to interleukin-3 in sickle cell anemia: CFU-E-like behavior of circulating erythroid progenitors in liquid culture. Author(s): Isoyama K, Baliga S, Shah A, Mankad VN. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1951299&query_hl=18&itool=pubmed_docsum

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Induction of fetal hemoglobin synthesis in children with sickle cell anemia on lowdose oral sodium phenylbutyrate therapy. Author(s): Resar LM, Segal JB, Fitzpatric LK, Friedmann A, Brusilow SW, Dover GJ. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12468915&query_hl=18&itool=pubmed_docsum

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Influence of alpha-thalassemia trait on spleen function in sickle cell anemia patients with high HbF. Author(s): Adekile AD, Tuli M, Haider MZ, Al-Zaabi K, Mohannadi S, Owunwanne A. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8813088&query_hl=18&itool=pubmed_docsum

Studies

93

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Influence of bilirubin uridine diphosphate-glucuronosyltransferase 1A promoter polymorphisms on serum bilirubin levels and cholelithiasis in children with sickle cell anemia. Author(s): Passon RG, Howard TA, Zimmerman SA, Schultz WH, Ware RE. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11878580&query_hl=18&itool=pubmed_docsum

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Influence of penicillin prophylaxis on antimicrobial resistance in nasopharyngeal S. pneumoniae among children with sickle cell anemia. The Ancillary Nasopharyngeal Culture Study of Prophylactic Penicillin Study II. Author(s): Woods GM, Jorgensen JH, Waclawiw MA, Reid C, Wang W, Pegelow CH, Rogers ZR, Iyer RV, Holbrook CT, Kinney TR, Vichinsky E, DeBaun MR, Grossman NJ, Thomas MD, Falletta JM. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9256832&query_hl=18&itool=pubmed_docsum

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Integrin alpha 4 beta 1 and glycoprotein IV (CD36) are expressed on circulating reticulocytes in sickle cell anemia. Author(s): Joneckis CC, Ackley RL, Orringer EP, Wayner EA, Parise LV. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7505118&query_hl=18&itool=pubmed_docsum

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Intracellular hemoglobin S polymerization and the clinical severity of sickle cell anemia. Author(s): Poillon WN, Kim BC, Castro O. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9473246&query_hl=18&itool=pubmed_docsum

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Intracranial aneurysms and sickle cell anemia: multiplicity and propensity for the vertebrobasilar territory. Author(s): Preul MC, Cendes F, Just N, Mohr G. Source: Neurosurgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9588540&query_hl=18&itool=pubmed_docsum

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Intrathoracic extramedullary hematopoiesis simulating tumor, in a patient with sickle cell anemia. Author(s): Kouraklis G, Dosios T. Source: European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8031567&query_hl=18&itool=pubmed_docsum

94

Sickle Cell Anemia

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Iron deficiency in sickle cell anemia. Author(s): Ozsoylu S. Source: European Journal of Haematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8405338&query_hl=18&itool=pubmed_docsum

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Is it reactivation of fetal hemoglobin synthesis after transplantation of cord blood stem cells from a donor with heterozygous sickle cell anemia or beta-thalassemia? Author(s): Ohnuma K, Toyoda Y, Nishihira H. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9202630&query_hl=18&itool=pubmed_docsum

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K(86Rb) transport heterogeneity in the low-density fraction of sickle cell anemia red blood cells. Author(s): Etzion Z, Lew VL, Bookchin RM. Source: The American Journal of Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8897817&query_hl=18&itool=pubmed_docsum

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Klebsiella pneumoniae osteomyelitis in sickle cell anemia. Author(s): Manglani M, Rao S, Jog A, Patel S, Kulkarni M, Lokeshwar MR. Source: Indian Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7875871&query_hl=18&itool=pubmed_docsum

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Klebsiella pneumoniae osteomyelitis in sickle cell anemia. Author(s): Patel RB, Ramani S, Parmar B. Source: Indian J Pediatr. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2684851&query_hl=18&itool=pubmed_docsum

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Known and potential sources for epistatic effects in sickle cell anemia. Author(s): Nagel RL, Fabry ME, Kaul DK, Billett H, Croizat H, Labie D, Canessa M. Source: Annals of the New York Academy of Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2476062&query_hl=18&itool=pubmed_docsum

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Left ventricular filling pressure in sickle cell anemia. Author(s): Norris SL, Johnson C, Haywood LJ. Source: J Assoc Acad Minor Phys. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1576456&query_hl=18&itool=pubmed_docsum

Studies

95

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Left ventricular systolic and diastolic functions in patients with sickle cell anemia. Author(s): Taksande A, Vilhekar K, Jain M, Ganvir B. Source: Indian Heart J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16521640&query_hl=18&itool=pubmed_docsum

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Less intensive long-term transfusion therapy for sickle cell anemia and cerebrovascular accident. Author(s): Miller ST, Jensen D, Rao SP. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1731025&query_hl=18&itool=pubmed_docsum

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Lessons from the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study. Author(s): Adams RJ. Source: Journal of Child Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10830201&query_hl=18&itool=pubmed_docsum

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Level of fetal hemoglobin in children with sickle cell anemia: influence of gender, haplotype and alpha-thalassemia-2 trait. Author(s): Adekile AD, Huisman TH. Source: Acta Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7694436&query_hl=18&itool=pubmed_docsum

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Levels of endothelial, neutrophil and platelet-specific factors in sickle cell anemia patients during hydroxyurea therapy. Author(s): Saleh AW, Hillen HF, Duits AJ. Source: Acta Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10473885&query_hl=18&itool=pubmed_docsum

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Limitations of a mouse model of sickle cell anemia. Author(s): Ieremia J, Blau CA. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12064910&query_hl=18&itool=pubmed_docsum

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Liver abscess as an unusual complication in sickle cell anemia. Author(s): Chong SK, Dick MC, Howard ER, Mowat AP. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8450394&query_hl=18&itool=pubmed_docsum

96

Sickle Cell Anemia

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Liver transplantation in sickle cell anemia: a case of acute sickle cell intrahepatic cholestasis and a case of sclerosing cholangitis. Author(s): Baichi MM, Arifuddin RM, Mantry PS, Bozorgzadeh A, Ryan C. Source: Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16371935&query_hl=18&itool=pubmed_docsum

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Longitudinal changes in ferritin during chronic transfusion: a report from the Stroke Prevention Trial in Sickle Cell Anemia (STOP). Author(s): Files B, Brambilla D, Kutlar A, Miller S, Vichinsky E, Wang W, Granger S, Adams RJ. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11972097&query_hl=18&itool=pubmed_docsum

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Longitudinal exercise hemodynamics in children with sickle cell anemia. Author(s): Alpert BS, Dover EV, Strong WB, Covitz W. Source: Am J Dis Child. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6496419&query_hl=18&itool=pubmed_docsum

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Long-term follow-up and booster immunization with polyvalent pneumococcal polysaccharide in patients with sickle cell anemia. Author(s): Weintrub PS, Schiffman G, Addiego JE Jr, Matthay KK, Vichinsky E, Johnson R, Lubin B, Mentzer WC, Ammann AJ. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6747758&query_hl=18&itool=pubmed_docsum

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Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study. Author(s): Hankins JS, Ware RE, Rogers ZR, Wynn LW, Lane PA, Scott JP, Wang WC. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16172253&query_hl=18&itool=pubmed_docsum

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Long-term use of hydroxyurea for sickle cell anemia. Author(s): Lee DA, Mueller BU. Source: Jama : the Journal of the American Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12915425&query_hl=18&itool=pubmed_docsum

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Long-term use of hydroxyurea for sickle cell anemia. Author(s): Hagar W. Source: Jama : the Journal of the American Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12915424&query_hl=18&itool=pubmed_docsum

Studies

97

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Long-term use of hydroxyurea for sickle cell anemia. Author(s): Feldman L, Allen S, Westerman M, Feldman L, Gilman-Sachs A, Beaman K. Source: Jama : the Journal of the American Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12915423&query_hl=18&itool=pubmed_docsum

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Long-term use of hydroxyurea for sickle cell anemia. Author(s): Spell DW. Source: Jama : the Journal of the American Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12915422&query_hl=18&itool=pubmed_docsum

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Low number of antibody producing cells in patients with sickle cell anemia. Author(s): Rautonen N, Martin NL, Rautonen J, Rooks Y, Mentzer WC, Wara DW. Source: Immunology Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1487307&query_hl=18&itool=pubmed_docsum

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Low-density lipoprotein susceptibility to oxidation and cytotoxicity to endothelium in sickle cell anemia. Author(s): Belcher JD, Marker PH, Geiger P, Girotti AW, Steinberg MH, Hebbel RP, Vercellotti GM. Source: The Journal of Laboratory and Clinical Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10360636&query_hl=18&itool=pubmed_docsum

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Mechanisms of homogeneous nucleation of polymers of sickle cell anemia hemoglobin in deoxy state. Author(s): Galkin O, Vekilov PG. Source: Journal of Molecular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14741202&query_hl=18&itool=pubmed_docsum

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Minor elective surgical procedures using general anesthesia in children with sickle cell anemia without pre-operative blood transfusion. Author(s): Fu T, Corrigan NJ, Quinn CT, Rogers ZR, Buchanan GR. Source: Pediatric Blood & Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15880471&query_hl=18&itool=pubmed_docsum

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Mitral valve reconstruction in a compound heterozygote for sickle cell anemia and hemoglobin Lepore. Author(s): Tziomalos K, Garipidou V, Houmpouridou E, Pitsis AA, Basayannis E. Source: The Journal of Thoracic and Cardiovascular Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16153972&query_hl=18&itool=pubmed_docsum

98

Sickle Cell Anemia

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Modifier genes and sickle cell anemia. Author(s): Steinberg MH, Adewoye AH. Source: Current Opinion in Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16567954&query_hl=18&itool=pubmed_docsum

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Molecular analysis of beta-thalassemia and sickle cell anemia in Antalya. Author(s): Keser I, Sanlioglu AD, Manguoglu E, Guzeloglu Kayisli O, Nal N, Sargin F, Yesilipek A, Simsek M, Mendilcioglu I, Canatan D, Luleci G. Source: Acta Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15153712&query_hl=18&itool=pubmed_docsum

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Multi-drug resistance to Streptococcus pneumoniae in sickle cell anemia. Author(s): Wong WY, Powars DR, Hiti AL. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7717378&query_hl=18&itool=pubmed_docsum

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Myocardial bridge in a patient with sickle cell anemia. Author(s): de Seixas MA, Franchin Junior CA, Silva CE, Leal SM, Ortiz J. Source: Arquivos Brasileiros De Cardiologia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10488578&query_hl=18&itool=pubmed_docsum

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Myonecrosis in sickle cell anemia. Author(s): Malekgoudarzi B, Feffer S. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9988624&query_hl=18&itool=pubmed_docsum

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Myonecrosis in sickle cell anemia: case report and review of the literature. Author(s): Vicari P, Achkar R, Oliveira KR, Miszpupten ML, Fernandes AR, Figueiredo MS, Bordin JO. Source: Southern Medical Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15455982&query_hl=18&itool=pubmed_docsum

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Myth: blood transfusion is effective for sickle cell anemia-associated priapism. Author(s): Merritt AL, Haiman C, Henderson SO. Source: Cjem. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17175874&query_hl=18&itool=pubmed_docsum

Studies

99

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Natural coagulation inhibitors (protein C, protein S, antithrombin) in patients with sickle cell anemia in a steady state. Author(s): Bayazit AK, Kilinc Y. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11737735&query_hl=18&itool=pubmed_docsum

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Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia. Author(s): Pegelow CH, Colangelo L, Steinberg M, Wright EC, Smith J, Phillips G, Vichinsky E. Source: The American Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9217567&query_hl=18&itool=pubmed_docsum

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Neurologic complications after allogeneic marrow transplantation for sickle cell anemia. Author(s): Walters MC, Sullivan KM, Bernaudin F, Souillet G, Vannier JP, Johnson FL, Lenarsky C, Powars D, Bunin N, Ohene-Frempong K, et al. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7849310&query_hl=18&itool=pubmed_docsum

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Neuropsychologic effects of stroke in children with sickle cell anemia. Author(s): Craft S, Schatz J, Glauser TA, Lee B, DeBaun MR. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8229478&query_hl=18&itool=pubmed_docsum

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New results in clinical severity of homozygous sickle cell anemia, in Dakar, Senegal. Author(s): Diop S, Thiam D, Cisse M, Toure-Fall AO, Fall K, Diakhate L. Source: Hematology and Cell Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10651122&query_hl=18&itool=pubmed_docsum

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Nodular regenerative hyperplasia of the liver and focal global glomerulosclerosis associated with sickle cell anemia. Author(s): Al-Mukhaizeem KA, Lamoureux E, Rosenberg A, Sherker AH. Source: Digestive Diseases and Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11855565&query_hl=18&itool=pubmed_docsum

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Noninvasive central nervous system imaging in sickle cell anemia. A preliminary study comparing transcranial Doppler with magnetic resonance angiography. Author(s): DeBaun MR, Glauser TA, Siegel M, Borders J, Lee B. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7743234&query_hl=18&itool=pubmed_docsum

100

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Nontraumatic fat embolism syndrome in sickle cell anemia. Author(s): Horton DP, Ferriero DM, Mentzer WC. Source: Pediatric Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7748367&query_hl=18&itool=pubmed_docsum

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Normal cortisol secretion in sickle cell anemia. Author(s): Saad ST, Saad MJ. Source: Trop Geogr Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1323163&query_hl=18&itool=pubmed_docsum

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Nutritional status and dietary intake of children with sickle cell anemia. Author(s): Gray NT, Bartlett JM, Kolasa KM, Marcuard SP, Holbrook CT, Horner RD. Source: Am J Pediatr Hematol Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1550264&query_hl=18&itool=pubmed_docsum

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Oral complications associated with sickle cell anemia: a review and case report. Author(s): Kelleher M, Bishop K, Briggs P. Source: Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8863314&query_hl=18&itool=pubmed_docsum

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Oral lesions of sickle cell anemia: case report and review of the literature. Author(s): Michaelson J, Bhola M. Source: J Mich Dent Assoc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15524263&query_hl=18&itool=pubmed_docsum

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Oral penicillin prophylaxis in children with sickle cell anemia in Saudi Arabia. Author(s): Salamah MM. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3796706&query_hl=18&itool=pubmed_docsum

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Ossified soft tissue leiomyoma in a patient with sickle cell anemia. Author(s): Xu Y, Lacouture M, Petronic-Rosic V, Soltani K, Shea CR. Source: Journal of Cutaneous Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16293183&query_hl=18&itool=pubmed_docsum

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Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients. Author(s): Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Source: Medicine; Analytical Reviews of General Medicine, Neurology, Psychiatry, Dermatology, and Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16267411&query_hl=18&itool=pubmed_docsum

Studies

101

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Outpatient penile aspiration and epinephrine irrigation for young patients with sickle cell anemia and prolonged priapism. Author(s): Mantadakis E, Ewalt DH, Cavender JD, Rogers ZR, Buchanan GR. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10607688&query_hl=18&itool=pubmed_docsum

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Overt and incomplete (silent) cerebral infarction in sickle cell anemia: diagnosis and management. Author(s): Wong WY, Powars DR. Source: Hematology/Oncology Clinics of North America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16214647&query_hl=18&itool=pubmed_docsum

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Overview of pathophysiology and rationale for treatment of sickle cell anemia. Author(s): Rodgers GP. Source: Semin Hematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9317195&query_hl=18&itool=pubmed_docsum

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Percutaneous glue embolization of a visceral artery pseudoaneurysm in a case of sickle cell anemia. Author(s): Gulati GS, Gulati MS, Makharia G, Hatimota P, Saikia N, Paul SB, Acharya S. Source: Cardiovascular and Interventional Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16132392&query_hl=18&itool=pubmed_docsum

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Persistent splenomegaly in an adult female with homozygous sickle cell anemia. Author(s): Singh S, Singh DK, Gupta R, Nigam S, Singh T. Source: Hematology (Amsterdam, Netherlands). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16522553&query_hl=18&itool=pubmed_docsum

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Perspectives: molecular medicine. "Sickle cell anemia, a molecular disease". Author(s): Strasser BJ. Source: Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10610548&query_hl=18&itool=pubmed_docsum

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Plasma lipids in Iranians with sickle cell disease: hypocholesterolemia in sickle cell anemia and increase of HDL-cholesterol in sickle cell trait. Author(s): Rahimi Z, Merat A, Haghshenass M, Madani H, Rezaei M, Nagel RL. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16185676&query_hl=18&itool=pubmed_docsum

102

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Predicting the effectiveness of hydroxyurea in individual sickle cell anemia patients. Author(s): Valafar H, Valafar F, Darvill A, Albersheim P, Kutlar A, Woods KF, Hardin J. Source: Artificial Intelligence in Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10648847&query_hl=18&itool=pubmed_docsum

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Prenatal diagnosis of sickle cell anemia in twin pregnancies and identification by VNTRs. Author(s): Attila G, Yalin S, Tuli A, Yalin E, Aksoy K. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15530470&query_hl=18&itool=pubmed_docsum

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Prevalence of priapism in children and adolescents with sickle cell anemia. Author(s): Mantadakis E, Cavender JD, Rogers ZR, Ewalt DH, Buchanan GR. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10598664&query_hl=18&itool=pubmed_docsum

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Preventing stroke in sickle cell anemia. Author(s): Platt OS. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16382060&query_hl=18&itool=pubmed_docsum

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Punctate echogenic foci in spleen and increased echogenicity in renal cortex in sickle cell anemia. Author(s): Namjoshi SP. Source: Journal of Clinical Ultrasound : Jcu. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9888101&query_hl=18&itool=pubmed_docsum

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Quantitation of three types of gamma chain of HbF by high pressure liquid chromatography; application of this method to the HbF of patients with sickle cell anemia or the S-HPFH condition. Author(s): Huisman TH, Altay C, Webber B, Reese AL, Gravely ME, Okonjo K, Wilson JB. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6160889&query_hl=18&itool=pubmed_docsum

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Recent advances in globin gene transfer for the treatment of beta-thalassemia and sickle cell anemia. Author(s): Sadelain M. Source: Current Opinion in Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16567956&query_hl=18&itool=pubmed_docsum

Studies

103

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Renal amyloidosis in a child with sickle cell anemia. Author(s): Simsek B, Bayazit AK, Ergin M, Soran M, Dursun H, Kilinc Y. Source: Pediatric Nephrology (Berlin, Germany). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16570202&query_hl=18&itool=pubmed_docsum

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Renal dysfunction in patients with sickle cell anemia or sickle cell trait. Author(s): Sesso R, Almeida MA, Figueiredo MS, Bordin JO. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9876295&query_hl=18&itool=pubmed_docsum

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Renal reabsorption of phosphate in children with sickle cell anemia. Author(s): Al-Harbi N, Annobil SH, Abbag F, Adzaku F, Bassuni W. Source: American Journal of Nephrology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10575182&query_hl=18&itool=pubmed_docsum

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Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia. Author(s): Iannone R, Casella JF, Fuchs EJ, Chen AR, Jones RJ, Woolfrey A, Amylon M, Sullivan KM, Storb RF, Walters MC. Source: Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12931121&query_hl=18&itool=pubmed_docsum

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Right ventricular abnormalities in sickle cell anemia: evidence of a progressive increase in pulmonary vascular resistance. Author(s): Qureshi N, Joyce JJ, Qi N, Chang RK. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16860121&query_hl=18&itool=pubmed_docsum

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Risk factors and prediction of outcomes in children and adolescents who have sickle cell anemia. Author(s): Quinn CT, Miller ST. Source: Hematology/Oncology Clinics of North America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15511619&query_hl=18&itool=pubmed_docsum

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Risk of cholelithiasis in sickle cell anemia. Author(s): Heeney MM. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15713573&query_hl=18&itool=pubmed_docsum

104

Sickle Cell Anemia

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Role of epistatic (modifier) genes in the modulation of the phenotypic diversity of sickle cell anemia. Author(s): Nagel RL, Steinberg MH. Source: Pediatric Pathology & Molecular Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12673837&query_hl=18&itool=pubmed_docsum

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Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group. Author(s): Kinney TR, Helms RW, O'Branski EE, Ohene-Frempong K, Wang W, Daeschner C, Vichinsky E, Redding-Lallinger R, Gee B, Platt OS, Ware RE. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10477679&query_hl=18&itool=pubmed_docsum

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Seroprevalence of hepatitis B and hepatitis C in patients with thalassemia and sickle cell anemia in a long-term follow-up. Author(s): Ocak S, Kaya H, Cetin M, Gali E, Ozturk M. Source: Archives of Medical Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16971232&query_hl=18&itool=pubmed_docsum

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Sickle cell anemia day hospital: an approach for the management of uncomplicated painful crises. Author(s): Benjamin LJ, Swinson GI, Nagel RL. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10666181&query_hl=18&itool=pubmed_docsum

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Sickle cell anemia identified in a multiple-transfused patient through analysis of mRNA with an RT-PCR-based technique. Author(s): Smetanina NS, Gu LH, Leonova JYe, Huisman TH. Source: Acta Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7639050&query_hl=18&itool=pubmed_docsum

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Sickle cell anemia therapy: progress since Pauling. Author(s): Schechter AN, Rodgers GP. Source: Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10691539&query_hl=18&itool=pubmed_docsum

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Sickle cell anemia: a review of the dental concerns and a retrospective study of dental and bony changes. Author(s): Taylor LB, Nowak AJ, Giller RH, Casamassimo PS. Source: Spec Care Dentist. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7676364&query_hl=18&itool=pubmed_docsum

Studies

105

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Sickle cell anemia: severe ischemic colitis responding to conservative management. Author(s): Moukarzel AA, Rajaram M, Sundeep A, Guarini L, Feldman F. Source: Clinical Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10791138&query_hl=18&itool=pubmed_docsum

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Social competence of siblings of children with sickle cell anemia. Author(s): Noll RB, Yosua LA, Vannatta K, Kalinyak K, Bukowski WM, Davies WH. Source: Journal of Pediatric Psychology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7760217&query_hl=18&itool=pubmed_docsum

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Splenic function in sickle cell anemia patients in Qatif, Saudi Arabia. Author(s): Al-Jam'a AH, Al-Dabbous IA, Chirala SK, Al-Majid H, Al-Ali J. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10629571&query_hl=18&itool=pubmed_docsum

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The case: Bone disease in sickle cell anemia. Author(s): Patel A, Klassen C, Griffiths HJ. Source: Orthopedics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16786934&query_hl=18&itool=pubmed_docsum

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The effect of hydroxyurea on the coagulation system in sickle cell anemia and betathalassemia intermedia patients: a preliminary study. Author(s): Koc A, Gumruk F, Gurgey A. Source: Pediatric Hematology and Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14631615&query_hl=18&itool=pubmed_docsum

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The influence of uridine diphosphate glucuronosyl transferase 1A promoter polymorphisms, beta-globin gene haplotype, co-inherited alpha-thalassemia trait and Hb F on steady-state serum bilirubin levels in sickle cell anemia. Author(s): Adekile A, Kutlar F, McKie K, Addington A, Elam D, Holley L, Clair B, Kutlar A. Source: European Journal of Haematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16004608&query_hl=18&itool=pubmed_docsum

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The nonexpression of CD36 on reticulocytes and mature red blood cells does not modify the clinical course of patients with sickle cell anemia. Author(s): Lee K, Gane P, Roudot-Thoraval F, Godeau B, Bachir D, Bernaudin F, Cartron JP, Galacteros F, Bierling P. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11493440&query_hl=18&itool=pubmed_docsum

106

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The outcomes of sickle cell disease in adulthood are clear, but the origins and progression of sickle cell anemia-induced problems in the heart and lung in childhood are not. Author(s): Boyd JH, Strunk RC, Morgan WJ. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16860112&query_hl=18&itool=pubmed_docsum

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The pain experience of patients with sickle cell anemia. Author(s): Jacob E. Source: Pain Management Nursing : Official Journal of the American Society of Pain Management Nurses. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11710089&query_hl=18&itool=pubmed_docsum

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Thrombosis-associated gene variants in sickle cell anemia. Author(s): Romana M, Muralitharan S, Ramasawmy R, Nagel RL, Krishnamoorthy R. Source: Thrombosis and Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11858507&query_hl=18&itool=pubmed_docsum

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Transplantation of a child with sickle cell anemia with an unrelated cord blood unit after reduced intensity conditioning. Author(s): Mazur M, Kurtzberg J, Halperin E, Ciocci G, Szabolcs P. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17164657&query_hl=18&itool=pubmed_docsum

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Treatment of post-traumatic trabecular mashwork thrombosis and secondary glaucoma with intracameral tissue plasminogen activator in previously unrecognized sickle cell anemia. Author(s): Karaman K, Culic S, Erceg I, Culic V, Siniilc A, Salamunic I, Znaor L. Source: Coll Antropol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16193693&query_hl=18&itool=pubmed_docsum

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Trichobezoar: an unusual cause for pancreatitis in a patient with sickle cell anemia. Author(s): Stein-Wexler R, Wootton-Gorges SL, Shakibai S, Graf J, Miller SM, Taylor D, Zwerdling T. Source: Clin Adv Hematol Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16981670&query_hl=18&itool=pubmed_docsum

Studies

107

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UDP-glucuronosyltransferase 1 gene promoter polymorphism is associated with increased serum bilirubin levels and cholecystectomy in patients with sickle cell anemia. Author(s): Fertrin KY, Melo MB, Assis AM, Saad ST, Costa FF. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12859413&query_hl=18&itool=pubmed_docsum

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UGT1A promoter polymorphisms influence bilirubin response to hydroxyurea therapy in sickle cell anemia. Author(s): Heeney MM, Howard TA, Zimmerman SA, Ware RE. Source: The Journal of Laboratory and Clinical Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12677174&query_hl=18&itool=pubmed_docsum

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UGT1A1 polymorphism outweighs the modest effect of deletional (-3.7 kb) alphathalassemia on cholelithogenesis in sickle cell anemia. Author(s): Chaar V, Keclard L, Etienne-Julan M, Diara JP, Elion J, Krishnamoorthy R, Romana M. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16628735&query_hl=18&itool=pubmed_docsum

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Ultrastructural alterations in the myocardium of patients with sickle cell anemia. Author(s): Tap, San M, Mete UO, Kaya M. Source: J Submicrosc Cytol Pathol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11686396&query_hl=18&itool=pubmed_docsum

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Uncommon orbital bone infarctions in a sickle cell anemia patient. Author(s): Koren A, Garty I, Ben-Ami M, Katzuni E. Source: Clinical Nuclear Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6239730&query_hl=18&itool=pubmed_docsum

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Unexpected hemoglobin electrophoresis results following red cell exchange in a sickle cell anemia patient with acute chest syndrome. Author(s): Robertson PB, Danielson CF, McCarthy LJ. Source: Transfusion Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10174684&query_hl=18&itool=pubmed_docsum

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Unusual causes of abdominal pain: sickle cell anemia. Author(s): Ahmed S, Shahid RK, Russo LA. Source: Best Practice & Research. Clinical Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15833695&query_hl=18&itool=pubmed_docsum

108

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Urea and sickle cell anemia. Author(s): Vener KJ. Source: Journal of Theoretical Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=886876&query_hl=18&itool=pubmed_docsum

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Use of general anesthesia in dental care of the child with sickle cell anemia. A case report. Author(s): Demas DC, Cantin RY, Poole A, Thomas HF. Source: Oral Surg Oral Med Oral Pathol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2971907&query_hl=18&itool=pubmed_docsum

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Use of protocols for ED patients with sickle cell anemia. Author(s): Bojanowski C. Source: Journal of Emergency Nursing: Jen : Official Publication of the Emergency Department Nurses Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2649723&query_hl=18&itool=pubmed_docsum

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Variations in the relative activities of erythrocyte membrane ATPase with changes in severity of sickle cell anemia. Author(s): Eluwa EO, Obidoa O, Obi GO, Onwubiko HA. Source: Biochemical Medicine and Metabolic Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2445366&query_hl=18&itool=pubmed_docsum

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Vasoocclusion in sickle cell anemia: are platelets really involved? Author(s): Bennett JS. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16794229&query_hl=18&itool=pubmed_docsum

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Vaso-occlusion in sickle cell anemia: role of interactions between blood cells and endothelium. Author(s): Elion JE, Brun M, Odievre MH, Lapoumeroulie CL, Krishnamoorthy R. Source: The Hematology Journal : the Official Journal of the European Haematology Association / Eha. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15190308&query_hl=18&itool=pubmed_docsum

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Venous thromboembolism, factor V Leiden, and methylenetetrahydrofolate reductase in a sickle cell anemia patient. Author(s): Koren A, Zalman L, Levin C, Abu Hana M, Mader R, Shalev S. Source: Pediatric Hematology and Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10505325&query_hl=18&itool=pubmed_docsum

Studies

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Ventilation and gas exchange during exercise in sickle cell anemia. Author(s): Pianosi P, D'Souza SJ, Esseltine DW, Charge TD, Coates AL. Source: Am Rev Respir Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1990932&query_hl=18&itool=pubmed_docsum

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Viral burden and disease progression in HIV-1-infected patients with sickle cell anemia. Author(s): Bagasra O, Steiner RM, Ballas SK, Castro O, Dornadula G, Embury S, Jungkind D, Bobroski L, Kutlar A, Burchott S. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9798657&query_hl=18&itool=pubmed_docsum

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Vitamin C deficiency in patients with sickle cell anemia. Author(s): Chiu D, Vichinsky E, Ho SL, Liu T, Lubin BH. Source: Am J Pediatr Hematol Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2240472&query_hl=18&itool=pubmed_docsum

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Water sports and sickle cell anemia. Author(s): Ratner SJ, Athanasian EA. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3777727&query_hl=18&itool=pubmed_docsum

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What do you remember about sickle cell anemia? Author(s): Hibbeln J, Tarver D. Source: Ohio Nurses Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9385174&query_hl=18&itool=pubmed_docsum

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What the school health team should know about sickle cell anemia. Author(s): Walker JE. Source: The Journal of School Health. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1039043&query_hl=18&itool=pubmed_docsum

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Yersinia enterocolitica bacteremia in a chronically transfused patient with sickle cell anemia. Case report and review of the literature. Author(s): Blei F, Puder DR. Source: Am J Pediatr Hematol Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8214368&query_hl=18&itool=pubmed_docsum

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Zinc and antioxidant vitamin deficiency in patients with severe sickle cell anemia. Author(s): Hasanato RM. Source: Ann Saudi Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16521870&query_hl=18&itool=pubmed_docsum

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Zinc and copper status in patients with sickle cell anemia. Author(s): Alayash AI, Dafallah A, Al-Quorain A, Omer AH, Wilson MT. Source: Acta Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3111146&query_hl=18&itool=pubmed_docsum

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Zinc and some zinc dependent enzymes in sickle cell anemia. Author(s): Alayash AI. Source: Int J Vitam Nutr Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2634046&query_hl=18&itool=pubmed_docsum

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Zinc in the treatment of homozygous sickle cell anemia: studies in an animal model. Author(s): Schoomaker EB, Brewer GJ, Oelshlegel FJ Jr. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=984036&query_hl=18&itool=pubmed_docsum

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Zinc metabolism in sickle cell anemia. Author(s): Niell HB, Leach BE, Kraus AP. Source: Jama : the Journal of the American Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=501865&query_hl=18&itool=pubmed_docsum

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CHAPTER 2. ALTERNATIVE MEDICINE AND SICKLE CELL ANEMIA Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to sickle cell anemia. At the conclusion of this chapter, we will provide additional sources.

National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to sickle cell anemia and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select CAM on PubMed. Enter sickle cell anemia (or synonyms) into the search box. Click Go. The following references provide information on particular aspects of complementary and alternative medicine that are related to sickle cell anemia: •

Acetazolamide in the treatment of sickle cell anemia. Author(s): KHANDELWAL MK. Source: Indian J Pediatr. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14455551&query_hl=1&itool=pubmed_docsum

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Aged garlic extract therapy for sickle cell anemia patients. Author(s): Takasu J, Uykimpang R, Sunga M, Amagase H, Niihara Y. Source: Bmc Blood Disorders [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12086586&query_hl=1&itool=pubmed_docsum

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Blood pressure, hematologic and erythrocyte fragility changes in children suffering from sickle cell anemia following ascorbic acid supplementation. Author(s): Jaja SI, Ikotun AR, Gbenebitse S, Temiye EO.

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Source: Journal of Tropical Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12521281&query_hl=1&itool=pubmed_docsum •

Cardiac abnormalities in children with sickle cell anemia. Author(s): Batra AS, Acherman RJ, Wong WY, Wood JC, Chan LS, Ramicone E, Ebrahimi M, Wong PC. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12210812&query_hl=1&itool=pubmed_docsum

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Cobaltous chloride therapy in sickle cell anemia. Author(s): STOHLMAN F Jr, RATH CE. Source: Bull Georgetown Univ Med Cent. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=13106576&query_hl=1&itool=pubmed_docsum

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Coenzyme Q10 in plasma and erythrocytes: comparison of antioxidant levels in healthy probands after oral supplementation and in patients suffering from sickle cell anemia. Author(s): Niklowitz P, Menke T, Wiesel T, Mayatepek E, Zschocke J, Okun JG, Andler W. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12417107&query_hl=1&itool=pubmed_docsum

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Does a clinical pathway improve the quality of care for sickle cell anemia? Author(s): Co JP, Johnson KB, Duggan AK, Casella JF, Wilson M. Source: Jt Comm J Qual Saf. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12698808&query_hl=1&itool=pubmed_docsum

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Effect of zinc supplementation on serum testosterone level in adult male sickle cell anemia subjects. Author(s): Prasad AS, Abbasi AA, Rabbani P, DuMouchelle E. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6786094&query_hl=1&itool=pubmed_docsum

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Eight children with coexistent sickle cell anemia and plumbism. Author(s): Seeler RA. Source: Clinical Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=4209022&query_hl=1&itool=pubmed_docsum

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Erythrocytic ecdysis in smears of EDTA venous blood in eight patients with sickle cell anemia. Author(s): Rao KR, Patel AR.

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Source: Blood Cells. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3115341&query_hl=1&itool=pubmed_docsum •

Evaluation of Fagara zanthoxyloides root extract in sickle cell anemia blood in vitro. Author(s): Honig GR, Farnsworth NR, Ferenc C, Vida LN. Source: Lloydia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1202311&query_hl=1&itool=pubmed_docsum

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Excretion of iron in response to deferoxamine in sickle cell anemia. Author(s): Cohen A, Schwartz E. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=633013&query_hl=1&itool=pubmed_docsum

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Folate supplementation in sickle cell anemia. Author(s): Hoffer LJ. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12930937&query_hl=1&itool=pubmed_docsum

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Further studies in the use of hyperbaric oxygen in retinal detachment with sickle cell anemia. Author(s): Freilich DB, Seelenfreund MH. Source: Mod Probl Ophthalmol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1160909&query_hl=1&itool=pubmed_docsum

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Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Author(s): Brittenham GM, Cohen AR, McLaren CE, Martin MB, Griffith PM, Nienhuis AW, Young NS, Allen CJ, Farrell DE, Harris JW. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8416302&query_hl=1&itool=pubmed_docsum

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Homocysteine levels and sickle cell anemia: response to Rana et al. Author(s): Wang WC. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10779040&query_hl=1&itool=pubmed_docsum

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Hyperbaric oxygen, retinal detachment, and sickle cell anemia. Author(s): Freilich DB, Seelenfreund MH.

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Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=4721212&query_hl=1&itool=pubmed_docsum •

Hypnotically induced pain control in sickle cell anemia. Author(s): Zeltzer L, Dash J, Holland JP. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=492819&query_hl=1&itool=pubmed_docsum

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Iron chelation therapy in sickle cell anemia. Author(s): Cohen A, Schwartz E. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=507048&query_hl=1&itool=pubmed_docsum

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Oral glutamine supplementation decreases resting energy expenditure in children and adolescents with sickle cell anemia. Author(s): Williams R, Olivi S, Li CS, Storm M, Cremer L, Mackert P, Wang W. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15454831&query_hl=1&itool=pubmed_docsum

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Oral L-glutamine therapy for sickle cell anemia: I. Subjective clinical improvement and favorable change in red cell NAD redox potential. Author(s): Niihara Y, Zerez CR, Akiyama DS, Tanaka KR. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9625578&query_hl=1&itool=pubmed_docsum

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Pernicious anemia with neuropsychiatric dysfunction in a patient with sickle cell anemia treated with folate supplementation. Author(s): Dhar M, Bellevue R, Carmel R. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12773647&query_hl=1&itool=pubmed_docsum

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Plasma homocysteine levels and folate status in children with sickle cell anemia. Author(s): Rodriguez-Cortes HM, Griener JC, Hyland K, Bottiglieri T, Bennett MJ, Kamen BA, Buchanan GR. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10363855&query_hl=1&itool=pubmed_docsum

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Prevention of the painful crises of sickle cell anemia with prothrombinopenic anticoagulants: report of a case. Author(s): RODMAN T, MYERSON RM, PASTOR BH. Source: The American Journal of the Medical Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14493136&query_hl=1&itool=pubmed_docsum

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Rational bases for using oxygen-ozonetherapy as a biological response modifier in sickle cell anemia and beta-thalassemia: a therapeutic perspective. Author(s): Bocci V, Aldinucci C. Source: J Biol Regul Homeost Agents. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15323359&query_hl=1&itool=pubmed_docsum

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Reticulocytosis following ACTH in sickle cell anemia; case report. Author(s): BISGEIER GP. Source: J Med Soc N J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=13023352&query_hl=1&itool=pubmed_docsum

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Self-regulation and assessment approaches for vaso-occlusive pain management for pediatric sickle cell anemia patients. Author(s): Hall H, Chiarucci K, Berman B. Source: Int J Psychosom. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1428615&query_hl=1&itool=pubmed_docsum

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Sickle cell anemia. Author(s): ADAMS RC. Source: Phys Ther Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14370978&query_hl=1&itool=pubmed_docsum

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Sickle cell anemia. Author(s): JAMES GW 3rd, PORTER WB. Source: Postgraduate Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14920314&query_hl=1&itool=pubmed_docsum

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Sickle cell anemia: a potential nutritional approach for a molecular disease. Author(s): Ohnishi ST, Ohnishi T, Ogunmola GB. Source: Nutrition (Burbank, Los Angeles County, Calif.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10793299&query_hl=1&itool=pubmed_docsum

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The influence of faith and religion and the role of religious and community leaders in prenatal decisions for sickle cell disorders and thalassaemia major. Author(s): Ahmed S, Atkin K, Hewison J, Green J.

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Source: Prenatal Diagnosis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16927359&query_hl=1&itool=pubmed_docsum •

Transfusional hemosiderosis in sickle cell anemia: another cause of an echogenic pancreas. Author(s): Flyer MA, Haller JO, Sundaram R. Source: Pediatric Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8516039&query_hl=1&itool=pubmed_docsum

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Treatment of sickle cell anemia with cobalt chloride. Author(s): WOLF J, LEVY IJ. Source: Ama Arch Intern Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=13123563&query_hl=1&itool=pubmed_docsum

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Treatment of sickle cell anemia. Author(s): LEAVELL BS. Source: Ama Arch Intern Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=13206460&query_hl=1&itool=pubmed_docsum

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Zinc deficiency and effects of zinc supplementation on sickle cell anemia subjects. Author(s): Prasad AS. Source: Prog Clin Biol Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7291206&query_hl=1&itool=pubmed_docsum

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

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

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AOL: http://health.aol.com/healthyliving/althealth

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Chinese Medicine: http://www.newcenturynutrition.com/

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drkoop.com: http://www.drkoop.com/naturalmedicine.html

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

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

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

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

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

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The following is a specific Web list relating to sickle cell anemia; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

General Overview Anemia Source: Integrative Medicine Communications; www.drkoop.com Night Blindness Source: Healthnotes, Inc.; www.healthnotes.com Sickle Cell Anemia Source: Healthnotes, Inc.; www.healthnotes.com Sickle Cell Anemia Source: Integrative Medicine Communications; www.drkoop.com

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Herbs and Supplements Beta-Carotene Source: Healthnotes, Inc.; www.healthnotes.com Carotenoids Source: Healthnotes, Inc.; www.healthnotes.com

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

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CHAPTER 3. PATENTS ON SICKLE CELL ANEMIA Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.7 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “sickle cell anemia“ (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on sickle cell anemia, we have not necessarily excluded nonmedical patents in this bibliography.

Patent Applications on Sickle Cell Anemia As of December 2000, U.S. patent applications are open to public viewing.8 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to sickle cell anemia:

7Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm. 8 This has been a common practice outside the United States prior to December 2000.

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Methods for treatment of sickle cell anemia Inventor(s): Chen, Long-Shiuh; (San Diego, CA), Lai, Ching-San; (Encinitas, CA), Vassilev, Vassil P.; (San Diego, CA) Correspondence: Stephen E. Reiter; Foley & Lardner; P.O. Box 80278; San Diego; CA; 92138-0278; US Patent Application Number: 20030022923 Date filed: March 12, 2002 Abstract: The preparation and use of a protected organic aldehyde is described wherein bioavailability of the orally administered therapeutic aldehyde is improved. The protected aldehyde is prepared by reacting the aldehyde with a protecting group, for example, condensing the aldehyde chemically with a thiazolidine-4-carboxylic acid. The improved bioavailability of such orally administered drugs increases the feasibility of delivering sufficient amounts of vanillin or other therapeutic organic aldehydes in vivo to prevent sickling in sickle cell anemia. Combination therapy is also described wherein a protected organic aldehyde is administered to a subject in treatment of sickle cell anemia in conjunction with one or more other drugs, such as pain killers, used in treatment of the symptoms of sickle cell anemia or sickle cell disease. Excerpt(s): The present invention generally relates to methods for treating anemia. More specifically, the present invention relates to methods for treating sickle cell anemia using protected forms(s) of organic aldehydes. Sickle cell disease is a hemolytic disorder, which affects, in its most severe form, approximately 80,000 patients in the United States (see, for example, D. L. Rucknagel, in R. D. Levere, Ed., Sickle Cell Anemia and Other Hemoglobinopathies, Academic Press, New York, 1975, p.1). The disease is caused by a single mutation in the hemoglobin molecule;.beta.6 glutamic acid in normal adult hemoglobin A is changed to valine in sickle hemoglobin S. (see, for example, V. M. Ingram in Nature, 178:792-794 (1956)). Hemoglobin S has a markedly decreased solubility in the deoxygenated state when compared to that of hemoglobin A. Therefore, upon deoxygenation, hemoglobin S molecules within the erythrocyte tend to aggregate and form helical fibers that cause the red cell to assume a variety of irregular shapes, most commonly in the sickled form. After repeated cycles of oxygenation and deoxygenation, the sickle cell in the circulation becomes rigid and no longer can squeeze through the small capillaries in tissues, resulting in delivery of insufficient oxygen and nutrients to the organ, which eventually leads to local tissue necrosis. The prolonged blockage of microvascular circulation and the subsequent induction of tissue necrosis lead to various symptoms of sickle cell anemia, including painful crises of vasoocclusion. Now, most patients with sickle cell disease can be expected to survive into adulthood, but still face a lifetime of crises and complications, including chronic hemolytic anemia, vaso-occlusive crises and pain, and the side effects of therapy. Currently, most common therapeutic interventions include blood transfusions, opioid and hydroxyurea therapies (see, for example, S. K. Ballas in Cleveland Clin. J. Med., 66:48-58 (1999). However, all of these therapies are associated with some undesirable side-effects. For example, repeated blood transfusions are known to be associated with the risks of transmission of infectious disease, iron overload, and allergic and febrile reactions. Complications of opioid therapy may include addiction, seizures, dependency, respiratory depression and constipation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Keeping Current In order to stay informed about patents and patent applications dealing with sickle cell anemia, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under Issued Patents, click Quick Search. Then, type sickle cell anemia (or a synonym) into the Term 1 box. After clicking on the search button, scroll down to see the various patents which have been granted to date on sickle cell anemia. You can also use this procedure to view pending patent applications concerning sickle cell anemia. Simply go back to http://www.uspto.gov/patft/index.html. Select Quick Search under Published Applications. Then proceed with the steps listed above.

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CHAPTER 4. BOOKS ON SICKLE CELL ANEMIA Overview This chapter provides bibliographic book references relating to sickle cell anemia. In addition to online booksellers such as www.amazon.com and www.bn.com, the National Library of Medicine is an excellent source for book titles on sickle cell anemia. Your local medical library also may have these titles available for loan.

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

21st Century Complete Medical Guide to Sickle Cell Anemia, Authoritative Government Documents, Clinical References, and Practical Information for Patients and Physicians (CD-ROM) PM Medical Health News (2004); ISBN: 1592489206; http://www.amazon.com/exec/obidos/ASIN/1592489206/icongroupinterna

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A child with sickle cell anemia in your class: (a guide for teachers) Roland B Scott (1977); ISBN: B0006YM5IK; http://www.amazon.com/exec/obidos/ASIN/B0006YM5IK/icongroupinterna

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Against All Odds: The Story of My Battle With Sickle Cell Anemia Janice Gillespie (1994); ISBN: 0966054903; http://www.amazon.com/exec/obidos/ASIN/0966054903/icongroupinterna

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An analysis of a sickle cell anemia screening program Barbara Metzger Rich (1973); ISBN: B0007AQXKO; http://www.amazon.com/exec/obidos/ASIN/B0007AQXKO/icongroupinterna

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Anesthesia and sickle cell anemia Beverley A Smith (1992); ISBN: B0006P3GEG; http://www.amazon.com/exec/obidos/ASIN/B0006P3GEG/icongroupinterna

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Back to Our Roots: Cooking for Control of Sickle Cell Anemia and Cancer Prevention Dawud Ujamaa (1995); ISBN: 1884938019; http://www.amazon.com/exec/obidos/ASIN/1884938019/icongroupinterna

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Concentrations of B vitamins and homocysteine in children with sickle cell anemia.(Original Article): An article from: Southern Medical Journal Jodi B. Segal, Edgar R., III Miller, Nga Hong Brereton, and Linda M.S. Resar (2005); ISBN: B00081UZTM; http://www.amazon.com/exec/obidos/ASIN/B00081UZTM/icongroupinterna

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Crystals in My Bones: One Sickle Cell Anemia Journey Bern Brewer (2005); ISBN: 1420842277; http://www.amazon.com/exec/obidos/ASIN/1420842277/icongroupinterna

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Delayed skeletal maturation in sickle cell anemia in Jamaica Graham R Serjeant (1973); ISBN: B0007C39YA; http://www.amazon.com/exec/obidos/ASIN/B0007C39YA/icongroupinterna

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Depression and ego integration manifested in drawings of adolescents with sickle cell anemia: A pilot study Kathryn D'Arcy Lyness (1979); ISBN: B00071213G; http://www.amazon.com/exec/obidos/ASIN/B00071213G/icongroupinterna

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Dying in the City of the Blues: Sickle Cell Anemia and the Politics of Race and Health Keith Wailoo (2001); ISBN: 0807848964; http://www.amazon.com/exec/obidos/ASIN/0807848964/icongroupinterna

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Estimating rates of psychosocial problems in urban and poor children with sickle cell anemia. (Special Issue on Women and Children): An article from: Health and Social Work Oscar A. Barbarin, Charles F. Whitten, and Sandy M. Bonds (2005); ISBN: B000921UT4; http://www.amazon.com/exec/obidos/ASIN/B000921UT4/icongroupinterna

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Gale Encyclopedia of Alternative Medicine: Sickle cell anemia Beth Kapes (2004); ISBN: B0006VHRLI; http://www.amazon.com/exec/obidos/ASIN/B0006VHRLI/icongroupinterna

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Hope and Destiny: A Patient's and Parent's Guide to Sickle Cell Anemia Allan Platt and Alan Sacerdote (2006); ISBN: 0976444356; http://www.amazon.com/exec/obidos/ASIN/0976444356/icongroupinterna

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How I cope with sickle cell anemia: By Joseph R. Phillips Joseph R Phillips (1976); ISBN: B000729FHK; http://www.amazon.com/exec/obidos/ASIN/B000729FHK/icongroupinterna

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Hydroxyurea extends life span in adult sickle cell anemia. (Upto 9 years of Followup).: An article from: Internal Medicine News Heidi Splete (2005); ISBN: B0008DJ2MG; http://www.amazon.com/exec/obidos/ASIN/B0008DJ2MG/icongroupinterna

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In the Blood: Sickle Cell Anemia and the Politics of Race (Critical Histories) Melbourne Tapper (1999); ISBN: 0812234715; http://www.amazon.com/exec/obidos/ASIN/0812234715/icongroupinterna

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Law, medicine and public policy: The Sickle Cell Anemia Control Act of 1972, a case study Robert Milton Schmidt (1982); ISBN: B0007AVU0C; http://www.amazon.com/exec/obidos/ASIN/B0007AVU0C/icongroupinterna

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Let's Talk About Sickle Cell Anemia (Let's Talk Library) Melanie Apel Gordon (1999); ISBN: 082395417X; http://www.amazon.com/exec/obidos/ASIN/082395417X/icongroupinterna

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Medicine, culture, and sickle cell disease.(Dying in the City of the Blues: Sickle Cell Anemia and the Politics of Race and Health): An article from: The Hastings Center Report Troy Duster (2005); ISBN: B0008FDXXI; http://www.amazon.com/exec/obidos/ASIN/B0008FDXXI/icongroupinterna

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Modulation of fetal hemoglobin in sickle cell anemia. Alex. Saleh (1998); ISBN: B000GS0D12; http://www.amazon.com/exec/obidos/ASIN/B000GS0D12/icongroupinterna

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Myonecrosis in sickle cell anemia: case report and review of the literature.(Case Report): An article from: Southern Medical Journal Perla Vicari, Ruth Achkar, Kathia R.B. Oliveira, and Milton L. Miszpupten (2005); ISBN: B000848LAY; http://www.amazon.com/exec/obidos/ASIN/B000848LAY/icongroupinterna

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New hope for people with sickle cell anemia (SuDoc HE 20.4010/A:SI 1/997) Eleanor Mayfield; ISBN: B00010V8TG; http://www.amazon.com/exec/obidos/ASIN/B00010V8TG/icongroupinterna

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NHLBI sickle cell and stroke risk trial halted: young sickle cell anemia patients who are at high risk for stroke can't forgo regular blood transfusions.(Clinical. An article from: Family Practice News Doug Brunk (2006); ISBN: B00096TEUM; http://www.amazon.com/exec/obidos/ASIN/B00096TEUM/icongroupinterna

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Pain and Sickle Cell Anemia.(discussion of patient-controlled analgesia): An article from: The Hastings Center Report David Resnik, Marsha Rehm, and Ben A. Rich (2005); ISBN: B0008I4DDE; http://www.amazon.com/exec/obidos/ASIN/B0008I4DDE/icongroupinterna

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Shortening of the digits in sickle cell anemia: A sequela of the hand-foot syndrome Graham R Serjeant (1971); ISBN: B0007C3LXE; http://www.amazon.com/exec/obidos/ASIN/B0007C3LXE/icongroupinterna

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Sickle Cell Anemia - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References ICON Health Publications (2004); ISBN: 0597843104; http://www.amazon.com/exec/obidos/ASIN/0597843104/icongroupinterna

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Sickle Cell Anemia (Diseases and People) Alvin Silverstein, Virginia B. Silverstein, and Laura Silverstein Nunn (1997); ISBN: 0894907115; http://www.amazon.com/exec/obidos/ASIN/0894907115/icongroupinterna

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Sickle cell anemia (Hematologic diseases in children) Philip Lanzkowsky (1976); ISBN: B0006XM9FK; http://www.amazon.com/exec/obidos/ASIN/B0006XM9FK/icongroupinterna

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Sickle cell anemia (LC science tracer bullet) Leroy D Davis (1982); ISBN: B0006Y83S6; http://www.amazon.com/exec/obidos/ASIN/B0006Y83S6/icongroupinterna

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Sickle cell anemia (SuDoc HE 20.3031:Si 1) U.S. Dept of Health and Human Services (1990); ISBN: B0001058C4; http://www.amazon.com/exec/obidos/ASIN/B0001058C4/icongroupinterna

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Sickle Cell Anemia (Venture Bks.) George (editor) Beshore (1994); ISBN: B000LU5PYK; http://www.amazon.com/exec/obidos/ASIN/B000LU5PYK/icongroupinterna

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Sickle cell anemia and your child: Questions and answers on sickle cell anemia for parents Roland B Scott (1971); ISBN: B0006WHZG4; http://www.amazon.com/exec/obidos/ASIN/B0006WHZG4/icongroupinterna

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Sickle cell anemia fact book Robert B Scott (1974); ISBN: B0006YWK1W; http://www.amazon.com/exec/obidos/ASIN/B0006YWK1W/icongroupinterna

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Sickle cell anemia research in Memphis: Interview with Alfred P. Kraus, M.D., October 27, 1989 Frankie L Winchester (1989); ISBN: B00072BHBM; http://www.amazon.com/exec/obidos/ASIN/B00072BHBM/icongroupinterna

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Sickle cell/stroke prevention trim halted.(News)(Stroke Prevention Trial in Sickle Cell Anemia II): An article from: Pediatric News Doug Brunk (2005); ISBN: B00081XUNK; http://www.amazon.com/exec/obidos/ASIN/B00081XUNK/icongroupinterna

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Skin manifestations of sickle cell anemia, Thomas Hodge McGavack (1942); ISBN: B0007FWRL8; http://www.amazon.com/exec/obidos/ASIN/B0007FWRL8/icongroupinterna

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The 2002 Official Patient's Sourcebook on Sickle Cell Anemia James N. Parker and Philip M. Parker (2002); ISBN: 0597831572; http://www.amazon.com/exec/obidos/ASIN/0597831572/icongroupinterna

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The Early Life of Jeomie East: Struggling With Sickle Cell Anemia Phyllis East (2002); ISBN: 0759668019; http://www.amazon.com/exec/obidos/ASIN/0759668019/icongroupinterna

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The feasibility of using ethnicity as a primary tool for antenatal selective screening for sickle cell disorders: pointers from the research evidence P.J. Aspinall, S.M. Dyson, and E.N. Anionwu (2003); ISBN: B000MCHLO4; http://www.amazon.com/exec/obidos/ASIN/B000MCHLO4/icongroupinterna

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The Official Patient's Sourcebook on Sickle Cell Anemia: Directory for the Internet Age Icon Health Publications (1980); ISBN: B000MUBFKW; http://www.amazon.com/exec/obidos/ASIN/B000MUBFKW/icongroupinterna

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The role of the occupational health nurse in genetic counseling of sickle cell anemia Gertrude L. McNally White (1973); ISBN: B0007ARC7C; http://www.amazon.com/exec/obidos/ASIN/B0007ARC7C/icongroupinterna

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The Sickle Cell Anemia Update (Disease Update) Alvin Silverstein, Virginia B. Silverstein, and Laura Silverstein Nunn (2006); ISBN: 0766024792; http://www.amazon.com/exec/obidos/ASIN/0766024792/icongroupinterna

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Zoology and Entomology.(Symposium on Sickle Cell Anemia and Its Prevalence among Blacks in some Southern States of the USA): An article from: Journal of the Mississippi Academy of Sciences (2005); ISBN: B0008IS6J6; http://www.amazon.com/exec/obidos/ASIN/B0008IS6J6/icongroupinterna

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select LocatorPlus. Once you are in the search area, simply type sickle cell anemia (or synonyms) into the search box, and select the Quick Limit Option for Keyword, Title, or Journal Title Search: Books. From there, results can be sorted

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by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine9: •

Amendments to revise programs for sickle cell anemia and other genetic disorders, 1975: hearing. Ninety-fourth Congress, first session, on S. 1619. S. 1620. S. 1714. S. 1715. July 15, 1975. Author: United States. Congress. Senate. Committee on Labor and Public Welfare. Subcommittee on Health.; Year: 1975; Washington: U. S. Govt. Print. Off., 1976

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National sickle cell anemia act: report to accompany S. 2676. Author: United States. Congress. Senate. Committee on Labor and Public Welfare.; Year: 1971; Washington: Govt. Print. Off.], 1971

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Research, treatment, and prevention of sickle cell anemia. Hearing. Ninety-second Congress, first session, on H. R. 11742, H. R. 7654, and H. R. 11171. November 12, 1971. Author: United States. Congress. House. Committee on Interstate and Foreign Commerce. Subcommittee on Public Health and Environment.; Year: 1972; Washington, U. S. Govt. Print. Off., 1972

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Sickle cell anemia: a selected annotated bibliography Author: Davis, Lenwood G.; Newark, Del.: National Black Bibliographic and Research Center, 1978-

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Sickle cell anemia and other hemoglobinopathies. Edited by Richard D. Levere. Author: Levere, Richard D.; Year: 1975; New York, Academic Press, 1975; ISBN: 9780124447 http://www.amazon.com/exec/obidos/ASIN/9780124447/icongroupinterna

9 In addition to LocatorPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a Books button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

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CHAPTER 5. MULTIMEDIA ON SICKLE CELL ANEMIA Overview In this chapter, we show you how to find bibliographic information related to multimedia sources of information on sickle cell anemia.

Bibliography: Multimedia on Sickle Cell Anemia The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select LocatorPlus. Once you are in the search area, simply type sickle cell anemia (or synonyms) into the search box, and select the Quick Limit Option for Keyword, Title, or Journal Title Search: Audiovisuals and Computer Files. From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on sickle cell anemia: •

Clinical alert, drug treatment for sickle cell anemia [electronic resource] Source: National Heart, Lung, and Blood Institute (NHLBI); Year: 1995; Format: Electronic resource; Bethesda, MD: U.S. National Library of Medicine, National Institutes of Health, Health & Human Services, 1995

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Clinical alert, NHLBI stops study testing how long children with sickle cell anemia should have blood transfusions to prevent stroke [electronic resource] Source: United States National Library of Medicine, National Institutes of Health; Year: 2004; Format: Electronic resource; Bethesda, MD: U.S. National Library of Medicine, National Institutes of Health, Health & Human Services, 2004

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Clinical alert, periodic transfusions lower stroke risk in children with sickle cell anemia [electronic resource] Source: National Heart, Lung, and Blood Institute (NHLBI); Year: 1997; Format: Electronic resource; Bethesda, MD: U.S. National Library of Medicine, National Institutes of Health, Health & Human Services, 1977

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Sickle cell anemia [motion picture] Source: produced in cooperation with the University of Chicago, Comprehensive Sickle Cell Center; [produced by] Learning Garden; Year: 1975; Format: Motion picture; Chicago: The University, c1975

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Sickle cell anemia [slide] Source: David J. Gerrick; Year: 1979; Format: Slide; Lorain, OH: Dayton Lab, c1979

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Sickle cell anemia [videorecording] Source: AHC, Association of Academic Health Centers; CenterNet; produced by International Information Resources; produced in cooperation with the Medical Arts and Photography Branch, National Institutes of Health; Year: 2000; Format: Videorecording; Bethesda, Md.]: National Institutes of Health, [2000]

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Sickle cell anemia [videorecording]: the facts Source: Virginia Sickle Cell Anemia Awareness Program of the Medical College of Virginia/VCU; produced by Visual Education Dept., Medical College of Virginia; Year: 1978; Format: Videorecording; Richmond: The College: [for loan or sale by its Learning Resource Centers], 1978

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Sickle cell anemia with pericardial friction rub [videorecording] Source: [presented by] the Texas Heart Institute; Year: 1982; Format: Videorecording; Houston, Tex.]: The Institute, 1982

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The Management of sickle cell anemia and evaluation of treatment programs [videorecording] Source: presented by Department of Pediatrics, Emory Univ., School of Medicine; Year: 1977; Format: Videorecording; Atlanta: Georgia Regional Medical Television Network, [1977]

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APPENDIX A. HELP ME UNDERSTAND GENETICS Overview This appendix presents basic information about genetics in clear language and provides links to online resources.10

The Basics: Genes and How They Work This section gives you information on the basics of cells, DNA, genes, chromosomes, and proteins.

What Is a Cell? Cells are the basic building blocks of all living things. The human body is composed of trillions of cells. They provide structure for the body, take in nutrients from food, convert those nutrients into energy, and carry out specialized functions. Cells also contain the body’s hereditary material and can make copies of themselves. Cells have many parts, each with a different function. Some of these parts, called organelles, are specialized structures that perform certain tasks within the cell. Human cells contain the following major parts, listed in alphabetical order: •

Cytoplasm: The cytoplasm is fluid inside the cell that surrounds the organelles.

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Endoplasmic reticulum (ER): This organelle helps process molecules created by the cell and transport them to their specific destinations either inside or outside the cell.

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Golgi apparatus: The golgi apparatus packages molecules processed by the endoplasmic reticulum to be transported out of the cell.

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Lysosomes and peroxisomes: These organelles are the recycling center of the cell. They digest foreign bacteria that invade the cell, rid the cell of toxic substances, and recycle worn-out cell components.

10 This appendix is an excerpt from the National Library of Medicine’s handbook, Help Me Understand Genetics. For the full text of the Help Me Understand Genetics handbook, see http://ghr.nlm.nih.gov/handbook.

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•

Mitochondria: Mitochondria are complex organelles that convert energy from food into a form that the cell can use. They have their own genetic material, separate from the DNA in the nucleus, and can make copies of themselves.

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Nucleus: The nucleus serves as the cell’s command center, sending directions to the cell to grow, mature, divide, or die. It also houses DNA (deoxyribonucleic acid), the cell’s hereditary material. The nucleus is surrounded by a membrane called the nuclear envelope, which protects the DNA and separates the nucleus from the rest of the cell.

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Plasma membrane: The plasma membrane is the outer lining of the cell. It separates the cell from its environment and allows materials to enter and leave the cell.

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Ribosomes: Ribosomes are organelles that process the cell’s genetic instructions to create proteins. These organelles can float freely in the cytoplasm or be connected to the endoplasmic reticulum.

What Is DNA? DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA). The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion bases, and more than 99 percent of those bases are the same in all people. The order, or sequence, of these bases determines the information available for building and maintaining an organism, similar to the way in which letters of the alphabet appear in a certain order to form words and sentences. DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladder’s rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder. An important property of DNA is that it can replicate, or make copies of itself. Each strand of DNA in the double helix can serve as a pattern for duplicating the sequence of bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA present in the old cell.

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DNA is a double helix formed by base pairs attached to a sugar-phosphate backbone.

What Is Mitochondrial DNA? Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Each cell contains hundreds to thousands of mitochondria, which are located in the fluid that surrounds the nucleus (the cytoplasm). Mitochondria produce energy through a process called oxidative phosphorylation. This process uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell’s main energy source. A set of enzyme complexes, designated as complexes I-V, carry out oxidative phosphorylation within mitochondria. In addition to energy production, mitochondria play a role in several other cellular activities. For example, mitochondria help regulate the self-destruction of cells (apoptosis). They are also necessary for the production of substances such as cholesterol and heme (a component of hemoglobin, the molecule that carries oxygen in the blood). Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation. The remaining genes provide instructions for making molecules called transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), which are chemical cousins of

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DNA. These types of RNA help assemble protein building blocks (amino acids) into functioning proteins.

What Is a Gene? A gene is the basic physical and functional unit of heredity. Genes, which are made up of DNA, act as instructions to make molecules called proteins. In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. The Human Genome Project has estimated that humans have between 20,000 and 25,000 genes. Every person has two copies of each gene, one inherited from each parent. Most genes are the same in all people, but a small number of genes (less than 1 percent of the total) are slightly different between people. Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person’s unique physical features.

Genes are made up of DNA. Each chromosome contains many genes.

What Is a Chromosome? In the nucleus of each cell, the DNA molecule is packaged into thread-like structures called chromosomes. Each chromosome is made up of DNA tightly coiled many times around proteins called histones that support its structure. Chromosomes are not visible in the cell’s nucleus—not even under a microscope—when the cell is not dividing. However, the DNA that makes up chromosomes becomes more tightly packed during cell division and is then visible under a microscope. Most of what researchers know about chromosomes was learned by observing chromosomes during cell division. Each chromosome has a constriction point called the centromere, which divides the chromosome into two sections, or “arms.” The short arm of the chromosome is labeled the “p arm.” The long arm of the chromosome is labeled the “q arm.” The location of the centromere on each chromosome gives the chromosome its characteristic shape, and can be used to help describe the location of specific genes.

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DNA and histone proteins are packaged into structures called chromosomes.

How Many Chromosomes Do People Have? In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46. Twentytwo of these pairs, called autosomes, look the same in both males and females. The 23rd pair, the sex chromosomes, differ between males and females. Females have two copies of the X chromosome, while males have one X and one Y chromosome.

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The 22 autosomes are numbered by size. The other two chromosomes, X and Y, are the sex chromosomes. This picture of the human chromosomes lined up in pairs is called a karyotype.

How Do Geneticists Indicate the Location of a Gene? Geneticists use maps to describe the location of a particular gene on a chromosome. One type of map uses the cytogenetic location to describe a gene’s position. The cytogenetic location is based on a distinctive pattern of bands created when chromosomes are stained with certain chemicals. Another type of map uses the molecular location, a precise description of a gene’s position on a chromosome. The molecular location is based on the sequence of DNA building blocks (base pairs) that make up the chromosome.

Cytogenetic Location Geneticists use a standardized way of describing a gene’s cytogenetic location. In most cases, the location describes the position of a particular band on a stained chromosome: 17q12 It can also be written as a range of bands, if less is known about the exact location: 17q12-q21 The combination of numbers and letters provide a gene’s “address” on a chromosome. This address is made up of several parts: •

The chromosome on which the gene can be found. The first number or letter used to describe a gene’s location represents the chromosome. Chromosomes 1 through 22 (the autosomes) are designated by their chromosome number. The sex chromosomes are designated by X or Y.

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•

The arm of the chromosome. Each chromosome is divided into two sections (arms) based on the location of a narrowing (constriction) called the centromere. By convention, the shorter arm is called p, and the longer arm is called q. The chromosome arm is the second part of the gene’s address. For example, 5q is the long arm of chromosome 5, and Xp is the short arm of the X chromosome.

•

The position of the gene on the p or q arm. The position of a gene is based on a distinctive pattern of light and dark bands that appear when the chromosome is stained in a certain way. The position is usually designated by two digits (representing a region and a band), which are sometimes followed by a decimal point and one or more additional digits (representing sub-bands within a light or dark area). The number indicating the gene position increases with distance from the centromere. For example: 14q21 represents position 21 on the long arm of chromosome 14. 14q21 is closer to the centromere than 14q22.

Sometimes, the abbreviations “cen” or “ter” are also used to describe a gene’s cytogenetic location. “Cen” indicates that the gene is very close to the centromere. For example, 16pcen refers to the short arm of chromosome 16 near the centromere. “Ter” stands for terminus, which indicates that the gene is very close to the end of the p or q arm. For example, 14qter refers to the tip of the long arm of chromosome 14. (“Tel” is also sometimes used to describe a gene’s location. “Tel” stands for telomeres, which are at the ends of each chromosome. The abbreviations “tel” and “ter” refer to the same location.)

The CFTR gene is located on the long arm of chromosome 7 at position 7q31.2.

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Molecular Location The Human Genome Project, an international research effort completed in 2003, determined the sequence of base pairs for each human chromosome. This sequence information allows researchers to provide a more specific address than the cytogenetic location for many genes. A gene’s molecular address pinpoints the location of that gene in terms of base pairs. For example, the molecular location of the APOE gene on chromosome 19 begins with base pair 50,100,901 and ends with base pair 50,104,488. This range describes the gene’s precise position on chromosome 19 and indicates the size of the gene (3,588 base pairs). Knowing a gene’s molecular location also allows researchers to determine exactly how far the gene is from other genes on the same chromosome. Different groups of researchers often present slightly different values for a gene’s molecular location. Researchers interpret the sequence of the human genome using a variety of methods, which can result in small differences in a gene’s molecular address. For example, the National Center for Biotechnology Information (NCBI) identifies the molecular location of the APOE gene as base pair 50,100,901 to base pair 50,104,488 on chromosome 19. The Ensembl database identifies the location of this gene as base pair 50,100,879 to base pair 50,104,489 on chromosome 19. Neither of these addresses is incorrect; they represent different interpretations of the same data. For consistency, Genetics Home Reference presents data from NCBI for the molecular location of genes.

What Are Proteins and What Do They Do? Proteins are large, complex molecules that play many critical roles in the body. They do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs. Proteins are made up of hundreds or thousands of smaller units called amino acids, which are attached to one another in long chains. There are 20 different types of amino acids that can be combined to make a protein. The sequence of amino acids determines each protein’s unique 3-dimensional structure and its specific function.

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Examples of Protein Functions Proteins can be described according to their large range of functions in the body, listed in alphabetical order: Function Antibody

Description Antibodies bind to specific foreign particles, such as viruses and bacteria, to help protect the body.

Example Immunoglobulin G (IgG)

Enzyme

Enzymes carry out almost all of the thousands of chemical reactions that take place in cells. They also assist with the formation of new molecules by reading the genetic information stored in DNA.

Phenylalanine hydroxylase

Messenger

Messenger proteins, such as some types of hormones, transmit signals to coordinate biological processes between different cells, tissues, and organs.

Growth hormone

Structural component

These proteins provide structure and support for cells. On a larger scale, they also allow the body to move. These proteins bind and carry atoms and small molecules within cells and throughout the body.

Actin

Transport/storage

Ferritin

How Does a Gene Make a Protein? Most genes contain the information needed to make functional molecules called proteins. (A few genes produce other molecules that help the cell assemble proteins.) The journey from gene to protein is complex and tightly controlled within each cell. It consists of two major steps: transcription and translation. Together, transcription and translation are known as gene expression. During the process of transcription, the information stored in a gene’s DNA is transferred to a similar molecule called RNA (ribonucleic acid) in the cell nucleus. Both RNA and DNA are made up of a chain of nucleotide bases, but they have slightly different chemical properties. The type of RNA that contains the information for making a protein is called messenger RNA (mRNA) because it carries the information, or message, from the DNA out of the nucleus into the cytoplasm. Translation, the second step in getting from a gene to a protein, takes place in the cytoplasm. The mRNA interacts with a specialized complex called a ribosome, which “reads” the sequence of mRNA bases. Each sequence of three bases, called a codon, usually codes for

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one particular amino acid. (Amino acids are the building blocks of proteins.) A type of RNA called transfer RNA (tRNA) assembles the protein, one amino acid at a time. Protein assembly continues until the ribosome encounters a “stop” codon (a sequence of three bases that does not code for an amino acid). The flow of information from DNA to RNA to proteins is one of the fundamental principles of molecular biology. It is so important that it is sometimes called the “central dogma.”

Through the processes of transcription and translation, information from genes is used to make proteins.

Can Genes Be Turned On and Off in Cells? Each cell expresses, or turns on, only a fraction of its genes. The rest of the genes are repressed, or turned off. The process of turning genes on and off is known as gene regulation. Gene regulation is an important part of normal development. Genes are turned on and off in different patterns during development to make a brain cell look and act different from a liver cell or a muscle cell, for example. Gene regulation also allows cells to react quickly to changes in their environments. Although we know that the regulation of genes is critical for life, this complex process is not yet fully understood. Gene regulation can occur at any point during gene expression, but most commonly occurs at the level of transcription (when the information in a gene’s DNA is transferred to mRNA). Signals from the environment or from other cells activate proteins called transcription factors. These proteins bind to regulatory regions of a gene and increase or decrease the level of transcription. By controlling the level of transcription, this process can determine the amount of protein product that is made by a gene at any given time.

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How Do Cells Divide? There are two types of cell division: mitosis and meiosis. Most of the time when people refer to “cell division,” they mean mitosis, the process of making new body cells. Meiosis is the type of cell division that creates egg and sperm cells. Mitosis is a fundamental process for life. During mitosis, a cell duplicates all of its contents, including its chromosomes, and splits to form two identical daughter cells. Because this process is so critical, the steps of mitosis are carefully controlled by a number of genes. When mitosis is not regulated correctly, health problems such as cancer can result. The other type of cell division, meiosis, ensures that humans have the same number of chromosomes in each generation. It is a two-step process that reduces the chromosome number by half—from 46 to 23—to form sperm and egg cells. When the sperm and egg cells unite at conception, each contributes 23 chromosomes so the resulting embryo will have the usual 46. Meiosis also allows genetic variation through a process of DNA shuffling while the cells are dividing.

Mitosis and meiosis, the two types of cell division.

How Do Genes Control the Growth and Division of Cells? A variety of genes are involved in the control of cell growth and division. The cell cycle is the cell’s way of replicating itself in an organized, step-by-step fashion. Tight regulation of this process ensures that a dividing cell’s DNA is copied properly, any errors in the DNA are repaired, and each daughter cell receives a full set of chromosomes. The cycle has checkpoints (also called restriction points), which allow certain genes to check for mistakes and halt the cycle for repairs if something goes wrong.

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If a cell has an error in its DNA that cannot be repaired, it may undergo programmed cell death (apoptosis). Apoptosis is a common process throughout life that helps the body get rid of cells it doesn’t need. Cells that undergo apoptosis break apart and are recycled by a type of white blood cell called a macrophage. Apoptosis protects the body by removing genetically damaged cells that could lead to cancer, and it plays an important role in the development of the embryo and the maintenance of adult tissues. Cancer results from a disruption of the normal regulation of the cell cycle. When the cycle proceeds without control, cells can divide without order and accumulate genetic defects that can lead to a cancerous tumor.

Genetic Mutations and Health This section presents basic information about gene mutations, chromosomal changes, and conditions that run in families.11

What Is a Gene Mutation and How Do Mutations Occur? A gene mutation is a permanent change in the DNA sequence that makes up a gene. Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome. Gene mutations occur in two ways: they can be inherited from a parent or acquired during a person’s lifetime. Mutations that are passed from parent to child are called hereditary mutations or germline mutations (because they are present in the egg and sperm cells, which are also called germ cells). This type of mutation is present throughout a person’s life in virtually every cell in the body. Mutations that occur only in an egg or sperm cell, or those that occur just after fertilization, are called new (de novo) mutations. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder. Acquired (or somatic) mutations occur in the DNA of individual cells at some time during a person’s life. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation. Mutations may also occur in a single cell within an early embryo. As all the cells divide during growth and development, the individual will have some cells with the mutation and some cells without the genetic change. This situation is called mosaicism. Some genetic changes are very rare; others are common in the population. Genetic changes that occur in more than 1 percent of the population are called polymorphisms. They are common enough to be considered a normal variation in the DNA. Polymorphisms are

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This section has been adapted from the National Library of Medicine’s handbook, Help Me Understand Genetics, which presents basic information about genetics in clear language and provides links to online resources: http://ghr.nlm.nih.gov/handbook.

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responsible for many of the normal differences between people such as eye color, hair color, and blood type. Although many polymorphisms have no negative effects on a person’s health, some of these variations may influence the risk of developing certain disorders.

How Can Gene Mutations Affect Health and Development? To function correctly, each cell depends on thousands of proteins to do their jobs in the right places at the right times. Sometimes, gene mutations prevent one or more of these proteins from working properly. By changing a gene’s instructions for making a protein, a mutation can cause the protein to malfunction or to be missing entirely. When a mutation alters a protein that plays a critical role in the body, it can disrupt normal development or cause a medical condition. A condition caused by mutations in one or more genes is called a genetic disorder. In some cases, gene mutations are so severe that they prevent an embryo from surviving until birth. These changes occur in genes that are essential for development, and often disrupt the development of an embryo in its earliest stages. Because these mutations have very serious effects, they are incompatible with life. It is important to note that genes themselves do not cause disease—genetic disorders are caused by mutations that make a gene function improperly. For example, when people say that someone has “the cystic fibrosis gene,” they are usually referring to a mutated version of the CFTR gene, which causes the disease. All people, including those without cystic fibrosis, have a version of the CFTR gene.

Do All Gene Mutations Affect Health and Development? No, only a small percentage of mutations cause genetic disorders—most have no impact on health or development. For example, some mutations alter a gene’s DNA base sequence but do not change the function of the protein made by the gene. Often, gene mutations that could cause a genetic disorder are repaired by certain enzymes before the gene is expressed (makes a protein). Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, DNA repair is an important process by which the body protects itself from disease. A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment. For example, a beneficial mutation could result in a protein that protects the organism from a new strain of bacteria.

For More Information about DNA Repair and the Health Effects of Gene Mutations •

The University of Utah Genetic Science Learning Center provides information about genetic disorders that explains why some mutations cause disorders but others do not. (Refer to the questions in the far right column.) See http://learn.genetics.utah.edu/units/disorders/whataregd/.

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Additional information about DNA repair is available from the NCBI Science Primer. In the chapter called “What Is A Cell?”, scroll down to the heading “DNA Repair Mechanisms.” See http://www.ncbi.nlm.nih.gov/About/primer/genetics_cell.html.

What Kinds of Gene Mutations Are Possible? The DNA sequence of a gene can be altered in a number of ways. Gene mutations have varying effects on health, depending on where they occur and whether they alter the function of essential proteins. The types of mutations include: •

Missense mutation: This type of mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene.

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Nonsense mutation: A nonsense mutation is also a change in one DNA base pair. Instead of substituting one amino acid for another, however, the altered DNA sequence prematurely signals the cell to stop building a protein. This type of mutation results in a shortened protein that may function improperly or not at all.

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Insertion: An insertion changes the number of DNA bases in a gene by adding a piece of DNA. As a result, the protein made by the gene may not function properly.

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Deletion: A deletion changes the number of DNA bases by removing a piece of DNA. Small deletions may remove one or a few base pairs within a gene, while larger deletions can remove an entire gene or several neighboring genes. The deleted DNA may alter the function of the resulting protein(s).

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Duplication: A duplication consists of a piece of DNA that is abnormally copied one or more times. This type of mutation may alter the function of the resulting protein.

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Frameshift mutation: This type of mutation occurs when the addition or loss of DNA bases changes a gene’s reading frame. A reading frame consists of groups of 3 bases that each code for one amino acid. A frameshift mutation shifts the grouping of these bases and changes the code for amino acids. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations.

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Repeat expansion: Nucleotide repeats are short DNA sequences that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of 3-base-pair sequences, and a tetranucleotide repeat is made up of 4-base-pair sequences. A repeat expansion is a mutation that increases the number of times that the short DNA sequence is repeated. This type of mutation can cause the resulting protein to function improperly.

Can Changes in Chromosomes Affect Health and Development? Changes that affect entire chromosomes or segments of chromosomes can cause problems with growth, development, and function of the body’s systems. These changes can affect many genes along the chromosome and alter the proteins made by those genes. Conditions caused by a change in the number or structure of chromosomes are known as chromosomal disorders. Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes in each cell. A change in the number of chromosomes leads to a chromosomal disorder. These changes can occur during the formation of reproductive cells (eggs and sperm) or in early fetal development. A gain or loss of chromosomes from the normal 46 is called aneuploidy.

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The most common form of aneuploidy is trisomy, or the presence of an extra chromosome in each cell. “Tri-” is Greek for “three”; people with trisomy have three copies of a particular chromosome in each cell instead of the normal two copies. Down syndrome is an example of a condition caused by trisomy—people with Down syndrome typically have three copies of chromosome 21 in each cell, for a total of 47 chromosomes per cell. Monosomy, or the loss of one chromosome from each cell, is another kind of aneuploidy. “Mono-” is Greek for “one”; people with monosomy have one copy of a particular chromosome in each cell instead of the normal two copies. Turner syndrome is a condition caused by monosomy. Women with Turner syndrome are often missing one copy of the X chromosome in every cell, for a total of 45 chromosomes per cell. Chromosomal disorders can also be caused by changes in chromosome structure. These changes are caused by the breakage and reunion of chromosome segments when an egg or sperm cell is formed or in early fetal development. Pieces of DNA can be rearranged within one chromosome, or transferred between two or more chromosomes. The effects of structural changes depend on their size and location. Many different structural changes are possible; some cause medical problems, while others may have no effect on a person’s health. Many cancer cells also have changes in their chromosome number or structure. These changes most often occur in somatic cells (cells other than eggs and sperm) during a person’s lifetime.

Can Changes in Mitochondrial DNA Affect Health and Development? Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA). In some cases, inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body’s systems. These mutations disrupt the mitochondria’s ability to generate energy efficiently for the cell. Conditions caused by mutations in mitochondrial DNA often involve multiple organ systems. The effects of these conditions are most pronounced in organs and tissues that require a lot of energy (such as the heart, brain, and muscles). Although the health consequences of inherited mitochondrial DNA mutations vary widely, frequently observed features include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision. Mitochondrial DNA is also prone to noninherited (somatic) mutations. Somatic mutations occur in the DNA of certain cells during a person’s lifetime, and typically are not passed to future generations. Because mitochondrial DNA has a limited ability to repair itself when it is damaged, these mutations tend to build up over time. A buildup of somatic mutations in mitochondrial DNA has been associated with some forms of cancer and an increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease. Additionally, research suggests that the progressive accumulation of these mutations over a person’s lifetime may play a role in the normal process of aging.

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What Are Complex or Multifactorial Disorders? Researchers are learning that nearly all conditions and diseases have a genetic component. Some disorders, such as sickle cell anemia and cystic fibrosis, are caused by mutations in a single gene. The causes of many other disorders, however, are much more complex. Common medical problems such as heart disease, diabetes, and obesity do not have a single genetic cause—they are likely associated with the effects of multiple genes in combination with lifestyle and environmental factors. Conditions caused by many contributing factors are called complex or multifactorial disorders. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. By 2010, however, researchers predict they will have found the major contributing genes for many common complex disorders.

What Information about a Genetic Condition Can Statistics Provide? Statistical data can provide general information about how common a condition is, how many people have the condition, or how likely it is that a person will develop the condition. Statistics are not personalized, however—they offer estimates based on groups of people. By taking into account a person’s family history, medical history, and other factors, a genetics professional can help interpret what statistics mean for a particular patient.

Common Statistical Terms Some statistical terms are commonly used when describing genetic conditions and other disorders. These terms include: Statistical Term Incidence

Description The incidence of a gene mutation or a genetic disorder is the number of people who are born with the mutation or disorder in a specified group per year. Incidence is often written in the form “1 in [a number]” or as a total number of live births.

Examples About 1 in 200,000 people in the United States are born with syndrome A each year. An estimated 15,000 infants with syndrome B were born last year worldwide.

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Prevalence

The prevalence of a gene mutation or a genetic disorder is the total number of people in a specified group at a given time who have the mutation or disorder. This term includes both newly diagnosed and preexisting cases in people of any age. Prevalence is often written in the form “1 in [a number]” or as a total number of people who have a condition.

Approximately 1 in 100,000 people in the United States have syndrome A at the present time. About 100,000 children worldwide currently have syndrome B.

Mortality

Mortality is the number of deaths from a particular disorder occurring in a specified group per year. Mortality is usually expressed as a total number of deaths.

An estimated 12,000 people worldwide died from syndrome C in 2002.

Lifetime risk

Lifetime risk is the average risk of developing a particular disorder at some point during a lifetime. Lifetime risk is often written as a percentage or as “1 in [a number].” It is important to remember that the risk per year or per decade is much lower than the lifetime risk. In addition, other factors may increase or decrease a person’s risk as compared with the average.

Approximately 1 percent of people in the United States develop disorder D during their lifetimes. The lifetime risk of developing disorder D is 1 in 100.

Naming Genetic Conditions Genetic conditions are not named in one standard way (unlike genes, which are given an official name and symbol by a formal committee). Doctors who treat families with a particular disorder are often the first to propose a name for the condition. Expert working groups may later revise the name to improve its usefulness. Naming is important because it allows accurate and effective communication about particular conditions, which will ultimately help researchers find new approaches to treatment. Disorder names are often derived from one or a combination of sources: •

The basic genetic or biochemical defect that causes the condition (for example, alpha-1 antitrypsin deficiency)

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One or more major signs or symptoms of the disorder (for example, sickle cell anemia)

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The parts of the body affected by the condition (for example, retinoblastoma)

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The name of a physician or researcher, often the first person to describe the disorder (for example, Marfan syndrome, which was named after Dr. Antoine Bernard-Jean Marfan)

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A geographic area (for example, familial Mediterranean fever, which occurs mainly in populations bordering the Mediterranean Sea)

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The name of a patient or family with the condition (for example, amyotrophic lateral sclerosis, which is also called Lou Gehrig disease after a famous baseball player who had the condition).

Disorders named after a specific person or place are called eponyms. There is debate as to whether the possessive form (e.g., Alzheimer’s disease) or the nonpossessive form (Alzheimer disease) of eponyms is preferred. As a rule, medical geneticists use the nonpossessive form, and this form may become the standard for doctors in all fields of medicine. Genetics Home Reference uses the nonpossessive form of eponyms. Genetics Home Reference consults with experts in the field of medical genetics to provide the current, most accurate name for each disorder. Alternate names are included as synonyms. Naming genes The HUGO Gene Nomenclature Committee (HGNC) designates an official name and symbol (an abbreviation of the name) for each known human gene. Some official gene names include additional information in parentheses, such as related genetic conditions, subtypes of a condition, or inheritance pattern. The HGNC is a non-profit organization funded by the U.K. Medical Research Council and the U.S. National Institutes of Health. The Committee has named more than 13,000 of the estimated 20,000 to 25,000 genes in the human genome. During the research process, genes often acquire several alternate names and symbols. Different researchers investigating the same gene may each give the gene a different name, which can cause confusion. The HGNC assigns a unique name and symbol to each human gene, which allows effective organization of genes in large databanks, aiding the advancement of research. For specific information about how genes are named, refer to the HGNC’s Guidelines for Human Gene Nomenclature. Genetics Home Reference describes genes using the HGNC’s official gene names and gene symbols. Genetics Home Reference frequently presents the symbol and name separated with a colon (for example, FGFR4: Fibroblast growth factor receptor 4).

Inheriting Genetic Conditions This section gives you information on inheritance patterns and understanding risk.

What Does It Mean If a Disorder Seems to Run in My Family? A particular disorder might be described as “running in a family” if more than one person in the family has the condition. Some disorders that affect multiple family members are caused by gene mutations, which can be inherited (passed down from parent to child). Other conditions that appear to run in families are not inherited. Instead, environmental factors

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such as dietary habits or a combination of genetic and environmental factors are responsible for these disorders. It is not always easy to determine whether a condition in a family is inherited. A genetics professional can use a person’s family history (a record of health information about a person’s immediate and extended family) to help determine whether a disorder has a genetic component.

Some disorders are seen in more than one generation of a family.

Why Is It Important to Know My Family Medical History? A family medical history is a record of health information about a person and his or her close relatives. A complete record includes information from three generations of relatives,

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including children, brothers and sisters, parents, aunts and uncles, nieces and nephews, grandparents, and cousins. Families have many factors in common, including their genes, environment, and lifestyle. Together, these factors can give clues to medical conditions that may run in a family. By noticing patterns of disorders among relatives, healthcare professionals can determine whether an individual, other family members, or future generations may be at an increased risk of developing a particular condition. A family medical history can identify people with a higher-than-usual chance of having common disorders, such as heart disease, high blood pressure, stroke, certain cancers, and diabetes. These complex disorders are influenced by a combination of genetic factors, environmental conditions, and lifestyle choices. A family history also can provide information about the risk of rarer conditions caused by mutations in a single gene, such as cystic fibrosis and sickle cell anemia. While a family medical history provides information about the risk of specific health concerns, having relatives with a medical condition does not mean that an individual will definitely develop that condition. On the other hand, a person with no family history of a disorder may still be at risk of developing that disorder. Knowing one’s family medical history allows a person to take steps to reduce his or her risk. For people at an increased risk of certain cancers, healthcare professionals may recommend more frequent screening (such as mammography or colonoscopy) starting at an earlier age. Healthcare providers may also encourage regular checkups or testing for people with a medical condition that runs in their family. Additionally, lifestyle changes such as adopting a healthier diet, getting regular exercise, and quitting smoking help many people lower their chances of developing heart disease and other common illnesses. The easiest way to get information about family medical history is to talk to relatives about their health. Have they had any medical problems, and when did they occur? A family gathering could be a good time to discuss these issues. Additionally, obtaining medical records and other documents (such as obituaries and death certificates) can help complete a family medical history. It is important to keep this information up-to-date and to share it with a healthcare professional regularly.

What Are the Different Ways in which a Genetic Condition Can Be Inherited? Some genetic conditions are caused by mutations in a single gene. These conditions are usually inherited in one of several straightforward patterns, depending on the gene involved: Inheritance Pattern Autosomal dominant

Description One mutated copy of the gene in each cell is sufficient for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. Autosomal dominant disorders tend to occur in every generation of an affected family.

Examples Huntington disease, neurofibromatosis type 1

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Autosomal recessive

Two mutated copies of the gene are present in each cell when a person has an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers). Autosomal recessive disorders are typically not seen in every generation of an affected family.

cystic fibrosis, sickle cell anemia

X-linked dominant

X-linked dominant disorders are caused by mutations in genes on the X chromosome. Females are more frequently affected than males, and the chance of passing on an X-linked dominant disorder differs between men and women. Families with an X-linked dominant disorder often have both affected males and affected females in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).

fragile X syndrome

X-linked recessive

X-linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. Families with an X-linked recessive disorder often have affected males, but rarely affected females, in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).

hemophilia, Fabry disease

Codominant

In codominant inheritance, two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein. Both alleles influence the genetic trait or determine the characteristics of the genetic condition.

ABO blood group, alpha-1 antitrypsin deficiency

Mitochondrial

This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Mitochondria, which are structures in each cell that convert molecules into energy, each contain a small amount of DNA. Because only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children.

Leber hereditary optic neuropathy (LHON)

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Many other disorders are caused by a combination of the effects of multiple genes or by interactions between genes and the environment. Such disorders are more difficult to analyze because their genetic causes are often unclear, and they do not follow the patterns of inheritance described above. Examples of conditions caused by multiple genes or gene/environment interactions include heart disease, diabetes, schizophrenia, and certain types of cancer. Disorders caused by changes in the number or structure of chromosomes do not follow the straightforward patterns of inheritance listed above. Other genetic factors can also influence how a disorder is inherited.

If a Genetic Disorder Runs in My Family, What Are the Chances That My Children Will Have the Condition? When a genetic disorder is diagnosed in a family, family members often want to know the likelihood that they or their children will develop the condition. This can be difficult to predict in some cases because many factors influence a person’s chances of developing a genetic condition. One important factor is how the condition is inherited. For example: •

Autosomal dominant inheritance: A person affected by an autosomal dominant disorder has a 50 percent chance of passing the mutated gene to each child. The chance that a child will not inherit the mutated gene is also 50 percent.

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Autosomal recessive inheritance: Two unaffected people who each carry one copy of the mutated gene for an autosomal recessive disorder (carriers) have a 25 percent chance with each pregnancy of having a child affected by the disorder. The chance with each pregnancy of having an unaffected child who is a carrier of the disorder is 50 percent, and the chance that a child will not have the disorder and will not be a carrier is 25 percent.

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X-linked dominant inheritance: The chance of passing on an X-linked dominant condition differs between men and women because men have one X chromosome and one Y chromosome, while women have two X chromosomes. A man passes on his Y chromosome to all of his sons and his X chromosome to all of his daughters. Therefore, the sons of a man with an X-linked dominant disorder will not be affected, but all of his daughters will inherit the condition. A woman passes on one or the other of her X chromosomes to each child. Therefore, a woman with an X-linked dominant disorder has a 50 percent chance of having an affected daughter or son with each pregnancy.

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X-linked recessive inheritance: Because of the difference in sex chromosomes, the probability of passing on an X-linked recessive disorder also differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene. With each pregnancy, a woman who carries an X-linked recessive disorder has a 50 percent chance of having sons who are affected and a 50 percent chance of having daughters who carry one copy of the mutated gene.

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Codominant inheritance: In codominant inheritance, each parent contributes a different version of a particular gene, and both versions influence the resulting genetic trait. The chance of developing a genetic condition with codominant inheritance, and the characteristic features of that condition, depend on which versions of the gene are passed from parents to their child.

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Mitochondrial inheritance: Mitochondria, which are the energy-producing centers inside cells, each contain a small amount of DNA. Disorders with mitochondrial inheritance result from mutations in mitochondrial DNA. Although mitochondrial

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disorders can affect both males and females, only females can pass mutations in mitochondrial DNA to their children. A woman with a disorder caused by changes in mitochondrial DNA will pass the mutation to all of her daughters and sons, but the children of a man with such a disorder will not inherit the mutation. It is important to note that the chance of passing on a genetic condition applies equally to each pregnancy. For example, if a couple has a child with an autosomal recessive disorder, the chance of having another child with the disorder is still 25 percent (or 1 in 4). Having one child with a disorder does not “protect” future children from inheriting the condition. Conversely, having a child without the condition does not mean that future children will definitely be affected. Although the chances of inheriting a genetic condition appear straightforward, factors such as a person’s family history and the results of genetic testing can sometimes modify those chances. In addition, some people with a disease-causing mutation never develop any health problems or may experience only mild symptoms of the disorder. If a disease that runs in a family does not have a clear-cut inheritance pattern, predicting the likelihood that a person will develop the condition can be particularly difficult. Estimating the chance of developing or passing on a genetic disorder can be complex. Genetics professionals can help people understand these chances and help them make informed decisions about their health.

Factors that Influence the Effects of Particular Genetic Changes Reduced penetrance and variable expressivity are factors that influence the effects of particular genetic changes. These factors usually affect disorders that have an autosomal dominant pattern of inheritance, although they are occasionally seen in disorders with an autosomal recessive inheritance pattern.

Reduced Penetrance Penetrance refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance. Reduced penetrance often occurs with familial cancer syndromes. For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not. Doctors cannot predict which people with these mutations will develop cancer or when the tumors will develop. Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. This phenomenon can make it challenging for genetics professionals to interpret a person’s family medical history and predict the risk of passing a genetic condition to future generations.

Variable Expressivity Although some genetic disorders exhibit little variation, most have signs and symptoms that differ among affected individuals. Variable expressivity refers to the range of signs and

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symptoms that can occur in different people with the same genetic condition. For example, the features of Marfan syndrome vary widely— some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others also experience lifethreatening complications involving the heart and blood vessels. Although the features are highly variable, most people with this disorder have a mutation in the same gene (FBN1). As with reduced penetrance, variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified. If a genetic condition has highly variable signs and symptoms, it may be challenging to diagnose.

What Do Geneticists Mean by Anticipation? The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next. This phenomenon is called anticipation. Anticipation is most often seen with certain genetic disorders of the nervous system, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. Anticipation typically occurs with disorders that are caused by an unusual type of mutation called a trinucleotide repeat expansion. A trinucleotide repeat is a sequence of three DNA building blocks (nucleotides) that is repeated a number of times in a row. DNA segments with an abnormal number of these repeats are unstable and prone to errors during cell division. The number of repeats can change as the gene is passed from parent to child. If the number of repeats increases, it is known as a trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand until the gene stops functioning normally. This expansion causes the features of some disorders to become more severe with each successive generation. Most genetic disorders have signs and symptoms that differ among affected individuals, including affected people in the same family. Not all of these differences can be explained by anticipation. A combination of genetic, environmental, and lifestyle factors is probably responsible for the variability, although many of these factors have not been identified. Researchers study multiple generations of affected family members and consider the genetic cause of a disorder before determining that it shows anticipation.

What Is Genomic Imprinting? Genomic imprinting is a factor that influences how some genetic conditions are inherited. People inherit two copies of their genes—one from their mother and one from their father. Usually both copies of each gene are active, or “turned on,” in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person’s father; others are active only when inherited from a person’s mother. This phenomenon is known as genomic imprinting. In genes that undergo genomic imprinting, the parent of origin is often marked, or “stamped,” on the gene during the formation of egg and sperm cells. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. These molecules identify which copy of a gene was inherited

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from the mother and which was inherited from the father. The addition and removal of methyl groups can be used to control the activity of genes. Only a small percentage of all human genes undergo genomic imprinting. Researchers are not yet certain why some genes are imprinted and others are not. They do know that imprinted genes tend to cluster together in the same regions of chromosomes. Two major clusters of imprinted genes have been identified in humans, one on the short (p) arm of chromosome 11 (at position 11p15) and another on the long (q) arm of chromosome 15 (in the region 15q11 to 15q13).

What Is Uniparental Disomy? Uniparental disomy is a factor that influences how some genetic conditions are inherited. Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development. In many cases, UPD likely has no effect on health or development. Because most genes are not imprinted, it doesn’t matter if a person inherits both copies from one parent instead of one copy from each parent. In some cases, however, it does make a difference whether a gene is inherited from a person’s mother or father. A person with UPD may lack any active copies of essential genes that undergo genomic imprinting. This loss of gene function can lead to delayed development, mental retardation, or other medical problems. Several genetic disorders can result from UPD or a disruption of normal genomic imprinting. The most well-known conditions include Prader-Willi syndrome, which is characterized by uncontrolled eating and obesity, and Angelman syndrome, which causes mental retardation and impaired speech. Both of these disorders can be caused by UPD or other errors in imprinting involving genes on the long arm of chromosome 15. Other conditions, such as Beckwith-Wiedemann syndrome (a disorder characterized by accelerated growth and an increased risk of cancerous tumors), are associated with abnormalities of imprinted genes on the short arm of chromosome 11.

Are Chromosomal Disorders Inherited? Although it is possible to inherit some types of chromosomal abnormalities, most chromosomal disorders (such as Down syndrome and Turner syndrome) are not passed from one generation to the next. Some chromosomal conditions are caused by changes in the number of chromosomes. These changes are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, a reproductive cell may accidentally gain or lose one copy of a chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra or missing chromosome in each of the body’s cells.

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Changes in chromosome structure can also cause chromosomal disorders. Some changes in chromosome structure can be inherited, while others occur as random accidents during the formation of reproductive cells or in early fetal development. Because the inheritance of these changes can be complex, people concerned about this type of chromosomal abnormality may want to talk with a genetics professional. Some cancer cells also have changes in the number or structure of their chromosomes. Because these changes occur in somatic cells (cells other than eggs and sperm), they cannot be passed from one generation to the next.

Why Are Some Genetic Conditions More Common in Particular Ethnic Groups? Some genetic disorders are more likely to occur among people who trace their ancestry to a particular geographic area. People in an ethnic group often share certain versions of their genes, which have been passed down from common ancestors. If one of these shared genes contains a disease-causing mutation, a particular genetic disorder may be more frequently seen in the group. Examples of genetic conditions that are more common in particular ethnic groups are sickle cell anemia, which is more common in people of African, African-American, or Mediterranean heritage; and Tay-Sachs disease, which is more likely to occur among people of Ashkenazi (eastern and central European) Jewish or French Canadian ancestry. It is important to note, however, that these disorders can occur in any ethnic group.

Genetic Consultation This section presents information on finding and visiting a genetic counselor or other genetics professional.

What Is a Genetic Consultation? A genetic consultation is a health service that provides information and support to people who have, or may be at risk for, genetic disorders. During a consultation, a genetics professional meets with an individual or family to discuss genetic risks or to diagnose, confirm, or rule out a genetic condition. Genetics professionals include medical geneticists (doctors who specialize in genetics) and genetic counselors (certified healthcare workers with experience in medical genetics and counseling). Other healthcare professionals such as nurses, psychologists, and social workers trained in genetics can also provide genetic consultations. Consultations usually take place in a doctor’s office, hospital, genetics center, or other type of medical center. These meetings are most often in-person visits with individuals or families, but they are occasionally conducted in a group or over the telephone.

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Why Might Someone Have a Genetic Consultation? Individuals or families who are concerned about an inherited condition may benefit from a genetic consultation. The reasons that a person might be referred to a genetic counselor, medical geneticist, or other genetics professional include: •

A personal or family history of a genetic condition, birth defect, chromosomal disorder, or hereditary cancer.

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Two or more pregnancy losses (miscarriages), a stillbirth, or a baby who died.

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A child with a known inherited disorder, a birth defect, mental retardation, or developmental delay.

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A woman who is pregnant or plans to become pregnant at or after age 35. (Some chromosomal disorders occur more frequently in children born to older women.)

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Abnormal test results that suggest a genetic or chromosomal condition.

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An increased risk of developing or passing on a particular genetic disorder on the basis of a person’s ethnic background.

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People related by blood (for example, cousins) who plan to have children together. (A child whose parents are related may be at an increased risk of inheriting certain genetic disorders.)

A genetic consultation is also an important part of the decision-making process for genetic testing. A visit with a genetics professional may be helpful even if testing is not available for a specific condition, however.

What Happens during a Genetic Consultation? A genetic consultation provides information, offers support, and addresses a patient’s specific questions and concerns. To help determine whether a condition has a genetic component, a genetics professional asks about a person’s medical history and takes a detailed family history (a record of health information about a person’s immediate and extended family). The genetics professional may also perform a physical examination and recommend appropriate tests. If a person is diagnosed with a genetic condition, the genetics professional provides information about the diagnosis, how the condition is inherited, the chance of passing the condition to future generations, and the options for testing and treatment. During a consultation, a genetics professional will: •

Interpret and communicate complex medical information.

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Help each person make informed, independent decisions about their health care and reproductive options.

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Respect each person’s individual beliefs, traditions, and feelings.

A genetics professional will NOT: •

Tell a person which decision to make.

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Advise a couple not to have children.

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Recommend that a woman continue or end a pregnancy.

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Tell someone whether to undergo testing for a genetic disorder.

How Can I Find a Genetics Professional in My Area? To find a genetics professional in your community, you may wish to ask your doctor for a referral. If you have health insurance, you can also contact your insurance company to find a medical geneticist or genetic counselor in your area who participates in your plan. Several resources for locating a genetics professional in your community are available online: •

GeneTests from the University of Washington provides a list of genetics clinics around the United States and international genetics clinics. You can also access the list by clicking on “Clinic Directory” at the top of the GeneTests home page. Clinics can be chosen by state or country, by service, and/or by specialty. State maps can help you locate a clinic in your area. See http://www.genetests.org/.

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The National Society of Genetic Counselors offers a searchable directory of genetic counselors in the United States. You can search by location, name, area of practice/specialization, and/or ZIP Code. See http://www.nsgc.org/resourcelink.cfm.

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The National Cancer Institute provides a Cancer Genetics Services Directory, which lists professionals who provide services related to cancer genetics. You can search by type of cancer or syndrome, location, and/or provider name at the following Web site: http://cancer.gov/search/genetics_services/.

Genetic Testing This section presents information on the benefits, costs, risks, and limitations of genetic testing.

What Is Genetic Testing? Genetic testing is a type of medical test that identifies changes in chromosomes, genes, or proteins. Most of the time, testing is used to find changes that are associated with inherited disorders. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. Several hundred genetic tests are currently in use, and more are being developed. Genetic testing is voluntary. Because testing has both benefits and limitations, the decision about whether to be tested is a personal and complex one. A genetic counselor can help by providing information about the pros and cons of the test and discussing the social and emotional aspects of testing.

What Are the Types of Genetic Tests? Genetic testing can provide information about a person’s genes and chromosomes. Available types of testing include:

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Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. Millions of babies are tested each year in the United States. All states currently test infants for phenylketonuria (a genetic disorder that causes mental retardation if left untreated) and congenital hypothyroidism (a disorder of the thyroid gland). Most states also test for other genetic disorders.

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Diagnostic testing is used to identify or rule out a specific genetic or chromosomal condition. In many cases, genetic testing is used to confirm a diagnosis when a particular condition is suspected based on physical signs and symptoms. Diagnostic testing can be performed before birth or at any time during a person’s life, but is not available for all genes or all genetic conditions. The results of a diagnostic test can influence a person’s choices about health care and the management of the disorder.

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Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder. This type of testing is offered to individuals who have a family history of a genetic disorder and to people in certain ethnic groups with an increased risk of specific genetic conditions. If both parents are tested, the test can provide information about a couple’s risk of having a child with a genetic condition.

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Prenatal testing is used to detect changes in a fetus’s genes or chromosomes before birth. This type of testing is offered during pregnancy if there is an increased risk that the baby will have a genetic or chromosomal disorder. In some cases, prenatal testing can lessen a couple’s uncertainty or help them make decisions about a pregnancy. It cannot identify all possible inherited disorders and birth defects, however.

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Preimplantation testing, also called preimplantation genetic diagnosis (PGD), is a specialized technique that can reduce the risk of having a child with a particular genetic or chromosomal disorder. It is used to detect genetic changes in embryos that were created using assisted reproductive techniques such as in-vitro fertilization. In-vitro fertilization involves removing egg cells from a woman’s ovaries and fertilizing them with sperm cells outside the body. To perform preimplantation testing, a small number of cells are taken from these embryos and tested for certain genetic changes. Only embryos without these changes are implanted in the uterus to initiate a pregnancy.

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Predictive and presymptomatic types of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a genetic disorder, but who have no features of the disorder themselves at the time of testing. Predictive testing can identify mutations that increase a person’s risk of developing disorders with a genetic basis, such as certain types of cancer. Presymptomatic testing can determine whether a person will develop a genetic disorder, such as hemochromatosis (an iron overload disorder), before any signs or symptoms appear. The results of predictive and presymptomatic testing can provide information about a person’s risk of developing a specific disorder and help with making decisions about medical care.

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Forensic testing uses DNA sequences to identify an individual for legal purposes. Unlike the tests described above, forensic testing is not used to detect gene mutations associated with disease. This type of testing can identify crime or catastrophe victims, rule out or implicate a crime suspect, or establish biological relationships between people (for example, paternity).

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How Is Genetic Testing Done? Once a person decides to proceed with genetic testing, a medical geneticist, primary care doctor, specialist, or nurse practitioner can order the test. Genetic testing is often done as part of a genetic consultation. Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue. For example, a procedure called a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside surface of the cheek. The sample is sent to a laboratory where technicians look for specific changes in chromosomes, DNA, or proteins, depending on the suspected disorder. The laboratory reports the test results in writing to a person’s doctor or genetic counselor. Newborn screening tests are done on a small blood sample, which is taken by pricking the baby’s heel. Unlike other types of genetic testing, a parent will usually only receive the result if it is positive. If the test result is positive, additional testing is needed to determine whether the baby has a genetic disorder. Before a person has a genetic test, it is important that he or she understands the testing procedure, the benefits and limitations of the test, and the possible consequences of the test results. The process of educating a person about the test and obtaining permission is called informed consent.

What Is Direct-to-Consumer Genetic Testing? Traditionally, genetic tests have been available only through healthcare providers such as physicians, nurse practitioners, and genetic counselors. Healthcare providers order the appropriate test from a laboratory, collect and send the samples, and interpret the test results. Direct-to-consumer genetic testing refers to genetic tests that are marketed directly to consumers via television, print advertisements, or the Internet. This form of testing, which is also known as at-home genetic testing, provides access to a person’s genetic information without necessarily involving a doctor or insurance company in the process. If a consumer chooses to purchase a genetic test directly, the test kit is mailed to the consumer instead of being ordered through a doctor’s office. The test typically involves collecting a DNA sample at home, often by swabbing the inside of the cheek, and mailing the sample back to the laboratory. In some cases, the person must visit a health clinic to have blood drawn. Consumers are notified of their results by mail or over the telephone, or the results are posted online. In some cases, a genetic counselor or other healthcare provider is available to explain the results and answer questions. The price for this type of at-home genetic testing ranges from several hundred dollars to more than a thousand dollars. The growing market for direct-to-consumer genetic testing may promote awareness of genetic diseases, allow consumers to take a more proactive role in their health care, and offer a means for people to learn about their ancestral origins. At-home genetic tests, however, have significant risks and limitations. Consumers are vulnerable to being misled by the results of unproven or invalid tests. Without guidance from a healthcare provider, they may make important decisions about treatment or prevention based on inaccurate, incomplete, or misunderstood information about their health. Consumers may also experience an invasion of genetic privacy if testing companies use their genetic information in an unauthorized way.

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Genetic testing provides only one piece of information about a person’s health—other genetic and environmental factors, lifestyle choices, and family medical history also affect a person’s risk of developing many disorders. These factors are discussed during a consultation with a doctor or genetic counselor, but in many cases are not addressed by athome genetic tests. More research is needed to fully understand the benefits and limitations of direct-to-consumer genetic testing.

What Do the Results of Genetic Tests Mean? The results of genetic tests are not always straightforward, which often makes them challenging to interpret and explain. Therefore, it is important for patients and their families to ask questions about the potential meaning of genetic test results both before and after the test is performed. When interpreting test results, healthcare professionals consider a person’s medical history, family history, and the type of genetic test that was done. A positive test result means that the laboratory found a change in a particular gene, chromosome, or protein of interest. Depending on the purpose of the test, this result may confirm a diagnosis, indicate that a person is a carrier of a particular genetic mutation, identify an increased risk of developing a disease (such as cancer) in the future, or suggest a need for further testing. Because family members have some genetic material in common, a positive test result may also have implications for certain blood relatives of the person undergoing testing. It is important to note that a positive result of a predictive or presymptomatic genetic test usually cannot establish the exact risk of developing a disorder. Also, health professionals typically cannot use a positive test result to predict the course or severity of a condition. A negative test result means that the laboratory did not find a change in the gene, chromosome, or protein under consideration. This result can indicate that a person is not affected by a particular disorder, is not a carrier of a specific genetic mutation, or does not have an increased risk of developing a certain disease. It is possible, however, that the test missed a disease-causing genetic alteration because many tests cannot detect all genetic changes that can cause a particular disorder. Further testing may be required to confirm a negative result. In some cases, a negative result might not give any useful information. This type of result is called uninformative, indeterminate, inconclusive, or ambiguous. Uninformative test results sometimes occur because everyone has common, natural variations in their DNA, called polymorphisms, that do not affect health. If a genetic test finds a change in DNA that has not been associated with a disorder in other people, it can be difficult to tell whether it is a natural polymorphism or a disease-causing mutation. An uninformative result cannot confirm or rule out a specific diagnosis, and it cannot indicate whether a person has an increased risk of developing a disorder. In some cases, testing other affected and unaffected family members can help clarify this type of result.

What Is the Cost of Genetic Testing, and How Long Does It Take to Get the Results? The cost of genetic testing can range from under $100 to more than $2,000, depending on the nature and complexity of the test. The cost increases if more than one test is necessary or if multiple family members must be tested to obtain a meaningful result. For newborn

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screening, costs vary by state. Some states cover part of the total cost, but most charge a fee of $15 to $60 per infant. From the date that a sample is taken, it may take a few weeks to several months to receive the test results. Results for prenatal testing are usually available more quickly because time is an important consideration in making decisions about a pregnancy. The doctor or genetic counselor who orders a particular test can provide specific information about the cost and time frame associated with that test.

Will Health Insurance Cover the Costs of Genetic Testing? In many cases, health insurance plans will cover the costs of genetic testing when it is recommended by a person’s doctor. Health insurance providers have different policies about which tests are covered, however. A person interested in submitting the costs of testing may wish to contact his or her insurance company beforehand to ask about coverage. Some people may choose not to use their insurance to pay for testing because the results of a genetic test can affect a person’s health insurance coverage. Instead, they may opt to pay out-of-pocket for the test. People considering genetic testing may want to find out more about their state’s privacy protection laws before they ask their insurance company to cover the costs.

What Are the Benefits of Genetic Testing? Genetic testing has potential benefits whether the results are positive or negative for a gene mutation. Test results can provide a sense of relief from uncertainty and help people make informed decisions about managing their health care. For example, a negative result can eliminate the need for unnecessary checkups and screening tests in some cases. A positive result can direct a person toward available prevention, monitoring, and treatment options. Some test results can also help people make decisions about having children. Newborn screening can identify genetic disorders early in life so treatment can be started as early as possible.

What Are the Risks and Limitations of Genetic Testing? The physical risks associated with most genetic tests are very small, particularly for those tests that require only a blood sample or buccal smear (a procedure that samples cells from the inside surface of the cheek). The procedures used for prenatal testing carry a small but real risk of losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or tissue from around the fetus. Many of the risks associated with genetic testing involve the emotional, social, or financial consequences of the test results. People may feel angry, depressed, anxious, or guilty about their results. In some cases, genetic testing creates tension within a family because the results can reveal information about other family members in addition to the person who is tested. The possibility of genetic discrimination in employment or insurance is also a concern.

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Genetic testing can provide only limited information about an inherited condition. The test often can’t determine if a person will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. Another major limitation is the lack of treatment strategies for many genetic disorders once they are diagnosed. A genetics professional can explain in detail the benefits, risks, and limitations of a particular test. It is important that any person who is considering genetic testing understand and weigh these factors before making a decision.

What Is Genetic Discrimination? Genetic discrimination occurs when people are treated differently by their employer or insurance company because they have a gene mutation that causes or increases the risk of an inherited disorder. People who undergo genetic testing may be at risk for genetic discrimination. The results of a genetic test are normally included in a person’s medical records. When a person applies for life, disability, or health insurance, the insurance company may ask to look at these records before making a decision about coverage. An employer may also have the right to look at an employee’s medical records. As a result, genetic test results could affect a person’s insurance coverage or employment. People making decisions about genetic testing should be aware that when test results are placed in their medical records, the results might not be kept private. Fear of discrimination is a common concern among people considering genetic testing. Several laws at the federal and state levels help protect people against genetic discrimination; however, genetic testing is a fast-growing field and these laws don’t cover every situation.

How Does Genetic Testing in a Research Setting Differ from Clinical Genetic Testing? The main differences between clinical genetic testing and research testing are the purpose of the test and who receives the results. The goals of research testing include finding unknown genes, learning how genes work, and advancing our understanding of genetic conditions. The results of testing done as part of a research study are usually not available to patients or their healthcare providers. Clinical testing, on the other hand, is done to find out about an inherited disorder in an individual patient or family. People receive the results of a clinical test and can use them to help them make decisions about medical care or reproductive issues. It is important for people considering genetic testing to know whether the test is available on a clinical or research basis. Clinical and research testing both involve a process of informed consent in which patients learn about the testing procedure, the risks and benefits of the test, and the potential consequences of testing.

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Gene Therapy This section presents information on experimental techniques, safety, ethics, and availability of gene therapy.

What Is Gene Therapy? Gene therapy is an experimental technique that uses genes to treat or prevent disease. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patient’s cells instead of using drugs or surgery. Researchers are testing several approaches to gene therapy, including: •

Replacing a mutated gene that causes disease with a healthy copy of the gene.

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Inactivating, or “knocking out,” a mutated gene that is functioning improperly.

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Introducing a new gene into the body to help fight a disease.

Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections), the technique remains risky and is still under study to make sure that it will be safe and effective. Gene therapy is currently only being tested for the treatment of diseases that have no other cures.

How Does Gene Therapy Work? Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein. A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is genetically engineered to deliver the gene. Certain viruses are often used as vectors because they can deliver the new gene by infecting the cell. The viruses are modified so they can’t cause disease when used in people. Some types of virus, such as retroviruses, integrate their genetic material (including the new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome. The vector can be injected or given intravenously (by IV) directly into a specific tissue in the body, where it is taken up by individual cells. Alternately, a sample of the patient’s cells can be removed and exposed to the vector in a laboratory setting. The cells containing the vector are then returned to the patient. If the treatment is successful, the new gene delivered by the vector will make a functioning protein. Researchers must overcome many technical challenges before gene therapy will be a practical approach to treating disease. For example, scientists must find better ways to deliver genes and target them to particular cells. They must also ensure that new genes are precisely controlled by the body.

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A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.

Is Gene Therapy Safe? Gene therapy is under study to determine whether it could be used to treat disease. Current research is evaluating the safety of gene therapy; future studies will test whether it is an effective treatment option. Several studies have already shown that this approach can have very serious health risks, such as toxicity, inflammation, and cancer. Because the techniques are relatively new, some of the risks may be unpredictable; however, medical researchers, institutions, and regulatory agencies are working to ensure that gene therapy research is as safe as possible. Comprehensive federal laws, regulations, and guidelines help protect people who participate in research studies (called clinical trials). The U.S. Food and Drug Administration (FDA) regulates all gene therapy products in the United States and oversees research in this area. Researchers who wish to test an approach in a clinical trial must first obtain permission from the FDA. The FDA has the authority to reject or suspend clinical trials that are suspected of being unsafe for participants. The National Institutes of Health (NIH) also plays an important role in ensuring the safety of gene therapy research. NIH provides guidelines for investigators and institutions (such as universities and hospitals) to follow when conducting clinical trials with gene therapy. These guidelines state that clinical trials at institutions receiving NIH funding for this type of research must be registered with the NIH Office of Biotechnology Activities. The protocol, or plan, for each clinical trial is then reviewed by the NIH Recombinant DNA Advisory Committee (RAC) to determine whether it raises medical, ethical, or safety issues that warrant further discussion at one of the RAC’s public meetings.

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An Institutional Review Board (IRB) and an Institutional Biosafety Committee (IBC) must approve each gene therapy clinical trial before it can be carried out. An IRB is a committee of scientific and medical advisors and consumers that reviews all research within an institution. An IBC is a group that reviews and approves an institution’s potentially hazardous research studies. Multiple levels of evaluation and oversight ensure that safety concerns are a top priority in the planning and carrying out of gene therapy research.

What Are the Ethical Issues surrounding Gene Therapy? Because gene therapy involves making changes to the body’s set of basic instructions, it raises many unique ethical concerns. The ethical questions surrounding gene therapy include: •

How can “good” and “bad” uses of gene therapy be distinguished?

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Who decides which traits are normal and which constitute a disability or disorder?

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Will the high costs of gene therapy make it available only to the wealthy?

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Could the widespread use of gene therapy make society less accepting of people who are different?

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Should people be allowed to use gene therapy to enhance basic human traits such as height, intelligence, or athletic ability?

Current gene therapy research has focused on treating individuals by targeting the therapy to body cells such as bone marrow or blood cells. This type of gene therapy cannot be passed on to a person’s children. Gene therapy could be targeted to egg and sperm cells (germ cells), however, which would allow the inserted gene to be passed on to future generations. This approach is known as germline gene therapy. The idea of germline gene therapy is controversial. While it could spare future generations in a family from having a particular genetic disorder, it might affect the development of a fetus in unexpected ways or have long-term side effects that are not yet known. Because people who would be affected by germline gene therapy are not yet born, they can’t choose whether to have the treatment. Because of these ethical concerns, the U.S. Government does not allow federal funds to be used for research on germline gene therapy in people.

Is Gene Therapy Available to Treat My Disorder? Gene therapy is currently available only in a research setting. The U.S. Food and Drug Administration (FDA) has not yet approved any gene therapy products for sale in the United States. Hundreds of research studies (clinical trials) are under way to test gene therapy as a treatment for genetic conditions, cancer, and HIV/AIDS. If you are interested in participating in a clinical trial, talk with your doctor or a genetics professional about how to participate. You can also search for clinical trials online. ClinicalTrials.gov, a service of the National Institutes of Health, provides easy access to information on clinical trials. You can search for specific trials or browse by condition or trial sponsor. You may wish to refer to a list of gene therapy trials that are accepting (or will accept) patients.

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The Human Genome Project and Genomic Research This section presents information on the goals, accomplishments, and next steps in understanding the human genome.

What Is a Genome? A genome is an organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism. In humans, a copy of the entire genome—more than 3 billion DNA base pairs—is contained in all cells that have a nucleus.

What Was the Human Genome Project and Why Has It Been Important? The Human Genome Project was an international research effort to determine the sequence of the human genome and identify the genes that it contains. The Project was coordinated by the National Institutes of Health and the U.S. Department of Energy. Additional contributors included universities across the United States and international partners in the United Kingdom, France, Germany, Japan, and China. The Human Genome Project formally began in 1990 and was completed in 2003, 2 years ahead of its original schedule. The work of the Human Genome Project has allowed researchers to begin to understand the blueprint for building a person. As researchers learn more about the functions of genes and proteins, this knowledge will have a major impact in the fields of medicine, biotechnology, and the life sciences.

What Were the Goals of the Human Genome Project? The main goals of the Human Genome Project were to provide a complete and accurate sequence of the 3 billion DNA base pairs that make up the human genome and to find all of the estimated 20,000 to 25,000 human genes. The Project also aimed to sequence the genomes of several other organisms that are important to medical research, such as the mouse and the fruit fly. In addition to sequencing DNA, the Human Genome Project sought to develop new tools to obtain and analyze the data and to make this information widely available. Also, because advances in genetics have consequences for individuals and society, the Human Genome Project committed to exploring the consequences of genomic research through its Ethical, Legal, and Social Implications (ELSI) program.

What Did the Human Genome Project Accomplish? In April 2003, researchers announced that the Human Genome Project had completed a high-quality sequence of essentially the entire human genome. This sequence closed the gaps from a working draft of the genome, which was published in 2001. It also identified the locations of many human genes and provided information about their structure and

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organization. The Project made the sequence of the human genome and tools to analyze the data freely available via the Internet. In addition to the human genome, the Human Genome Project sequenced the genomes of several other organisms, including brewers’ yeast, the roundworm, and the fruit fly. In 2002, researchers announced that they had also completed a working draft of the mouse genome. By studying the similarities and differences between human genes and those of other organisms, researchers can discover the functions of particular genes and identify which genes are critical for life. The Project’s Ethical, Legal, and Social Implications (ELSI) program became the world’s largest bioethics program and a model for other ELSI programs worldwide.

What Were Some of the Ethical, Legal, and Social Implications Addressed by the Human Genome Project? The Ethical, Legal, and Social Implications (ELSI) program was founded in 1990 as an integral part of the Human Genome Project. The mission of the ELSI program was to identify and address issues raised by genomic research that would affect individuals, families, and society. A percentage of the Human Genome Project budget at the National Institutes of Health and the U.S. Department of Energy was devoted to ELSI research. The ELSI program focused on the possible consequences of genomic research in four main areas: •

Privacy and fairness in the use of genetic information, including the potential for genetic discrimination in employment and insurance.

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The integration of new genetic technologies, such as genetic testing, into the practice of clinical medicine.

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Ethical issues surrounding the design and conduct of genetic research with people, including the process of informed consent.

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The education of healthcare professionals, policy makers, students, and the public about genetics and the complex issues that result from genomic research.

What Are the Next Steps in Genomic Research? Discovering the sequence of the human genome was only the first step in understanding how the instructions coded in DNA lead to a functioning human being. The next stage of genomic research will begin to derive meaningful knowledge from the DNA sequence. Research studies that build on the work of the Human Genome Project are under way worldwide. The objectives of continued genomic research include the following: •

Determine the function of genes and the elements that regulate genes throughout the genome.

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Find variations in the DNA sequence among people and determine their significance. These variations may one day provide information about a person’s disease risk and response to certain medications.

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Discover the 3-dimensional structures of proteins and identify their functions.

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Explore how DNA and proteins interact with one another and with the environment to create complex living systems.

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Develop and apply genome-based strategies for the early detection, diagnosis, and treatment of disease.

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Sequence the genomes of other organisms, such as the rat, cow, and chimpanzee, in order to compare similar genes between species.

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Develop new technologies to study genes and DNA on a large scale and store genomic data efficiently.

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Continue to explore the ethical, legal, and social issues raised by genomic research.

What Is Pharmacogenomics? Pharmacogenomics is the study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup. Many drugs that are currently available are “one size fits all,” but they don’t work the same way for everyone. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side effects (called adverse drug reactions). Adverse drug reactions are a significant cause of hospitalizations and deaths in the United States. With the knowledge gained from the Human Genome Project, researchers are learning how inherited differences in genes affect the body’s response to medications. These genetic differences will be used to predict whether a medication will be effective for a particular person and to help prevent adverse drug reactions. The field of pharmacogenomics is still in its infancy. Its use is currently quite limited, but new approaches are under study in clinical trials. In the future, pharmacogenomics will allow the development of tailored drugs to treat a wide range of health problems, including cardiovascular disease, Alzheimer disease, cancer, HIV/AIDS, and asthma.

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

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute12: •

National Institutes of Health (NIH); guidelines consolidated across agencies available at http://health.nih.gov/

•

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

•

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

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancertopics/pdq

•

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

•

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

•

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

•

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

•

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

12

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

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•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

National Institute of Biomedical Imaging and Bioengineering; general information at http://www.nibib.nih.gov/HealthEdu

•

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

•

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

•

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

•

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

NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.13 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic

13

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

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citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine14: •

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

14

See http://www.nlm.nih.gov/databases/index.html.

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The NLM Gateway15 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.16 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type sickle cell anemia (or synonyms) into the search box and click Search. The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 14297 355 44 24 0 14720

HSTAT17 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.18 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.19 Simply search by sickle cell anemia (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists20 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. 15

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

16

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

18 19

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

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration’s Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force’s Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 20 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

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Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.21 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.22 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

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

MD Consult: Access to electronic clinical resources, see http://www.mdconsult.com/.

•

Medical Matrix: Lists over 6000 medical Web sites and links to over 1.5 million documents with clinical content, see http://www.medmatrix.org/.

•

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

21

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 22 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

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APPENDIX C. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called Fact Sheets or Guidelines. They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on sickle cell anemia can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources This section directs you to sources which either publish fact sheets or can help you find additional guidelines on topics related to sickle cell anemia. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly.

The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below.

Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are health topic pages which list links to available materials relevant to sickle cell anemia. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for sickle cell anemia:

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Anemia http://www.nlm.nih.gov/medlineplus/anemia.html Blood and Blood Disorders http://www.nlm.nih.gov/medlineplus/bloodandblooddisorders.html Bone Marrow Diseases http://www.nlm.nih.gov/medlineplus/bonemarrowdiseases.html Sickle Cell Anemia http://www.nlm.nih.gov/medlineplus/sicklecellanemia.html Thalassemia http://www.nlm.nih.gov/medlineplus/thalassemia.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click Search. This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search.

Healthfinder™ Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

DAN Divers Alert Network : Diving and Sickle Cell Anemia Source: www.diversalertnetwork.org http://www.diversalertnetwork.org/medical/faq/faq.asp?faqid=129

•

Stem Cell Research Source: www.leukemiafoundation.org http://www.leukemiafoundation.org/stem-cell-research/page3.htm

The NIH Search Utility The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to sickle cell anemia. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://health.nih.gov/index.asp. Under Search Health Topics, type sickle cell anemia (or synonyms) into the search box, and click Search.

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

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

•

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

•

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

•

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

•

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

•

WebMDHealth: http://www.webmd.com/diseases_and_conditions/default.htm

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

The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about sickle cell anemia. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797.

Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://sis.nlm.nih.gov/dirline.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. Simply type in sickle cell anemia (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://healthhotlines.nlm.nih.gov/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information.

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The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type sickle cell anemia (or a synonym) into the search box, and click Submit Query.

Resources for Patients and Families The following are organizations that provide support and advocacy for patient with genetic conditions and their families23: •

Genetic Alliance: http://geneticalliance.org

•

Genetic and Rare Diseases Information Center: http://rarediseases.info.nih.gov/html/resources/info_cntr.html

•

Madisons Foundation: http://www.madisonsfoundation.org/

•

March of Dimes: http://www.marchofdimes.com

•

National Organization for Rare Disorders (NORD): http://www.rarediseases.org/

For More Information on Genetics The following publications offer detailed information for patients about the science of genetics: •

What Is a Genome?: http://www.ncbi.nlm.nih.gov/About/primer/genetics_genome.html

•

A Science Called Genetics: http://publications.nigms.nih.gov/genetics/science.html

•

Genetic Mapping: http://www.genome.gov/10000715

23

Adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/ghr/resource/patients.

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

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

•

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

•

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

•

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

•

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

•

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

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/archive//20040831/nichsr/ta101/ta10108.html

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

Basic Guidelines for Sickle Cell Anemia Sickle cell anemia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000527.htm Sickle cell anemia - resources Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002200.htm

•

Signs & Symptoms for Sickle Cell Anemia Abdominal pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003120.htm Blood in the urine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003138.htm Bone pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003180.htm

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Breathlessness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm Chest pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003079.htm Cough Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003072.htm Delayed growth Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003021.htm Fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Fever Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003090.htm Hematuria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003138.htm Jaundice Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003243.htm Joint pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003261.htm Paleness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003244.htm Priapism Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003166.htm Rapid heart rate Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003077.htm Stress Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Thirst, excessive Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003085.htm Urination, excessive volume Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003146.htm Vomiting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Weakness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003174.htm

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•

Diagnostics and Tests for Sickle Cell Anemia Bilirubin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003479.htm CBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm Creatinine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003475.htm ESR Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003638.htm Hemoglobin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003645.htm Hemoglobin electrophoresis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003639.htm Hemoglobin S screening test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003639.htm Hemoglobin; serum Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003677.htm MRI Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm Peripheral smear Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003665.htm Sickle cell test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003666.htm Sickle cell trait Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003666.htm Ulcers Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003228.htm Urinary casts Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003586.htm White blood cell count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003643.htm X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003337.htm

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Nutrition for Sickle Cell Anemia Folic acid Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002408.htm

•

Surgery and Procedures for Sickle Cell Anemia Bone marrow transplant Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003009.htm Exchange transfusion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002923.htm Gallbladder removal Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002930.htm Kidney transplant Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003005.htm Splenectomy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002944.htm

•

Background Topics for Sickle Cell Anemia Acute Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002215.htm Analgesics Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002123.htm Aplastic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002233.htm Chronic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002312.htm Electrolytes Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002350.htm Incidence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002387.htm Intravenous Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002383.htm Necrosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002266.htm Physical activity Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001941.htm

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Prenatal diagnosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002053.htm Sickle cell anemia - support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002200.htm

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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SICKLE CELL ANEMIA DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 3-dimensional: 3-D. A graphic display of depth, width, and height. Three-dimensional radiation therapy uses computers to create a 3-dimensional picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Abscess: A localized, circumscribed collection of pus. [NIH] Absenteeism: Chronic absence from work or other duty. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acculturation: Process of cultural change in which one group or members of a group assimilates various cultural patterns from another. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Triphosphate: Adenosine 5'-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually

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referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and older (aged, 80 and over). [NIH] Aged, 80 and Over: A person 80 years of age and older. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH]

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Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alpha-Thalassemia: A disorder characterized by reduced synthesis of the alpha chains of hemoglobin. The severity of this condition can vary from mild anemia to death, depending on the number of genes deleted. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amitriptyline: Tricyclic antidepressant with anticholinergic and sedative properties. It appears to prevent the re-uptake of norepinephrine and serotonin at nerve terminals, thus potentiating the action of these neurotransmitters. Amitriptyline also appears to antaganize cholinergic and alpha-1 adrenergic responses to bioactive amines. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]

Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH]

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Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anemic: Hypoxia due to reduction of the oxygen-carrying capacity of the blood as a result of a decrease in the total hemoglobin or an alteration of the hemoglobin constituents. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Aneuploidy: The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of chromosomes or chromosome pairs. In a normally diploid cell the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is monosomy (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is trisomy (symbol: 2N+1). [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Ankylosis: Fixation and immobility of a joint. [NIH] Anomalies: Birth defects; abnormalities. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another

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living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Anterior Cerebral Artery: Artery formed by the bifurcation of the internal carotid artery. Branches of the anterior cerebral artery supply the caudate nucleus, internal capsule, putamen, septal nuclei, gyrus cinguli, and surfaces of the frontal lobe and parietal lobe. [NIH] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticholinergic: An agent that blocks the parasympathetic nerves. Called also parasympatholytic. [EU] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antidepressant: A drug used to treat depression. [NIH] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiplasmin: A member of the serpin superfamily found in human plasma that inhibits the lysis of fibrin clots which are induced by plasminogen activator. It is a glycoprotein, molecular weight approximately 70,000 that migrates in the alpha 2 region in immunoelectrophoresis. It is the principal plasmin inactivator in blood, rapidly forming a very stable complex with plasmin. [NIH] Antisickling Agents: Agents used to prevent or reverse the pathological events leading to

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sickling of erythrocytes in sickle cell conditions. [NIH] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Aphakia: Absence of crystalline lens totally or partially from field of vision, from any cause except after cataract extraction. Aphakia is mainly congenital or as result of lens dislocation and subluxation. [NIH] Apnea: A transient absence of spontaneous respiration. [NIH] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articular: Of or pertaining to a joint. [EU] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aspiration: The act of inhaling. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord.

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Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Atmospheric Pressure: The pressure at any point in an atmosphere due solely to the weight of the atmospheric gases above the point concerned. [NIH] Atrial: Pertaining to an atrium. [EU] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Bacteremia: The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benign tumor: A noncancerous growth that does not invade nearby tissue or spread to other parts of the body. [NIH]

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Beta-Thalassemia: A disorder characterized by reduced synthesis of the beta chains of hemoglobin. There is retardation of hemoglobin A synthesis in the heterozygous form (thalassemia minor), which is asymptomatic, while in the homozygous form (thalassemia major, Cooley's anemia, Mediterranean anemia, erythroblastic anemia), which can result in severe complications and even death, hemoglobin A synthesis is absent. [NIH] Bewilderment: Impairment or loss of will power. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [NIH] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an

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active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Blood Cell Count: A count of the number of leukocytes and erythrocytes per unit volume in a sample of venous blood. A complete blood count (CBC) also includes measurement of the hemoglobin, hematocrit, and erythrocyte indices. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Groups: The classification systems (or schemes) of the different antigens located on erythrocytes.The antigens are the phenotypic expression of the genetic differences characteristic of specific blood groups. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Burden: The total amount of a chemical, metal or radioactive substance present at any time after absorption in the body of man or animal. [NIH] Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH]

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Bronchial: Pertaining to one or more bronchi. [EU] Bronchopulmonary: Pertaining to the lungs and their air passages; both bronchial and pulmonary. [EU] Bronchopulmonary Dysplasia: A chronic lung disease appearing in certain newborn infants treated for respiratory distress syndrome with mechanical ventilation and elevated concentration of inspired oxygen. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Butyrates: Salts and esters of butyric acid [NIH] Butyric Acid: A four carbon acid, CH3CH2CH2COOH, with an unpleasant odor that occurs in butter and animal fat as the glycerol ester. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium Channels: Voltage-dependent cell membrane glycoproteins selectively permeable to calcium ions. They are categorized as L-, T-, N-, P-, Q-, and R-types based on the activation and inactivation kinetics, ion specificity, and sensitivity to drugs and toxins. The L- and T-types are present throughout the cardiovascular and central nervous systems and the N-, P-, Q-, & R-types are located in neuronal tissue. [NIH] Calorimeter: Measures the amounts of heat absorbed or given off by a solid, a liquid, or a gas. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Cardiac: Having to do with the heart. [NIH] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart

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and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] Catastrophic Illness: An acute or prolonged illness usually considered to be life-threatening or with the threat of serious residual disability. Treatment may be radical and is frequently costly. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Ceftriaxone: Broad-spectrum cephalosporin antibiotic with a very long half-life and high penetrability to usually inaccessible infections, including those involving the meninges, eyes, inner ears, and urinary tract. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Adhesion Molecules: Surface ligands, usually glycoproteins, that mediate cell-to-cell adhesion. Their functions include the assembly and interconnection of various vertebrate systems, as well as maintenance of tissue integration, wound healing, morphogenic movements, cellular migrations, and metastasis. [NIH] Cell Count: A count of the number of cells of a specific kind, usually measured per unit

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volume of sample. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Centromere: The clear constricted portion of the chromosome at which the chromatids are joined and by which the chromosome is attached to the spindle during cell division. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Angiography: Radiography of the vascular system of the brain after injection of a contrast medium. [NIH] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]

Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Chelation: Combination with a metal in complexes in which the metal is part of a ring. [EU] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and

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activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemokines, C: Group of chemokines without adjacent cysteines that are chemoattractants for lymphocytes only. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotaxis: The movement of cells or organisms toward or away from a substance in response to its concentration gradient. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chest Pain: Pressure, burning, or numbness in the chest. [NIH] Chimeras: Organism that contains a mixture of genetically different cells. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chloroplasts: Plant cell inclusion bodies that contain the photosynthetic pigment chlorophyll, which is associated with the membrane of thylakoids. Chloroplasts occur in cells of leaves and young stems of higher plants. [NIH] Cholangitis: Inflammation of a bile duct. [NIH] Cholecystectomy: Surgical removal of the gallbladder. [NIH] Cholelithiasis: Presence or formation of gallstones. [NIH] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [NIH]

Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chromosome Banding: Staining of bands, or chromosome segments, allowing the precise identification of individual chromosomes or parts of chromosomes. Applications include the determination of chromosome rearrangements in malformation syndromes and cancer, the

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chemistry of chromosome segments, chromosome changes during evolution, and, in conjunction with cell hybridization studies, chromosome mapping. [NIH] Chromosome Fragility: Susceptibility of chromosomes to breakage and translocation or other aberrations. Chromosome fragile sites are regions that show up in karyotypes as a gap (uncondensed stretch) on the chromatid arm. They are associated with chromosome break sites and other aberrations. A fragile site on the X chromosome is associated with fragile X syndrome. Fragile sites are designated by the letters "FRA" followed by the designation for the specific chromosome and a letter which refers to the different fragile sites on a chromosome (e.g. FRAXA). [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [NIH] Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Clot Retraction: Retraction of a clot resulting from contraction of platelet pseudopods attached to fibrin strands that is dependent on the contractile protein thrombosthenin. Used as a measure of platelet function. [NIH] Cluster Analysis: A set of statistical methods used to group variables or observations into strongly inter-related subgroups. In epidemiology, it may be used to analyze a closely grouped series of events or cases of disease or other health-related phenomenon with welldefined distribution patterns in relation to time or place or both. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cobalt: A trace element that is a component of vitamin B12. It has the atomic symbol Co, atomic number 27, and atomic weight 58.93. It is used in nuclear weapons, alloys, and pigments. Deficiency in animals leads to anemia; its excess in humans can lead to

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erythrocytosis. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colonoscopy: Endoscopic examination, therapy or surgery of the luminal surface of the colon. [NIH] Competency: The capacity of the bacterium to take up DNA from its surroundings. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement

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activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Concentric: Having a common center of curvature or symmetry. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confidence Intervals: A range of values for a variable of interest, e.g., a rate, constructed so that this range has a specified probability of including the true value of the variable. [NIH] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Consensus Sequence: A theoretical representative nucleotide or amino acid sequence in which each nucleotide or amino acid is the one which occurs most frequently at that site in the different sequences which occur in nature. The phrase also refers to an actual sequence which approximates the theoretical consensus. A known conserved sequence set is represented by a consensus sequence. Commonly observed supersecondary protein structures (amino acid motifs) are often formed by conserved sequences. [NIH] Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a consensus sequence. Amino acid motifs are often composed of conserved

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sequences. [NIH] Consolidation: The healing process of a bone fracture. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contrast Media: Substances used in radiography that allow visualization of certain tissues. [NIH]

Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Cor pulmonale: Heart disease that results from resistance to the passage of blood through the lungs; it often leads to right heart failure. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH]

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Corpuscle: A small mass or body; a sensory nerve end bulb; a cell, especially that of the blood or the lymph. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Cromolyn Sodium: A chromone complex that acts by inhibiting the release of chemical mediators from sensitized mast cells. It is used in the prophylactic treatment of both allergic and exercise-induced asthma, but does not affect an established asthmatic attack. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cyanosis: A bluish or purplish discoloration of the skin and mucous membranes due to an increase in the amount of deoxygenated hemoglobin in the blood or a structural defect in the hemoglobin molecule. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cystathionine beta-Synthase: A multifunctional pyridoxal phosphate enzyme. In the second stage of cysteine biosynthesis it catalyzes the reaction of homocysteine with serine to form cystathionine with the elimination of water. Deficiency of this enzyme leads to hyperhomocysteinemia and homocystinuria. EC 4.2.1.22. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, .

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New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Death Certificates: Official records of individual deaths including the cause of death certified by a physician, and any other required identifying information. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Deferoxamine: Natural product isolated from Streptomyces pilosus. It forms iron complexes and is used as a chelating agent, particularly in the form of its mesylate. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydration: The condition that results from excessive loss of body water. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dental Care: The total of dental diagnostic, preventive, and restorative services provided to meet the needs of a patient (from Illustrated Dictionary of Dentistry, 1982). [NIH] Deoxycytidine: A drug that protects healthy tissues from the toxic effects of anticancer drugs. [NIH] Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary

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genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleic acid: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleotides: A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Dextroamphetamine: The d-form of amphetamine. It is a central nervous system stimulant and a sympathomimetic. It has also been used in the treatment of narcolepsy and of attention deficit disorders and hyperactivity in children. Dextroamphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulating release of monamines, and inhibiting monoamine oxidase. It is also a drug of abuse and a psychotomimetic. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diagnostic Services: Organized services for the purpose of providing diagnosis to promote and maintain health. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diathesis: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the person more than usually susceptible to certain diseases. [EU] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Diploid: Having two sets of chromosomes. [NIH] Dipyridamole: A drug that prevents blood cell clumping and enhances the effectiveness of fluorouracil and other chemotherapeutic agents. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place,

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or identity. [EU] Dissection: Cutting up of an organism for study. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dose-limiting: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Double-blinded: A clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duodenum: The first part of the small intestine. [NIH] Ectopic: Pertaining to or characterized by ectopia. [EU] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Ego: The conscious portion of the personality structure which serves to mediate between the demands of the primitive instinctual drives, (the id), of internalized parental and social

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prohibitions or the conscience, (the superego), and of reality. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embolism: Blocking of a blood vessel by a blood clot or foreign matter that has been transported from a distant site by the blood stream. [NIH] Embolization: The blocking of an artery by a clot or foreign material. Embolization can be done as treatment to block the flow of blood to a tumor. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood

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capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxin: Toxin from cell walls of bacteria. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enucleation: Removal of the nucleus from an eucaryiotic cell. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Erythroblasts: Immature, nucleated erythrocytes occupying the stage of erythropoiesis that follows formation of erythroid progenitor cells and precedes formation of reticulocytes. Popularly called normoblasts. [NIH] Erythrocyte Indices: Quantification of size and cell hemoglobin content or concentration of the erythrocyte, usually derived from erythrocyte count, blood hemoglobin concentration, and hematocrit. Includes the mean cell volume (MCV), mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC). Use also for cell diameter and thickness. [NIH] Erythrocyte Membrane: The semipermeable outer portion of the red corpuscle. It is known as a 'ghost' after hemolysis. [NIH] Erythrocyte Transfusion: The transfer of erythrocytes from a donor to a recipient or reinfusion to the donor. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH]

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Erythroid Progenitor Cells: Committed, erythroid stem cells derived from myeloid stem cells. The progenitor cells develop in two phases: erythroid burst-forming units (BFU-E) followed by erythroid colony-forming units (CFU-E). BFU-E differentiate into CFU-E on stimulation by erythropoietin, and then further differentiate into erythroblasts when stimulated by other factors. [NIH] Erythropoiesis: The production of erythrocytes. [EU] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Estrogens: A class of sex hormones associated with the development and maintenance of secondary female sex characteristics and control of the cyclical changes in the reproductive cycle. They are also required for pregnancy maintenance and have an anabolic effect on protein metabolism and water retention. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Euchromatin: Chromosome regions that are loosely packaged and more accessible to RNA polymerases than heterochromatin. These regions also stain differentially in chromosome banding preparations. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evacuation: An emptying, as of the bowels. [EU] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Excrete: To get rid of waste from the body. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Eye Color: Color of the iris. [NIH] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Eye socket: One of the two cavities in the skull which contains an eyeball. Each eye is located in a bony socket or orbit. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fathers: Male parents, human or animal. [NIH]

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Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Febrile: Pertaining to or characterized by fever. [EU] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Fetal Hemoglobin: The major component of hemoglobin in the fetus. This hemoglobin has two alpha and two gamma polypeptide subunits in comparison to normal adult hemoglobin, which has two alpha and two beta polypeptide subunits. Fetal hemoglobin concentrations can be elevated (usually above 0.5%) in children and adults affected by leukemia and several types of anemia. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibroid: A benign smooth muscle tumor, usually in the uterus or gastrointestinal tract. Also called leiomyoma. [NIH] Fibronectin: An adhesive glycoprotein. One form circulates in plasma, acting as an opsonin; another is a cell-surface protein which mediates cellular adhesive interactions. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Flatus: Gas passed through the rectum. [NIH] Fludarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Focus Groups: A method of data collection and a qualitative research tool in which a small group of individuals are brought together and allowed to interact in a discussion of their

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opinions about topics, issues, or questions. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Friction: Surface resistance to the relative motion of one body against the rubbing, sliding, rolling, or flowing of another with which it is in contact. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Products, rev: Trans-acting nuclear proteins whose functional expression are required for HIV viral replication. Specifically, the rev gene products are required for processing and translation of the HIV gag and env mRNAs, and thus rev regulates the expression of the viral structural proteins. rev can also regulate viral regulatory proteins. A cis-acting

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antirepression sequence (CAR) in env, also known as the rev-responsive element (RRE), is responsive to the rev gene product. rev is short for regulator of virion. [NIH] Gene Silencing: Interruption or suppression of the expression of a gene at transcriptional or translational levels. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genes, env: DNA sequences that form the coding region for the viral envelope (env) proteins in retroviruses. The env genes contain a cis-acting RNA target sequence for the rev protein (= gene products, rev), termed the rev-responsive element (RRE). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]

Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germline mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; germline mutations are passed on from parents to offspring. Also called hereditary mutation. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH] Glomeruli: Plural of glomerulus. [NIH] Glomerulosclerosis: Scarring of the glomeruli. It may result from diabetes mellitus (diabetic glomerulosclerosis) or from deposits in parts of the glomerulus (focal segmental glomerulosclerosis). The most common signs of glomerulosclerosis are proteinuria and

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kidney failure. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycogen Storage Disease: A group of inherited metabolic disorders involving the enzymes responsible for the synthesis and degradation of glycogen. In some patients, prominent liver involvement is presented. In others, more generalized storage of glycogen occurs, sometimes with prominent cardiac involvement. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Granule: A small pill made from sucrose. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Hair Color: Color of hair or fur. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of

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allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Health Education: Education that increases the awareness and favorably influences the attitudes and knowledge relating to the improvement of health on a personal or community basis. [NIH] Health Fairs: Community health education events focused on prevention of disease and promotion of health through audiovisual exhibits. [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heartbeat: One complete contraction of the heart. [NIH] Hematocrit: Measurement of the volume of packed red cells in a blood specimen by centrifugation. The procedure is performed using a tube with graduated markings or with automated blood cell counters. It is used as an indicator of erythrocyte status in disease. For example, anemia shows a low hematocrit, polycythemia, high values. [NIH] Hematologist: A doctor who specializes in treating diseases of the blood. [NIH] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic growth factors: A group of proteins that cause blood cells to grow and mature. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH]

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Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin A: Normal adult human hemoglobin. The globin moiety consists of two alpha and two beta chains. [NIH] Hemoglobin C: A commonly occurring abnormal hemoglobin in which lysine replaces a glutamic acid residue at the sixth position of the beta chains. It results in reduced plasticity of erythrocytes. [NIH] Hemoglobin E: An abnormal hemoglobin that results from the substitution of lysine for glutamic acid at position 26 of the beta chain. It is most frequently observed in southeast Asian populations. [NIH] Hemoglobin H: An abnormal hemoglobin composed of four beta chains. It is caused by the reduced synthesis of the alpha chain. This abnormality results in alpha-thalassemia. [NIH] Hemoglobin M: A group of abnormal hemoglobins in which amino acid substitutions take place in either the alpha or beta chains but near the heme iron. This results in facilitated oxidation of the hemoglobin to yield excess methemoglobin which leads to cyanosis. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemophilia: Refers to a group of hereditary disorders in which affected individuals fail to make enough of certain proteins needed to form blood clots. [NIH] Hemoptysis: Bronchial hemorrhage manifested with spitting of blood. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemosiderosis: Conditions in which there is a generalized increase in the iron stores of body tissues, particularly of liver and the reticuloendothelial system, without demonstrable tissue damage. The name refers to the presence of stainable iron in the tissue in the form of hemosiderin. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocyte: A liver cell. [NIH]

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Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Hereditary mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; hereditary mutations are passed on from parents to offspring. Also called germline mutation. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heritability: The proportion of observed variation in a particular trait that can be attributed to inherited genetic factors in contrast to environmental ones. [NIH] Heterochromatin: The portion of chromosome material that remains condensed and is transcriptionally inactive during interphase. [NIH] Heterodimer: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Heterozygote: An individual having different alleles at one or more loci in homologous chromosome segments. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histone Deacetylase: Hydrolyzes N-acetyl groups on histones. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Hydration: Combining with water. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH]

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Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. [NIH] Hyperbaric: Characterized by greater than normal pressure or weight; applied to gases under greater than atmospheric pressure, as hyperbaric oxygen, or to a solution of greater specific gravity than another taken as a standard of reference. [EU] Hyperbaric oxygen: Oxygen that is at an atmospheric pressure higher than the pressure at sea level. Breathing hyperbaric oxygen to enhance the effectiveness of radiation therapy is being studied. [NIH] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperhomocysteinemia: An inborn error of methionone metabolism which produces an excess of homocysteine in the blood. It is often caused by a deficiency of cystathionine betasynthase and is a risk factor for coronary vascular disease. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypoventilation: A reduction in the amount of air entering the pulmonary alveoli. [NIH] Hypoxanthine: A purine and a reaction intermediate in the metabolism of adenosine and in the formation of nucleic acids by the salvage pathway. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

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Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoelectrophoresis: A technique that combines protein electrophoresis and double immunodiffusion. In this procedure proteins are first separated by gel electrophoresis (usually agarose), then made visible by immunodiffusion of specific antibodies. A distinct elliptical precipitin arc results for each protein detectable by the antisera. [NIH] Immunoglobulins: Glycoproteins present in the blood (antibodies) and in other tissue. They are classified by structure and activity into five classes (IgA, IgD, IgE, IgG, IgM). [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppression: Deliberate prevention or diminution of the host's immune response. It may be nonspecific as in the administration of immunosuppressive agents (drugs or radiation) or by lymphocyte depletion or may be specific as in desensitization or the simultaneous administration of antigen and immunosuppressive drugs. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate

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agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant, Newborn: An infant during the first month after birth. [NIH] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Information Systems: Integrated set of files, procedures, and equipment for the storage, manipulation, and retrieval of information. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Integrins: A family of transmembrane glycoproteins consisting of noncovalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement, and other cells, while their intracellular domains interact with the cytoskeleton. The integrins consist of at least three identified families: the cytoadhesin receptors, the leukocyte adhesion receptors, and the very-late-antigen receptors. Each family

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contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and oncogenic transformation. [NIH] Interleukin-3: A multilineage cell growth factor secreted by lymphocytes, epithelial cells, and astrocytes which stimulates clonal proliferation and differentiation of various types of blood and tissue cells. Also called multi-CSF, it is considered one of the hematopoietic colony stimulating factors. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Interphase: The interval between two successive cell divisions during which the chromosomes are not individually distinguishable and DNA replication occurs. [NIH] Intestinal: Having to do with the intestines. [NIH] Intestinal Mucosa: The surface lining of the intestines where the cells absorb nutrients. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intracellular: Inside a cell. [NIH] Intrahepatic: Within the liver. [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Introns: Non-coding, intervening sequences of DNA that are transcribed, but are removed from within the primary gene transcript and rapidly degraded during maturation of messenger RNA. Most genes in the nuclei of eukaryotes contain introns, as do mitochondrial and chloroplast genes. [NIH] Inulin: A starch found in the tubers and roots of many plants. Since it is hydrolyzable to fructose, it is classified as a fructosan. It has been used in physiologic investigation for determination of the rate of glomerular function. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Invertebrates: Animals that have no spinal column. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is called an ion pump. Secondary active transport utilizes the voltage and ion gradients produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [NIH]

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Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Irrigation: The washing of a body cavity or surface by flowing solution which is inserted and then removed. Any drug in the irrigation solution may be absorbed. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Ischemic Colitis: Decreased blood flow to the colon. Causes fever, pain, and bloody diarrhea. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kinetic: Pertaining to or producing motion. [EU]

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Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lag: The time elapsing between application of a stimulus and the resulting reaction. [NIH] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Leg Ulcer: Ulceration of the skin and underlying structures of the lower extremity. About 90% of the cases are due to venous insufficiency (varicose ulcer), 5% to arterial disease, and the remaining 5% to other causes. [NIH] Leiomyoma: A benign tumor derived from smooth muscle tissue, also known as a fibroid tumor. They rarely occur outside of the uterus and the gastrointestinal tract but can occur in the skin and subcutaneous tissues, probably arising from the smooth muscle of small blood vessels in these tissues. [NIH] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukemia: Cancer of blood-forming tissue. [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Life Expectancy: A figure representing the number of years, based on known statistics, to which any person of a given age may reasonably expect to live. [NIH] Ligaments: Shiny, flexible bands of fibrous tissue connecting together articular extremities of bones. They are pliant, tough, and inextensile. [NIH] Ligands: A RNA simulation method developed by the MIT. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol,

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and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locus Control Region: A regulatory region first identified in the human beta-globin locus but subsequently found in other loci. The region is believed to regulate transcription by opening and remodeling chromatin structure. It may also have enhancer activity. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lucida: An instrument, invented by Wollaton, consisting essentially of a prism or a mirror through which an object can be viewed so as to appear on a plane surface seen in direct view and on which the outline of the object may be traced. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte Depletion: Immunosuppression by reduction of circulating lymphocytes or by T-cell depletion of bone marrow. The former may be accomplished in vivo by thoracic duct drainage or administration of antilymphocyte serum. The latter is performed ex vivo on bone marrow before its transplantation. [NIH] Lymphocyte Subsets: A classification of lymphocytes based on structurally or functionally different populations of cells. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in

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which lymphocytes develop. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Angiography: Non-invasive method of vascular imaging and determination of internal anatomy without injection of contrast media or radiation exposure. The technique is used especially in cerebral angiography as well as for studies of other vascular structures. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammography: Radiographic examination of the breast. [NIH] Mandible: The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. [NIH] Mandibular Condyle: The posterior process on the ramus of the mandible composed of two parts: a superior part, the articular portion, and an inferior part, the condylar neck. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU]

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Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] Methylphenidate: A central nervous system stimulant used most commonly in the treatment of attention-deficit disorders in children and for narcolepsy. Its mechanisms appear to be similar to those of dextroamphetamine. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes

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capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Miscarriage: Spontaneous expulsion of the products of pregnancy before the middle of the second trimester. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Monogenic: A human disease caused by a mutation in a single gene. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monosomy: The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2N-1. [NIH] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Mosaicism: The occurrence in an individual of two or more cell populations of different

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chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myeloproliferative Disorders: Disorders in which one or more stimuli cause proliferation of hemopoietically active tissue or of tissue which has embryonic hemopoietic potential. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]

Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myopia: That error of refraction in which rays of light entering the eye parallel to the optic axis are brought to a focus in front of the retina, as a result of the eyeball being too long from front to back (axial m.) or of an increased strength in refractive power of the media of the eye (index m.). Called also nearsightedness, because the near point is less distant than it is in emmetropia with an equal amplitude of accommodation. [EU] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Nalbuphine: A narcotic used as a pain medication. It appears to be an agonist at kappa opioid receptors and an antagonist or partial agonist at mu opioid receptors. [NIH]

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Narcolepsy: A condition of unknown cause characterized by a periodic uncontrollable tendency to fall asleep. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Nephropathy: Disease of the kidneys. [EU] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutrophil: A type of white blood cell. [NIH] Niche: The ultimate unit of the habitat, i. e. the specific spot occupied by an individual organism; by extension, the more or less specialized relationships existing between an organism, individual or synusia(e), and its environment. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

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Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Envelope: The membrane system of the cell nucleus that surrounds the nucleoplasm. It consists of two concentric membranes separated by the perinuclear space. The structures of the envelope where it opens to the cytoplasm are called the nuclear pores (nuclear pore). [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nurse Practitioners: Nurses who are specially trained to assume an expanded role in providing medical care under the supervision of a physician. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Observational study: An epidemiologic study that does not involve any intervention, experimental or otherwise. Such a study may be one in which nature is allowed to take its course, with changes in one characteristic being studied in relation to changes in other characteristics. Analytical epidemiologic methods, such as case-control and cohort study designs, are properly called observational epidemiology because the investigator is observing without intervention other than to record, classify, count, and statistically analyze results. [NIH] Occupational Health: The promotion and maintenance of physical and mental health in the work environment. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oncologist: A doctor who specializes in treating cancer. Some oncologists specialize in a particular type of cancer treatment. For example, a radiation oncologist specializes in treating cancer with radiation. [NIH] On-line: A sexually-reproducing population derived from a common parentage. [NIH]

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Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Orbit: One of the two cavities in the skull which contains an eyeball. Each eye is located in a bony socket or orbit. [NIH] Orbital: Pertaining to the orbit (= the bony cavity that contains the eyeball). [EU] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Osteogenic sarcoma: A malignant tumor of the bone. Also called osteosarcoma. [NIH] Osteomyelitis: Inflammation of bone caused by a pyogenic organism. It may remain localized or may spread through the bone to involve the marrow, cortex, cancellous tissue, and periosteum. [EU] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Overall survival: The percentage of subjects in a study who have survived for a defined period of time. Usually reported as time since diagnosis or treatment. Often called the survival rate. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous

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antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, cell respiration, or aerobic metabolism. [NIH] Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] Particle: A tiny mass of material. [EU] Paternity: Establishing the father relationship of a man and a child. [NIH] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH]

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Patient Selection: Criteria and standards used for the determination of the appropriateness of the inclusion of patients with specific conditions in proposed treatment plans and the criteria used for the inclusion of subjects in various clinical trials and other research protocols. [NIH] PDQ: Physician Data Query. PDQ is an online database developed and maintained by the National Cancer Institute. Designed to make the most current, credible, and accurate cancer information available to health professionals and the public, PDQ contains peer-reviewed summaries on cancer treatment, screening, prevention, genetics, and supportive care; a registry of cancer clinical trials from around the world; and directories of physicians, professionals who provide genetics services, and organizations that provide cancer care. Most of this information is available on the CancerNet Web site, and more specific information about PDQ can be found at http://cancernet.nci.nih.gov/pdq.html. [NIH] Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Penicillin Resistance: Nonsusceptibility of an organism to the action of penicillins. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periorbital: Situated around the orbit, or eye socket. [EU] Peripheral blood: Blood circulating throughout the body. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Pharmacodynamics: The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of actions and effects of drugs with their chemical structure; also, such effects on the actions of a particular drug or drugs. [EU] Pharmacogenetics: A branch of genetics which deals with the genetic components of variability in individual responses to and metabolism (biotransformation) of drugs. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions

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between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenylbutyrate: An anticancer drug that belongs to the family of drugs called differentiating agents. [NIH] Phlebotomy: The letting of blood from a vein. Although it is one of the techniques used in drawing blood to be used in diagnostic procedures, in modern medicine, it is used commonly in the treatment of erythrocytosis, hemochromocytosis, polycythemia vera, and porphyria cutanea tarda. Its historical counterpart is bloodletting. (From Cecil Textbook of Medicine, 19th ed & Wintrobe's Clinical Hematology, 9th ed) Venipuncture is not only for the letting of blood from a vein but also for the injecting of a drug into the vein for diagnostic analysis. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Phylogeny: The relationships of groups of organisms as reflected by their evolutionary history. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pilot Projects: Small-scale tests of methods and procedures to be used on a larger scale if the pilot study demonstrates that these methods and procedures can work. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH]

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Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Plumbism: Disease caused by the gradual accumulation of a significant body burden of lead. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyvalent: Having more than one valence. [EU] Porphyria: A group of disorders characterized by the excessive production of porphyrins or their precursors that arises from abnormalities in the regulation of the porphyrin-heme

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pathway. The porphyrias are usually divided into three broad groups, erythropoietic, hepatic, and erythrohepatic, according to the major sites of abnormal porphyrin synthesis. [NIH]

Porphyria Cutanea Tarda: A form of hepatic porphyria (porphyria, hepatic) characterized by photosensitivity resulting in bullae that rupture easily to form shallow ulcers. This condition occurs in two forms: a sporadic, nonfamilial form that begins in middle age and has normal amounts of uroporphyrinogen decarboxylase with diminished activity in the liver; and a familial form in which there is an autosomal dominant inherited deficiency of uroporphyrinogen decarboxylase in the liver and red blood cells. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Post-traumatic: Occurring as a result of or after injury. [EU] Potentiating: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Priapism: Persistent abnormal erection of the penis, usually without sexual desire, and accompanied by pain and tenderness. It is seen in diseases and injuries of the spinal cord, and may be caused by vesical calculus and certain injuries to the penis. [EU] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Progeny: The offspring produced in any generation. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU]

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Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Protein Subunits: Single chains of amino acids that are the units of a multimeric protein. They can be identical or non-identical subunits. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteoglycans: Glycoproteins which have a very high polysaccharide content. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]

Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Protozoan: 1. Any individual of the protozoa; protozoon. 2. Of or pertaining to the protozoa; protozoal. [EU] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU]

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Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychopharmacology: The study of the effects of drugs on mental and behavioral activity. [NIH]

Puberty: The period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. [EU] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Alveoli: Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Pyogenic: Producing pus; pyopoietic (= liquid inflammation product made up of cells and a thin fluid called liquor puris). [EU] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quiescent: Marked by a state of inactivity or repose. [EU] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation oncologist: A doctor who specializes in using radiation to treat cancer. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation

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therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Ramus: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reabsorption: 1. The act or process of absorbing again, as the selective absorption by the kidneys of substances (glucose, proteins, sodium, etc.) already secreted into the renal tubules, and their return to the circulating blood. 2. Resorption. [EU] Reaction Time: The time from the onset of a stimulus until the organism responds. [NIH] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH]

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Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]

Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Repopulation: The replacement of functional cells, usually by proliferation, following or during irradiation. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Research Support: Financial support of research activities. [NIH] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Reticulocytes: Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic "reticulum" (not the same as the endoplasmic reticulum), hence the name reticulocytes. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH]

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Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Detachment: Separation of the inner layers of the retina (neural retina) from the pigment epithelium. Retinal detachment occurs more commonly in men than in women, in eyes with degenerative myopia, in aging and in aphakia. It may occur after an uncomplicated cataract extraction, but it is seen more often if vitreous humor has been lost during surgery. (Dorland, 27th ed; Newell, Ophthalmology: Principles and Concepts, 7th ed, p310-12). [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retrospective: Looking back at events that have already taken place. [NIH] Retrospective study: A study that looks backward in time, usually using medical records and interviews with patients who already have or had a disease. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Rheology: The study of the deformation and flow of matter, usually liquids or fluids, and of the plastic flow of solids. The concept covers consistency, dilatancy, liquefaction, resistance to flow, shearing, thixotrophy, and viscosity. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ribonucleic acid: RNA. One of the two nucleic acids found in all cells. The other is deoxyribonucleic acid (DNA). Ribonucleic acid transfers genetic information from DNA to proteins produced by the cell. [NIH] Ribonucleoside Diphosphate Reductase: An enzyme of the oxidoreductase class that catalyzes the formation of 2'-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. (From Dorland, 27th ed) EC 1.17.4.1. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rickets: A condition caused by deficiency of vitamin D, especially in infancy and childhood, with disturbance of normal ossification. The disease is marked by bending and distortion of the bones under muscular action, by the formation of nodular enlargements on the ends and

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sides of the bones, by delayed closure of the fontanelles, pain in the muscles, and sweating of the head. Vitamin D and sunlight together with an adequate diet are curative, provided that the parathyroid glands are functioning properly. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risk-Taking: Undertaking a task involving a challenge for achievement or a desirable goal in which there is a lack of certainty or a fear of failure. It may also include the exhibiting of certain behaviors whose outcomes may present a risk to the individual or to those associated with him or her. [NIH] Rods: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide side vision and the ability to see objects in dim light (night vision). [NIH] Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH] Sequela: Any lesion or affection following or caused by an attack of disease. [EU] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important

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physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Sickle Cell Trait: The condition of being heterozygous for hemoglobin S. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep apnea: A serious, potentially life-threatening breathing disorder characterized by repeated cessation of breathing due to either collapse of the upper airway during sleep or absence of respiratory effort. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Work: The use of community resources, individual case work, or group work to promote the adaptive capacities of individuals in relation to their social and economic environments. It includes social service agencies. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH]

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Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Somatic mutations: Alterations in DNA that occur after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other diseases. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectroscopic: The recognition of elements through their emission spectra. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spherocytes: Small, abnormal spherical red blood cells with more than the normal amount of hemoglobin. [NIH] Spherocytosis: A condition in which there are abnormally thick, almost spherical, red blood cells or spherocytes in the blood. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Splenomegaly: Enlargement of the spleen. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stabilization: The creation of a stable state. [EU] Standardize: To compare with or conform to a standard; to establish standards. [EU] Stasis: A word termination indicating the maintenance of (or maintaining) a constant level; preventing increase or multiplication. [EU] Statistically significant: Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. [NIH] Steady state: Dynamic equilibrium. [EU] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the

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ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stenosis: Narrowing or stricture of a duct or canal. [EU] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Streptococcal: Caused by infection due to any species of streptococcus. [NIH] Streptococci: A genus of spherical Gram-positive bacteria occurring in chains or pairs. They are widely distributed in nature, being important pathogens but often found as normal commensals in the mouth, skin, and intestine of humans and other animals. [NIH] Streptococcus: A genus of gram-positive, coccoid bacteria whose organisms occur in pairs or chains. No endospores are produced. Many species exist as commensals or parasites on man or animals with some being highly pathogenic. A few species are saprophytes and occur in the natural environment. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroke Volume: The amount of blood pumped out of the heart per beat not to be confused with cardiac output (volume/time). [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally

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conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Sudden death: Cardiac arrest caused by an irregular heartbeat. The term "death" is somewhat misleading, because some patients survive. [NIH] Superego: The component of the personality associated with ethics, standards, and selfcriticism - the "conscience". It is derived mainly from identification with parents and parent substitutes. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Tachypnea: Rapid breathing. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH]

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Thalassemia: A group of hereditary hemolytic anemias in which there is decreased synthesis of one or more hemoglobin polypeptide chains. There are several genetic types with clinical pictures ranging from barely detectable hematologic abnormality to severe and fatal anemia. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thromboembolism: Obstruction of a vessel by a blood clot that has been transported from a distant site by the blood stream. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tissue Plasminogen Activator: A proteolytic enzyme in the serine protease family found in many tissues which converts plasminogen to plasmin. It has fibrin-binding activity and is immunologically different from urinary plasminogen activator. The primary sequence, composed of 527 amino acids, is identical in both the naturally occurring and synthetic proteases. EC 3.4.21.68. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a

Dictionary 243

heavy metal. [EU] Tonicity: The normal state of muscular tension. [NIH] Tonsils: Small masses of lymphoid tissue on either side of the throat. [NIH] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicokinetics: Study of the absorption, distribution, metabolism, and excretion of test substances. [NIH] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]

Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH]

244

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Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Transplantation Conditioning: Preparative treatment of transplant recipient with various conditioning regimens including radiation, immune sera, chemotherapy, and/or immunosuppressive agents, prior to transplantation. Transplantation conditioning is very common before bone marrow transplantation. [NIH] Transplantation Tolerance: An induced state of non-reactivity to grafted tissue from a donor organism that would ordinarily trigger a cell-mediated or humoral immune response. [NIH]

Trans-Splicing: The joining of RNA from two different genes. One type of trans-splicing is the "spliced leader" type (primarily found in protozoans such as trypanosomes and in lower invertebrates such as nematodes) which results in the addition of a capped, noncoding, spliced leader sequence to the 5' end of mRNAs. Another type of trans-splicing is the "discontinuous group II introns" type (found in plant/algal chloroplasts and plant mitochondria) which results in the joining of two independently transcribed coding sequences. Both are mechanistically similar to conventional nuclear pre-mRNA cis-splicing. Mammalian cells are also capable of trans-splicing. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series. [NIH]

Tricuspid Atresia: Absence of the orifice between the right atrium and ventricle, with the presence of an atrial defect through which all the systemic venous return reaches the left heart. As a result, there is left ventricular hypertrophy because the right ventricle is absent or not functional. [NIH] Trimetrexate: A nonclassical folic acid inhibitor through its inhibition of the enzyme dihydrofolate reductase. It is being tested for efficacy as an antineoplastic agent and as an antiparasitic agent against Pneumocystis carinii pneumonia in AIDS patients. Myelosuppression is its dose-limiting toxic effect. [NIH] Trinucleotide Repeat Expansion: DNA region comprised of a variable number of repetitive, contiguous trinucleotide sequences. The presence of these regions is associated with diseases such as Fragile X Syndrome and myotonic dystrophy. Many chromosome fragile sites (chromosome fragility) contain expanded trinucleotide repeats. [NIH] Trinucleotide Repeats: Microsatellite repeats consisting of three nucleotides dispersed in the euchromatic arms of chromosomes. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [NIH]

Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines

Dictionary 245

and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ultraviolet radiation: Invisible rays that are part of the energy that comes from the sun. UV radiation can damage the skin and cause melanoma and other types of skin cancer. UV radiation that reaches the earth's surface is made up of two types of rays, called UVA and UVB rays. UVB rays are more likely than UVA rays to cause sunburn, but UVA rays pass deeper into the skin. Scientists have long thought that UVB radiation can cause melanoma and other types of skin cancer. They now think that UVA radiation also may add to skin damage that can lead to skin cancer and cause premature aging. For this reason, skin specialists recommend that people use sunscreens that reflect, absorb, or scatter both kinds of UV radiation. [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Uraemia: 1. An excess in the blood of urea, creatinine, and other nitrogenous end products of protein and amino acids metabolism; more correctly referred to as azotemia. 2. In current usage the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic frost on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances. [EU]

Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Uridine Diphosphate: A uracil nucleotide containing a pyrophosphate group esterified to C5 of the sugar moiety. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]

246

Sickle Cell Anemia

Varicose: The common ulcer in the lower third of the leg or near the ankle. [NIH] Varicose Ulcer: Ulcer due to varicose veins. Chronic venous insufficiency in the deep veins of the legs leads to shunting the venous return into the superficial veins, in which pressure and flow rate, as well as oxygen content, are increased. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH]

Dictionary 247

Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Vitamin D: The vitamin that mediates intestinal calcium absorption, bone calcium metabolism, and probably muscle activity. It usually acts as a hormone precursor, requiring 2 stages of metabolism before reaching actual hormonal form. It is isolated from fish liver oils and used in the treatment and prevention of rickets. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitreous Humor: The transparent, colorless mass of gel that lies behind the lens and in front of the retina and fills the center of the eyeball. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xanthine: An urinary calculus. [NIH] Xanthine Oxidase: An iron-molybdenum flavoprotein containing FAD that oxidizes hypoxanthine, some other purines and pterins, and aldehydes. Deficiency of the enzyme, an autosomal recessive trait, causes xanthinuria. EC 1.1.3.22. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

248

INDEX 3 3-dimensional, 136, 167, 182 A Abdomen, 182, 204, 216, 219, 228, 239, 240, 247 Abdominal, 72, 107, 177, 182, 227 Abdominal Pain, 72, 107, 182 Abscess, 95, 182 Absenteeism, 89, 182 Acceptor, 182, 218, 227 Acculturation, 16, 182 Acetylcholine, 182, 194, 224 Acute renal, 182, 211 Adaptability, 182, 193 Adenine, 130, 182, 233 Adenosine, 131, 182, 213, 229 Adenosine Triphosphate, 131, 182, 229 Adenovirus, 163, 182 Adjustment, 51, 182 Adolescence, 182, 228 Adrenal Cortex, 183, 199 Adrenal Glands, 183, 185 Adrenal Medulla, 183, 192, 204, 225 Adrenergic, 183, 184, 204, 241 Adverse Effect, 23, 183, 238 Aerobic, 183, 222, 227 Affinity, 34, 46, 62, 92, 183, 188, 238 Age Groups, 50, 183 Aged, 80 and Over, 183 Agonist, 61, 183, 223 Airway, 59, 183, 238 Albumin, 183, 230 Aldehydes, 119, 183, 247 Algorithms, 183, 189 Alkaline, 183, 184, 191 Alkaloid, 183, 222 Alleles, 132, 149, 184, 212 Allogeneic, 13, 32, 45, 99, 184 Alopecia, 184, 199 Alpha-1, 145, 149, 184 Alpha-Thalassemia, 69, 78, 92, 95, 105, 107, 184, 211 Alternative medicine, 184 Amine, 184, 212 Amino Acid Sequence, 184, 186, 197 Amino Acid Substitution, 34, 184, 211 Amino Acids, 34, 132, 136, 142, 184, 196, 197, 226, 228, 230, 232, 236, 237, 242, 243, 245

Amitriptyline, 41, 184 Ammonia, 184, 209 Amnion, 184 Amniotic Fluid, 158, 160, 184 Amplification, 41, 184 Ampulla, 185, 194 Amyloidosis, 103, 185 Anaesthesia, 185, 214 Anal, 185, 219 Analgesic, 14, 185, 222, 226 Analogous, 185, 243 Anaphylatoxins, 185, 197 Anatomical, 50, 60, 185, 188, 194, 201, 214, 237 Anemic, 30, 33, 39, 185 Anesthesia, 97, 108, 122, 183, 185 Anesthetics, 185, 204 Aneuploidy, 142, 143, 185 Aneurysm, 185, 246 Angina, 44, 185 Animal model, 24, 26, 28, 43, 50, 110, 185 Ankylosis, 71, 185 Anomalies, 10, 185 Antagonism, 42, 185 Anterior Cerebral Artery, 186, 193 Antibiotic, 19, 69, 186, 192, 228, 239 Antibodies, 47, 65, 137, 186, 210, 211, 213, 214, 230 Antibody, 45, 51, 70, 97, 137, 183, 186, 196, 210, 212, 214, 215, 217, 220, 222, 234, 239 Anticholinergic, 184, 186 Anticoagulant, 186, 232 Antidepressant, 184, 186 Antigen, 45, 183, 186, 196, 212, 213, 214, 215, 220 Antigen-Antibody Complex, 186, 196 Anti-inflammatory, 20, 38, 186, 187 Anti-Inflammatory Agents, 20, 186, 187 Antimetabolite, 186, 206, 221 Antimicrobial, 19, 93, 186 Antineoplastic, 186, 199, 206, 213, 221, 244 Antioxidant, 110, 112, 186, 187, 227 Antiplasmin, 36, 186 Antisickling Agents, 11, 186 Anuria, 187, 217 Anus, 185, 187, 196 Aphakia, 187, 236 Apnea, 187 Apolipoproteins, 187, 219

Index 249

Apoptosis, 47, 48, 81, 131, 140, 187 Applicability, 53, 187 Aqueous, 187, 188, 200 Arachidonic Acid, 187, 218 Arginine, 58, 185, 187, 212, 224 Arterial, 187, 193, 194, 198, 213, 218, 232, 241 Arteries, 187, 190, 198, 219, 223, 233 Arterioles, 187, 190, 191, 221, 223, 246 Arteriovenous, 187, 222 Artery, 44, 101, 185, 186, 187, 198, 203, 223, 233, 235 Articular, 187, 218, 220 Ascorbic Acid, 111, 187 Aspiration, 101, 187 Aspirin, 17, 187 Assay, 12, 43, 187 Astrocytes, 187, 216 Asymptomatic, 15, 27, 188, 189, 227 Atmospheric Pressure, 188, 213 Atrial, 188, 198, 244 Atrioventricular, 188, 198 Atrium, 188, 198, 244, 246 Atrophy, 86, 188 Atypical, 3, 88, 153, 188 Autodigestion, 188, 227 Autologous, 32, 64, 188 B Bacteremia, 70, 88, 109, 188 Bacterium, 188, 196, 211 Base Sequence, 141, 188, 207 Basement Membrane, 46, 188, 205, 218 Benign, 17, 87, 188, 206, 210, 218 Benign tumor, 188, 218 Beta-Thalassemia, 11, 26, 28, 33, 40, 43, 54, 55, 56, 79, 81, 90, 94, 98, 102, 103, 105, 115, 189 Bewilderment, 189, 197 Bile, 189, 194, 207, 217, 219, 240 Bile duct, 189, 194 Bile Pigments, 189, 217 Biliary, 72, 189, 194, 227 Biliary Tract, 189, 227 Bilirubin, 38, 93, 105, 107, 179, 183, 189, 213 Bioavailability, 27, 119, 189 Bioavailable, 33, 189 Biochemical, 26, 62, 108, 145, 184, 186, 189, 217, 228, 237 Biological response modifier, 115, 189 Biological therapy, 189, 209 Biomarkers, 15, 50, 189

Biosynthesis, 34, 187, 189, 199, 237 Biotechnology, 5, 39, 68, 125, 136, 163, 165, 170, 189 Biotin, 24, 189 Biotransformation, 189, 228 Bladder, 190, 232, 245 Blastocyst, 190, 197 Blood Cell Count, 190, 210 Blood Coagulation, 92, 190, 191, 242 Blood Glucose, 190, 211, 215 Blood Groups, 20, 46, 190 Blood pressure, 4, 56, 99, 111, 148, 190, 192, 213, 222, 233, 238 Blood transfusion, 72, 82, 97, 98, 119, 123, 126, 190 Blot, 51, 190 Body Burden, 190, 230 Body Composition, 52, 190 Body Fluids, 189, 190, 238, 244 Bone Marrow, 18, 32, 33, 46, 54, 64, 66, 164, 174, 190, 205, 208, 214, 219, 222, 223, 244 Bone Marrow Transplantation, 54, 64, 66, 190, 244 Bradykinin, 190, 224, 230 Bronchi, 190, 191, 204, 243 Bronchial, 74, 191, 211, 212 Bronchopulmonary, 59, 191 Bronchopulmonary Dysplasia, 59, 191 Buccal, 158, 160, 191 Butyrates, 25, 191 Butyric Acid, 191 C Calcium, 40, 191, 196, 223, 232, 247 Calcium Channels, 41, 191 Calorimeter, 43, 191 Capillary, 190, 191, 208, 233, 246 Capsules, 191, 208 Carbohydrate, 191, 230 Carbon Dioxide, 191, 200, 207, 246 Carcinogenic, 191, 215, 225, 232, 240 Carcinogens, 191, 226 Cardiac, 43, 44, 63, 112, 191, 198, 204, 209, 223, 240, 241 Cardiac Output, 43, 191, 240 Cardiovascular, 16, 28, 97, 101, 167, 191, 218, 238 Cardiovascular disease, 28, 167, 191 Carnitine, 78, 192 Carotene, 117, 192, 236 Carrier Proteins, 192, 230

250

Sickle Cell Anemia

Case report, 98, 100, 108, 109, 115, 123, 192, 195 Case series, 192, 195 Catabolism, 43, 192 Cataract, 187, 192, 236 Catastrophic Illness, 19, 192 Catecholamine, 192, 228 Caudal, 192, 231 Causal, 60, 192, 211 Cause of Death, 192, 200 Ceftriaxone, 69, 83, 192 Cell Adhesion, 15, 38, 48, 58, 61, 62, 192, 216 Cell Adhesion Molecules, 15, 192 Cell Count, 15, 24, 192 Cell Cycle, 28, 139, 140, 193 Cell Death, 140, 187, 193, 224 Cell Division, 132, 139, 140, 152, 153, 188, 193, 209, 216, 221, 222, 229, 237 Cell membrane, 29, 46, 80, 191, 192, 193, 216, 229 Cell proliferation, 47, 193 Cell Respiration, 193, 222, 227 Cell Survival, 24, 77, 193, 209 Cell Transplantation, 12, 19, 35, 37, 46, 88, 193 Central Nervous System, 19, 60, 99, 182, 191, 193, 201, 207, 209, 210, 218, 221, 222, 226, 237 Central Nervous System Infections, 193, 210 Centrifugation, 28, 193, 210 Centromere, 132, 135, 193 Cerebral, 54, 74, 101, 186, 193, 204, 207, 220 Cerebral Angiography, 193, 220 Cerebral Infarction, 54, 101, 193 Cerebrovascular, 17, 50, 95, 192, 193 Cerebrum, 193 Chelation, 63, 66, 114, 193 Chemokines, 32, 193, 194 Chemotactic Factors, 194, 197 Chemotaxis, 59, 194 Chemotherapeutic agent, 194, 201 Chemotherapy, 19, 32, 194, 244 Chest Pain, 44, 59, 91, 194 Chimeras, 33, 194 Chin, 194, 221 Chloroplasts, 194, 244 Cholangitis, 96, 194 Cholecystectomy, 107, 194 Cholelithiasis, 71, 93, 103, 194

Cholestasis, 96, 194 Cholesterol, 101, 131, 189, 194, 195, 198, 213, 218, 219, 240 Cholesterol Esters, 194, 218 Cholinergic, 184, 194 Choroid, 50, 194, 235 Chromatin, 10, 25, 42, 44, 187, 194, 219 Chromosomal, 140, 142, 143, 153, 154, 155, 157, 184, 185, 194, 212, 223 Chromosome Banding, 194, 205 Chromosome Fragility, 195, 244 Chronic Disease, 38, 195 Chylomicrons, 195, 219 Cirrhosis, 63, 195, 210 CIS, 40, 42, 43, 51, 55, 56, 83, 195, 207, 208, 236, 244 Clinical Medicine, 38, 92, 97, 107, 166, 195, 231 Clinical Protocols, 56, 63, 195 Clinical study, 24, 65, 195, 198 Clinical trial, 12, 13, 14, 16, 18, 22, 25, 37, 41, 45, 57, 59, 65, 66, 79, 163, 164, 167, 170, 195, 198, 202, 228, 232, 234 Cloning, 26, 30, 189, 195 Clot Retraction, 195, 230 Cluster Analysis, 30, 195 Coagulation, 15, 17, 35, 49, 99, 105, 190, 195, 211, 230 Cobalt, 116, 195 Codon, 137, 196 Coenzyme, 112, 187, 196 Cofactor, 36, 196, 232, 242 Cognition, 60, 196 Collagen, 188, 196, 206, 230 Collapse, 196, 238 Colloidal, 183, 196, 203 Colon, 146, 196, 217 Colonoscopy, 148, 196 Competency, 52, 196 Complement, 15, 23, 65, 185, 196, 197, 208, 215, 217, 220, 230 Complementary medicine, 111, 197 Complementation, 26, 197 Computational Biology, 19, 170, 197 Concentric, 197, 225 Conception, 139, 197, 206, 239, 240 Cones, 197, 236 Confidence Intervals, 36, 197 Confounding, 49, 197 Confusion, 146, 197, 201, 245 Congestive heart failure, 27, 197

Index 251

Connective Tissue, 187, 190, 196, 197, 206, 207 Consciousness, 185, 197, 200, 202 Consensus Sequence, 197 Conserved Sequence, 83, 197 Consolidation, 18, 198 Constipation, 119, 198 Constriction, 132, 135, 198, 217, 246 Consultation, 154, 155, 158, 159, 198 Continuous infusion, 14, 39, 198 Contraindications, ii, 198 Contrast Media, 198, 220 Control group, 50, 198, 231, 234 Controlled clinical trial, 52, 198 Coordination, 21, 41, 198 Cor, 27, 198 Cor pulmonale, 27, 198 Coronary, 44, 192, 198, 213, 223 Coronary Arteriosclerosis, 198, 223 Coronary heart disease, 192, 198 Coronary Thrombosis, 198, 223 Corpuscle, 199, 204 Cortex, 102, 199, 226 Cortical, 60, 199, 205, 237 Cortisol, 100, 183, 199 Cranial, 199, 210, 226 Craniocerebral Trauma, 199, 210 Cromolyn Sodium, 75, 199 Crossing-over, 199, 234 Cultured cells, 39, 199 Curative, 12, 19, 37, 64, 199, 237, 242 Cyanosis, 199, 211 Cyclic, 199, 209, 224 Cyclophosphamide, 45, 199 Cystathionine beta-Synthase, 199, 213 Cysteine, 48, 194, 199 Cystine, 199 Cytochrome, 199, 227 Cytokine, 38, 48, 49, 200 Cytoplasm, 129, 130, 131, 137, 187, 193, 200, 209, 219, 222, 225, 236 Cytosine, 130, 200, 233 Cytoskeleton, 200, 215 Cytotoxic, 24, 200, 214 Cytotoxicity, 97, 200 D Data Collection, 200, 206 De novo, 28, 140, 200 Death Certificates, 148, 200 Decarboxylation, 200, 212 Decitabine, 25, 200 Defense Mechanisms, 200, 216

Deferoxamine, 39, 63, 113, 200 Degenerative, 200, 211, 236 Dehydration, 24, 29, 51, 54, 200 Deletion, 26, 30, 56, 142, 187, 200 Dementia, 143, 200 Dendrites, 200, 224 Dental Care, 108, 200 Deoxycytidine, 25, 200 Deoxyribonucleic, 130, 200, 201, 236 Deoxyribonucleic acid, 130, 201, 236 Deoxyribonucleotides, 200, 201, 236 Desensitization, 201, 214 Dextroamphetamine, 201, 221 Diabetes Mellitus, 201, 208, 211 Diagnostic procedure, 118, 201, 229 Diagnostic Services, 21, 201 Diarrhea, 201, 217 Diastole, 201 Diastolic, 78, 95, 201, 213 Diathesis, 48, 201 Diffusion, 201, 216 Digestion, 189, 201, 216, 219, 240, 245 Dihydrotestosterone, 201, 235 Dilatation, Pathologic, 201, 246 Dilation, 190, 201, 246 Diploid, 185, 197, 201, 222, 229, 244 Dipyridamole, 24, 201 Direct, iii, 12, 21, 25, 26, 33, 65, 158, 159, 160, 195, 201, 219, 235 Discrimination, 160, 161, 166, 201 Disease Progression, 15, 31, 109, 201 Disorientation, 197, 201 Dissection, 86, 202 Dissociation, 46, 183, 202 Dissociative Disorders, 202 Distal, 202, 232 Dorsal, 202, 231 Dose-limiting, 33, 202, 244 Double-blind, 13, 14, 52, 82, 202 Double-blinded, 14, 52, 202 Drive, 202, 216 Drug Resistance, 33, 98, 202 Drug Tolerance, 202, 242 Duodenum, 39, 189, 202, 240 E Ectopic, 26, 202 Effector, 13, 182, 196, 202 Efficacy, 13, 17, 23, 28, 39, 41, 42, 45, 64, 202, 244 Ego, 122, 202 Elective, 97, 203 Electrocoagulation, 195, 203

252

Sickle Cell Anemia

Electrolyte, 203, 217, 238, 245 Electrons, 186, 188, 203, 217, 226, 227, 233 Electrophoresis, 179, 203, 214 Elementary Particles, 203, 232 Emboli, 101, 203 Embolism, 100, 203 Embolization, 101, 203 Embolus, 203, 215 Embryo, 26, 56, 139, 140, 141, 149, 184, 190, 203, 214 Endemic, 203, 220, 239 Endogenous, 26, 33, 203, 226, 243 Endothelial cell, 27, 32, 35, 37, 40, 46, 48, 59, 61, 62, 65, 203, 242 Endothelium, 15, 27, 32, 35, 40, 48, 57, 61, 65, 97, 108, 203, 204, 224, 230 Endothelium, Lymphatic, 203 Endothelium, Vascular, 203 Endothelium-derived, 204, 224 Endotoxin, 204, 245 Energy balance, 43, 204 Enhancer, 204, 219 Enucleation, 46, 204 Environmental Health, 169, 170, 204 Enzymatic, 191, 192, 196, 204, 206, 212, 236 Enzyme Inhibitors, 204, 230 Epidemic, 204, 239 Epidemiological, 22, 62, 204 Epigastric, 204, 227 Epinephrine, 101, 183, 204, 224, 225, 245 Epithelial, 204, 216, 218 Epithelial Cells, 204, 216, 218 Epithelium, 188, 203, 204, 217, 236 Erection, 204, 231 Erythroblasts, 19, 40, 46, 204, 205 Erythrocyte Indices, 190, 204 Erythrocyte Membrane, 108, 204 Erythrocyte Transfusion, 63, 204 Erythrocytes, 25, 26, 29, 34, 37, 38, 54, 62, 65, 80, 112, 185, 187, 190, 204, 205, 211, 235 Erythroid Progenitor Cells, 204, 205 Erythropoiesis, 25, 33, 38, 46, 59, 75, 81, 204, 205 Erythropoietin, 10, 59, 82, 205 Estrogens, 205, 209 Ethnic Groups, 52, 154, 157, 205 Euchromatin, 44, 205 Eukaryotic Cells, 205, 214, 226, 245 Evacuation, 198, 205 Excitatory, 205, 209 Excrete, 187, 205, 217

Exhaustion, 186, 205, 220 Exocrine, 205, 227 Exogenous, 189, 203, 205 Extracellular, 188, 197, 205, 206, 215, 238 Extracellular Matrix, 197, 205, 206, 215 Extraction, 187, 205, 236 Extremity, 205, 218 Eye Color, 141, 205 Eye Infections, 182, 205 Eye socket, 205, 228 F Family Planning, 170, 205 Fat, 100, 187, 190, 191, 192, 198, 203, 205, 218, 238 Fathers, 29, 149, 205 Fatigue, 4, 178, 206, 210 Fatty acids, 42, 47, 183, 206 Febrile, 119, 206, 220 Feces, 198, 206, 240 Femur, 73, 206 Ferritin, 38, 96, 113, 137, 206 Fetal Hemoglobin, 25, 26, 33, 39, 43, 57, 58, 90, 92, 94, 95, 206 Fetus, 157, 158, 160, 164, 205, 206, 231, 240, 245 Fibrin, 186, 190, 195, 206, 230, 242 Fibrinogen, 206, 230, 242 Fibrinolysis, 36, 92, 206 Fibroblasts, 30, 206 Fibroid, 206, 218 Fibronectin, 65, 206 Fibrosis, 63, 67, 141, 144, 148, 149, 206, 237 Flatus, 206, 207 Fludarabine, 45, 206 Fluorescence, 62, 206 Fluorouracil, 201, 206 Focus Groups, 52, 206 Folate, 36, 113, 114, 207 Folic Acid, 207, 244 Forearm, 190, 207 Frameshift, 142, 207 Frameshift Mutation, 142, 207 Free Radicals, 186, 202, 207, 223 Friction, 127, 207 Frontal Lobe, 61, 186, 193, 207 G Gallbladder, 85, 180, 182, 189, 194, 207 Ganglia, 182, 207, 224 Gas, 109, 184, 191, 201, 206, 207, 212, 224, 225, 233, 246 Gas exchange, 109, 207, 233, 246 Gastric, 188, 192, 207, 212

Index 253

Gastrin, 207, 212 Gastrointestinal, 86, 190, 204, 206, 207, 218, 220, 237, 241, 244 Gastrointestinal tract, 206, 207, 218, 237, 244 Gene Expression, 25, 28, 30, 32, 33, 40, 42, 43, 56, 57, 64, 137, 138, 207, 208 Gene Products, rev, 207, 208 Gene Silencing, 25, 26, 40, 44, 208 Gene Therapy, 11, 19, 27, 34, 38, 64, 70, 81, 162, 163, 164, 182, 208 Genes, env, 148, 208 Genetic Engineering, 189, 195, 208 Genetic testing, 151, 155, 156, 157, 158, 159, 160, 161, 166, 208 Genital, 52, 208, 245 Genitourinary, 86, 208, 245 Genomics, 15, 18, 167, 208 Genotype, 13, 36, 65, 208, 229 Germ Cells, 140, 164, 208, 221, 239, 241 Germline mutation, 28, 140, 208, 212 Gestation, 208, 228 Gland, 183, 208, 227, 232, 237, 240, 242 Glomerular, 15, 78, 208, 216, 217 Glomerular Filtration Rate, 15, 208, 217 Glomeruli, 208 Glomerulosclerosis, 99, 208 Glomerulus, 208, 209 Glucose, 81, 187, 190, 201, 209, 211, 215, 234 Glutamate, 92, 209 Glutamic Acid, 9, 119, 207, 209, 211, 224 Glutamine, 92, 114, 209 Glycogen, 70, 209 Glycogen Storage Disease, 70, 209 Glycoprotein, 93, 186, 205, 206, 209, 218, 242, 244 Gonadotropin, 52, 88, 209 Governing Board, 209, 231 Graft, 37, 209, 223 Grafting, 37, 209, 214 Granule, 209, 236 Granulocytes, 209, 218, 247 Growth factors, 25, 32, 48, 209 Guanine, 130, 209, 233 Guanylate Cyclase, 40, 209, 224 H Habitat, 209, 224 Hair Color, 141, 209 Half-Life, 192, 209 Haplotypes, 46, 71, 72, 78, 88, 209 Haptens, 183, 210

Headache, 41, 210 Headache Disorders, 210 Health Education, 210 Health Fairs, 21, 210 Health Services, 6, 63, 210 Health Status, 53, 210 Heart attack, 44, 192, 210 Heart failure, 4, 198, 210 Heartbeat, 210, 241 Hematocrit, 48, 190, 204, 210 Hematologist, 17, 27, 53, 66, 210 Hematopoiesis, 93, 210 Hematopoietic growth factors, 31, 210 Hematopoietic Stem Cells, 27, 32, 64, 210 Hemochromatosis, 39, 157, 210 Hemodialysis, 210, 217 Hemodynamics, 91, 96, 210 Hemoglobinopathies, 11, 17, 21, 22, 23, 28, 32, 33, 36, 37, 43, 47, 48, 54, 119, 125, 208, 211 Hemolysis, 30, 37, 69, 83, 204, 211 Hemolytic, 32, 37, 56, 62, 70, 77, 88, 119, 211, 242 Hemophilia, 149, 211 Hemoptysis, 74, 211 Hemorrhage, 199, 203, 210, 211, 223, 240 Hemosiderosis, 116, 211 Hemostasis, 32, 211, 216, 238 Hepatic, 63, 76, 113, 183, 211, 231 Hepatitis, 104, 211 Hepatocyte, 194, 211 Hereditary, 27, 29, 129, 130, 140, 149, 155, 208, 211, 212, 236, 242 Hereditary mutation, 140, 208, 212 Heredity, 69, 132, 207, 208, 212 Heritability, 50, 57, 212 Heterochromatin, 44, 205, 212 Heterodimer, 26, 212 Heterogeneity, 30, 32, 82, 94, 183, 212 Heterozygote, 97, 212 Histamine, 14, 185, 212 Histidine, 212 Histone Deacetylase, 25, 57, 212 Histones, 132, 194, 212 Homogeneous, 97, 212 Homologous, 56, 184, 199, 208, 212, 237 Hormonal, 51, 188, 212, 247 Hormone, 88, 137, 199, 204, 205, 207, 212, 215, 241, 242, 247 Humoral, 212, 244 Hydration, 24, 29, 51, 212

254

Sickle Cell Anemia

Hydrogen, 182, 184, 188, 191, 212, 218, 222, 227, 232 Hydrolysis, 190, 212, 216, 230, 232 Hydrophobic, 213, 218 Hyperbaric, 113, 213 Hyperbaric oxygen, 113, 213 Hyperbilirubinemia, 213, 217 Hypercholesterolemia, 35, 213 Hyperhomocysteinemia, 36, 199, 213 Hyperlipidemia, 35, 213 Hyperplasia, 99, 213 Hypersensitivity, 201, 213, 218 Hypertension, 4, 16, 52, 99, 192, 210, 213, 245 Hypertrophy, 198, 213, 244 Hypotension, 56, 213 Hypoventilation, 56, 213 Hypoxanthine, 213, 247 Hypoxia, 20, 38, 57, 59, 185, 213 Hypoxic, 36, 65, 213 I Imaging procedures, 213, 243 Imidazole, 189, 212, 213 Immune response, 36, 45, 186, 210, 213, 214, 220, 241, 244, 245, 246 Immune Sera, 213, 214, 244 Immune system, 45, 189, 213, 214, 218, 220, 228, 245, 247 Immunity, 64, 213, 243 Immunization, 96, 214 Immunoelectrophoresis, 186, 214 Immunoglobulins, 214, 230 Immunologic, 194, 214 Immunology, 55, 97, 183, 214 Immunosuppressant, 206, 214, 221 Immunosuppression, 45, 214, 219 Immunosuppressive, 12, 199, 214, 244 Immunosuppressive Agents, 214, 244 Impairment, 60, 189, 194, 205, 214, 221 Implantation, 197, 214 Impotence, 51, 214 In situ, 51, 214 In Situ Hybridization, 51, 214 In vitro, 24, 25, 28, 33, 34, 42, 45, 46, 48, 55, 62, 113, 208, 214, 242 In vivo, 19, 25, 27, 28, 29, 33, 34, 39, 42, 45, 46, 48, 55, 58, 61, 62, 64, 119, 208, 214, 219, 226 Incubation, 214, 218 Incubation period, 214, 218 Induction, 24, 40, 43, 47, 57, 92, 119, 214 Infancy, 47, 167, 215, 236

Infant, Newborn, 183, 215 Infarction, 60, 86, 193, 215, 235 Infection, 19, 28, 36, 70, 74, 189, 194, 205, 213, 215, 218, 219, 224, 228, 240, 247 Information Systems, 65, 215 Informed Consent, 65, 158, 161, 166, 215 Infusion, 14, 215, 223, 243 Initiation, 215, 243 Inner ear, 192, 215 Inorganic, 39, 215 Insight, 27, 53, 59, 215 Insulator, 33, 215 Insulin, 52, 88, 215 Insulin-dependent diabetes mellitus, 215 Insulin-like, 52, 88, 215 Integrins, 46, 215 Interleukin-3, 92, 216 Intermittent, 33, 44, 50, 216 Internal Medicine, 16, 17, 38, 66, 87, 109, 122, 210, 216 Interphase, 212, 216 Intestinal, 39, 192, 216, 247 Intestinal Mucosa, 39, 216 Intestine, 216, 234, 238, 240 Intracellular, 25, 40, 93, 215, 216, 224 Intrahepatic, 74, 96, 216 Intravascular, 38, 216 Intravenous, 180, 215, 216 Intrinsic, 183, 188, 216 Introns, 58, 216, 244 Inulin, 208, 216 Invasive, 213, 216, 220 Invertebrates, 216, 244 Involuntary, 216, 223 Ion Channels, 44, 188, 216 Ion Transport, 29, 54, 216 Ions, 188, 191, 202, 203, 212, 216, 217, 232 Iris, 205, 217 Irradiation, 217, 235 Irrigation, 101, 217 Ischemia, 37, 44, 56, 60, 188, 217, 223, 235 Ischemic Colitis, 105, 217 J Jaundice, 4, 178, 213, 217 K Karyotype, 134, 217 Kb, 107, 217 Kidney Disease, 14, 169, 217 Kidney Failure, 143, 209, 217 Kidney Failure, Acute, 217 Kidney Failure, Chronic, 217 Kinetic, 217

Index 255

L Labile, 196, 218 Lag, 54, 218 Laminin, 46, 188, 218 Latent, 55, 218, 231 Leg Ulcer, 91, 218 Leiomyoma, 100, 206, 218 Lentivirus, 33, 64, 218 Lesion, 218, 237 Lethal, 65, 218 Leucocyte, 184, 218 Leukemia, 74, 206, 208, 218 Leukotrienes, 59, 187, 218 Life Expectancy, 49, 64, 218 Ligaments, 198, 218 Ligands, 192, 215, 218 Linkage, 26, 31, 32, 218 Lipid, 62, 187, 215, 218, 227 Lipid Peroxidation, 218, 227 Lipoprotein, 218, 219 Liver, 44, 86, 95, 96, 99, 138, 182, 183, 185, 187, 189, 192, 195, 199, 205, 206, 207, 209, 210, 211, 216, 219, 231, 247 Lobe, 186, 193, 219 Localized, 182, 185, 215, 218, 219, 226, 229 Locus Control Region, 56, 83, 219 Longitudinal study, 43, 219 Loop, 39, 219 Low-density lipoprotein, 35, 97, 219 Lucida, 218, 219 Lumbar, 73, 219 Lymph, 199, 203, 219 Lymphatic, 203, 215, 219, 239, 242 Lymphatic system, 219, 239, 242 Lymphocyte Depletion, 214, 219 Lymphocyte Subsets, 72, 219 Lymphocytes, 62, 186, 194, 214, 216, 218, 219, 239, 242, 247 Lymphoid, 186, 218, 219, 243 Lysine, 211, 212, 220 M Macrophage, 46, 140, 220 Magnetic Resonance Angiography, 99, 220 Magnetic Resonance Imaging, 17, 60, 83, 220 Major Histocompatibility Complex, 210, 220 Malaria, 36, 220 Malaria, Falciparum, 220 Malaria, Vivax, 220 Malnutrition, 183, 188, 220

Mammography, 148, 220 Mandible, 194, 220 Mandibular Condyle, 71, 220 Manifest, 47, 220 Mediate, 29, 38, 192, 202, 220 Mediator, 45, 220, 238 Medical Records, 148, 161, 221, 236 Medical Staff, 202, 221 MEDLINE, 170, 221 Meiosis, 139, 221 Melanin, 217, 221, 229, 245 Melanoma, 221, 245 Memory, 13, 60, 65, 200, 221 Meninges, 192, 193, 199, 221 Mental Disorders, 221, 232 Mental Health, iv, 11, 169, 171, 221, 225 Mental Processes, 202, 221, 233 Mental Retardation, 82, 153, 155, 157, 221 Mentors, 18, 221 Metabolic disorder, 209, 221 Metastasis, 192, 221 Methotrexate, 33, 77, 221 Methylphenidate, 13, 221 Microbe, 221, 243 Microbiology, 55, 74, 188, 221 Microcirculation, 58, 80, 221, 230 Microorganism, 196, 222, 247 Microscopy, 66, 188, 222 Miscarriage, 160, 222 Mitochondria, 130, 131, 143, 149, 150, 222, 223, 226, 244 Mitochondrial Swelling, 222, 224 Mitosis, 139, 187, 222 Mobility, 51, 62, 222 Modeling, 30, 60, 86, 222 Modification, 26, 31, 208, 222, 233 Molecule, 3, 9, 34, 38, 48, 61, 62, 130, 131, 132, 137, 186, 188, 196, 202, 204, 212, 222, 226, 227, 230, 234, 246 Monitor, 222, 225 Monoclonal, 45, 217, 222, 234 Monocytes, 20, 59, 222 Monogenic, 50, 222 Mononuclear, 222, 244 Monosomy, 143, 185, 222 Morphine, 14, 41, 56, 222, 224, 226 Morphological, 203, 222 Morphology, 50, 192, 210, 222 Mosaicism, 140, 222 Motion Sickness, 223, 224 Mutagenesis, 26, 42, 46, 48, 223 Mutagens, 207, 223

256

Sickle Cell Anemia

Myelogenous, 74, 223 Myeloproliferative Disorders, 18, 223 Myocardial infarction, 59, 69, 198, 223 Myocardial Ischemia, 69, 223 Myocardial Reperfusion, 223, 235 Myocardial Reperfusion Injury, 223, 235 Myocardium, 107, 223 Myopia, 223, 236 Myotonic Dystrophy, 152, 223, 244 N Nalbuphine, 14, 223 Narcolepsy, 201, 221, 224 Narcotic, 222, 223, 224 Nausea, 56, 224, 245 NCI, 1, 168, 195, 224, 228 Necrosis, 66, 71, 83, 119, 180, 187, 193, 215, 223, 224, 235 Nephropathy, 14, 217, 224 Nervous System, 19, 152, 193, 220, 224, 241 Networks, 22, 224 Neural, 212, 224, 236 Neuronal, 191, 224 Neurons, 44, 200, 205, 207, 224 Neuropathy, 149, 224 Neurotransmitter, 182, 190, 209, 212, 216, 224, 225, 241 Neutrophil, 95, 224 Niche, 24, 224 Nitric Oxide, 16, 27, 35, 47, 224 Nitrogen, 183, 184, 199, 209, 217, 225 Norepinephrine, 183, 184, 224, 225 Nuclear, 26, 30, 31, 47, 91, 107, 130, 195, 203, 205, 207, 224, 225, 244 Nuclear Envelope, 130, 225 Nuclear Pore, 225 Nuclei, 186, 203, 208, 212, 216, 220, 222, 225, 226, 232 Nucleic acid, 188, 200, 213, 214, 223, 225, 233, 236 Nurse Practitioners, 66, 158, 225 Nutritional Status, 19, 225 O Observational study, 8, 51, 100, 225 Occupational Health, 124, 225 Oliguria, 217, 225 Oncogenic, 216, 218, 225 Oncologist, 17, 225 On-line, 22, 177, 225 Open Reading Frames, 218, 226 Operon, 226, 235 Opiate, 222, 226

Opium, 222, 226 Opsin, 226, 236 Optic Nerve, 226, 235, 237 Orbit, 205, 226, 228 Orbital, 85, 107, 226 Organ Culture, 226, 242 Organelles, 129, 130, 193, 200, 222, 226, 230, 235 Osteogenic sarcoma, 226 Osteomyelitis, 94, 226 Osteosarcoma, 77, 226 Outpatient, 37, 101, 226 Ovaries, 157, 226, 238 Overall survival, 45, 226 Oxidants, 58, 226 Oxidation, 97, 182, 186, 190, 199, 211, 218, 226, 227 Oxidation-Reduction, 190, 226, 227 Oxidative metabolism, 218, 227 Oxidative Phosphorylation, 131, 227 Oxidative Stress, 35, 37, 50, 57, 227 Oxygenase, 38, 227 Oxygenation, 119, 227 P Palliative, 43, 227, 242 Pancreas, 116, 182, 189, 210, 215, 227, 244 Pancreatic, 192, 227 Pancreatitis, 106, 227 Particle, 62, 227, 243 Paternity, 157, 227 Pathologic, 13, 54, 187, 198, 213, 227, 246 Pathologic Processes, 187, 227 Pathologies, 78, 227 Pathophysiology, 13, 20, 29, 31, 37, 46, 47, 50, 51, 59, 62, 64, 101, 227 Patient Selection, 64, 228 PDQ, 168, 228 Pelvis, 182, 219, 226, 228, 245 Penicillin, 19, 64, 79, 88, 93, 100, 186, 228, 245 Penicillin Resistance, 64, 228 Penis, 228, 231 Peptide, 228, 230, 232 Perfusion, 40, 213, 228 Perinatal, 40, 228 Periorbital, 85, 228 Peripheral blood, 32, 45, 228 Phagocyte, 226, 228 Pharmacodynamics, 41, 228 Pharmacogenetics, 41, 228 Pharmacokinetic, 56, 228 Pharmacologic, 25, 43, 185, 209, 228, 243

Index 257

Pharmacotherapy, 13, 79, 90, 228 Phenotype, 26, 27, 29, 30, 32, 39, 41, 50, 197, 228 Phenylalanine, 137, 229, 245 Phenylbutyrate, 92, 229 Phlebotomy, 39, 63, 229 Phospholipids, 205, 218, 229 Phosphorus, 191, 229 Phosphorylation, 48, 131, 229 Photocoagulation, 195, 229 Phylogeny, 18, 229 Physical Examination, 49, 155, 229 Physiologic, 13, 183, 189, 209, 216, 229, 234 Physiology, 12, 39, 81, 92, 94, 210, 229, 246 Pigment, 189, 194, 221, 229, 236 Pilot Projects, 36, 229 Pilot study, 13, 17, 52, 53, 122, 229 Plants, 183, 191, 194, 209, 216, 222, 225, 229, 243 Plasma cells, 186, 230 Plasma protein, 62, 183, 203, 230, 232 Plasmin, 36, 186, 230, 242 Plasminogen Activators, 230 Plasticity, 211, 230 Plastids, 226, 230 Platelet Aggregation, 185, 224, 230 Platelets, 46, 61, 80, 108, 224, 230, 237, 242 Plumbism, 112, 230 Pneumonia, 198, 230, 244 Point Mutation, 26, 230 Poisoning, 224, 230 Polymerase, 230, 235 Polymers, 97, 230, 232 Polymorphism, 50, 68, 70, 71, 107, 159, 230 Polypeptide, 184, 196, 197, 206, 230, 242, 247 Polysaccharide, 96, 186, 230, 232 Polyvalent, 96, 230 Porphyria, 229, 230, 231 Porphyria Cutanea Tarda, 229, 231 Posterior, 61, 185, 194, 202, 217, 220, 227, 231, 237 Postnatal, 231, 240 Postoperative, 74, 231 Post-traumatic, 106, 210, 231 Potentiating, 184, 231 Practicability, 231, 244 Practice Guidelines, 171, 231 Preclinical, 12, 47, 64, 231 Precursor, 187, 199, 202, 204, 225, 229, 231, 232, 245, 247 Predisposition, 17, 231

Prenatal, 21, 102, 115, 116, 157, 160, 181, 203, 231 Prevalence, 27, 36, 49, 69, 71, 78, 102, 124, 145, 231 Priapism, 51, 79, 88, 98, 101, 102, 178, 231 Primary endpoint, 37, 231 Progeny, 26, 33, 231 Progression, 14, 17, 31, 106, 185, 231 Progressive, 14, 103, 143, 195, 200, 202, 217, 223, 224, 231 Promoter, 26, 40, 42, 44, 51, 93, 105, 107, 232 Prone, 143, 152, 232 Prophylaxis, 19, 64, 79, 88, 93, 100, 232, 245 Prospective study, 64, 219, 232 Prostate, 189, 232, 244 Protease, 232, 242 Protein Subunits, 4, 9, 232 Proteins, 15, 35, 40, 43, 46, 61, 129, 130, 132, 133, 136, 137, 138, 141, 142, 156, 158, 165, 167, 184, 186, 187, 189, 190, 192, 193, 194, 196, 207, 208, 210, 211, 212, 214, 222, 225, 228, 229, 230, 232, 234, 236, 238, 243, 246 Proteinuria, 208, 232 Proteoglycans, 188, 232 Proteolytic, 184, 196, 206, 230, 232, 242 Prothrombin, 15, 36, 68, 232, 242 Protocol, 13, 15, 22, 63, 91, 163, 232 Protons, 45, 212, 232, 233 Protozoan, 193, 220, 232 Proximal, 61, 73, 202, 232 Psychiatry, 53, 100, 232, 246 Psychic, 221, 232, 237 Psychology, 52, 53, 69, 105, 202, 233 Psychopharmacology, 13, 233 Puberty, 51, 233 Public Policy, 122, 170, 233 Pulmonary, 4, 8, 16, 20, 27, 40, 49, 59, 69, 78, 103, 190, 191, 198, 213, 217, 218, 233, 246 Pulmonary Alveoli, 213, 233 Pulmonary Artery, 190, 233, 246 Pulmonary Edema, 217, 233 Pulmonary hypertension, 4, 8, 20, 27, 78, 198, 233 Pulse, 76, 222, 233 Purifying, 26, 28, 233 Purines, 188, 233, 237, 247 Pyogenic, 226, 233 Pyridoxal, 36, 199, 233

258

Sickle Cell Anemia

Pyrimidines, 188, 233, 237 Q Quality of Life, 21, 22, 45, 53, 60, 63, 89, 233, 241 Quiescent, 28, 233 R Race, 36, 43, 52, 122, 123, 217, 233 Radiation, 182, 203, 206, 207, 213, 214, 217, 220, 225, 233, 234, 244, 245, 247 Radiation oncologist, 225, 233 Radiation therapy, 182, 213, 217, 233 Radioactive, 190, 209, 212, 214, 217, 225, 233, 234 Radioisotope, 234, 243 Radiology, 49, 60, 72, 74, 78, 85, 91, 100, 101, 116, 234 Ramus, 220, 234 Random Allocation, 234 Randomization, 22, 63, 234 Randomized, 13, 14, 24, 36, 46, 52, 63, 66, 69, 202, 234 Randomized clinical trial, 63, 234 Reabsorption, 103, 234 Reaction Time, 13, 234 Reactivation, 25, 44, 55, 57, 94, 234 Reactive Oxygen Species, 38, 234 Receptor, 14, 47, 48, 61, 146, 186, 234, 238 Recombinant, 33, 42, 82, 163, 234, 246 Recombination, 56, 208, 234 Rectum, 187, 196, 206, 207, 232, 234 Recurrence, 63, 234 Reductase, 33, 68, 108, 221, 235, 244 Refer, 1, 135, 139, 141, 146, 164, 191, 196, 235, 243 Refractory, 25, 203, 235 Regeneration, 84, 235 Regimen, 23, 25, 33, 45, 46, 195, 202, 228, 235 Reliability, 23, 235 Remission, 234, 235 Reperfusion, 37, 223, 235 Reperfusion Injury, 37, 235 Repopulation, 33, 235 Repressor, 25, 42, 226, 235 Reproductive cells, 142, 153, 154, 208, 212, 235 Research Support, 36, 235 Respiratory distress syndrome, 191, 235 Response rate, 33, 235 Reticulocytes, 14, 51, 65, 93, 105, 204, 235 Retina, 50, 65, 194, 197, 223, 226, 235, 236, 237, 247

Retinal, 48, 50, 66, 91, 113, 226, 236 Retinal Detachment, 113, 236 Retinoblastoma, 145, 236 Retinol, 236 Retinopathy, 48, 65, 229, 236 Retrospective, 82, 84, 104, 236 Retrospective study, 84, 104, 236 Retroviral vector, 27, 33, 208, 236 Rheology, 46, 57, 236 Rheumatoid, 227, 236 Rhodopsin, 226, 236 Ribonucleic acid, 137, 236 Ribonucleoside Diphosphate Reductase, 213, 236 Ribose, 182, 236 Ribosome, 137, 236, 243 Rickets, 236, 247 Risk factor, 8, 22, 27, 31, 103, 213, 232, 237 Risk-Taking, 60, 237 Rods, 236, 237 S Scatter, 237, 245 Schizophrenia, 150, 237 Sclera, 194, 237 Sclerosis, 146, 237 Screening, 5, 6, 7, 12, 67, 121, 124, 148, 157, 158, 160, 179, 195, 228, 237 Secretion, 40, 100, 212, 215, 237, 245 Secretory, 40, 237 Sedative, 184, 237 Sedimentation, 193, 237 Segmental, 208, 237 Segregation, 86, 234, 237 Seizures, 119, 237 Sepsis, 83, 237 Sequela, 123, 237 Sequencing, 25, 50, 165, 237 Serine, 199, 237, 242 Serotonin, 184, 224, 228, 237 Serous, 203, 238 Serum, 36, 76, 90, 93, 105, 107, 112, 179, 183, 185, 196, 209, 213, 217, 219, 238, 244 Sex Characteristics, 182, 205, 233, 238, 241 Shock, 66, 78, 238, 244 Sickle Cell Trait, 101, 103, 238 Side effect, 14, 56, 119, 164, 167, 183, 189, 199, 202, 238, 241, 243 Signs and Symptoms, 4, 5, 67, 151, 152, 157, 235, 238, 245 Skeletal, 122, 238 Skeleton, 206, 238 Skull, 199, 205, 226, 238, 241

Index 259

Sleep apnea, 50, 238 Small intestine, 195, 202, 212, 216, 238 Smooth muscle, 185, 206, 212, 218, 222, 238, 241 Social Environment, 233, 238 Social Work, 21, 52, 122, 154, 238 Sodium, 92, 234, 238 Soft tissue, 100, 190, 238 Soma, 239 Somatic, 140, 143, 154, 182, 212, 221, 222, 239 Somatic cells, 140, 143, 154, 221, 222, 239 Somatic mutations, 143, 239 Specialist, 158, 175, 201, 239 Specificity, 43, 183, 191, 239 Spectroscopic, 60, 239 Spectrum, 192, 239 Sperm, 28, 139, 140, 142, 143, 152, 153, 154, 157, 164, 194, 208, 212, 235, 239 Spherocytes, 239 Spherocytosis, 29, 239 Spinal cord, 187, 193, 194, 221, 224, 231, 239 Spleen, 4, 92, 102, 185, 219, 239 Splenomegaly, 101, 239 Sporadic, 29, 231, 236, 239 Stabilization, 33, 239 Standardize, 12, 239 Stasis, 38, 239 Statistically significant, 60, 239 Steady state, 77, 99, 239 Stem Cells, 28, 29, 32, 45, 75, 94, 205, 239 Stenosis, 240 Sterility, 79, 199, 240 Steroid, 199, 240 Stillbirth, 155, 240 Stimulant, 13, 201, 212, 221, 240, 245 Stimulus, 202, 216, 218, 234, 240, 242 Stomach, 182, 188, 207, 212, 224, 238, 239, 240 Stool, 196, 240 Strand, 130, 230, 240 Streptococcal, 88, 240 Streptococci, 69, 240 Streptococcus, 64, 98, 240 Stress, 15, 35, 38, 58, 61, 82, 178, 192, 199, 224, 227, 231, 240 Stricture, 74, 240 Stroke Volume, 191, 240 Subacute, 215, 240 Subarachnoid, 210, 240 Subclinical, 215, 237, 240

Subcutaneous, 39, 218, 240 Subspecies, 239, 240 Sudden death, 63, 241 Superego, 203, 241 Superoxide, 35, 241 Supplementation, 24, 36, 43, 50, 58, 111, 112, 113, 114, 116, 241 Support group, 21, 181, 241 Supportive care, 19, 228, 241 Suppression, 14, 37, 38, 45, 208, 241 Suppressive, 56, 241 Survival Rate, 226, 241 Sympathomimetic, 201, 204, 225, 241 Symptomatic, 15, 46, 227, 241 Synergistic, 24, 241 Systemic, 185, 190, 204, 210, 215, 217, 234, 241, 243, 244, 246 Systolic, 74, 82, 95, 213, 241 T Tachycardia, 188, 241 Tachypnea, 188, 241 Temporal, 51, 210, 241 Terminator, 196, 241 Testicular, 79, 241 Testis, 241 Testosterone, 52, 112, 235, 241 Thalassemia, 4, 6, 9, 10, 22, 27, 44, 49, 54, 81, 86, 104, 113, 174, 189, 242 Therapeutics, 47, 48, 242 Thermal, 202, 242 Threshold, 213, 242 Thrombin, 36, 40, 206, 230, 232, 242 Thrombocytes, 230, 242 Thromboembolism, 108, 242 Thrombomodulin, 232, 242 Thrombosis, 35, 41, 68, 72, 81, 92, 106, 108, 216, 232, 240, 242 Thymus, 214, 219, 242 Thyroid, 157, 242, 245 Thyroid Gland, 157, 242 Thyroid Hormones, 242, 245 Tissue Culture, 26, 39, 242 Tissue Plasminogen Activator, 106, 242 Tolerance, 13, 19, 182, 242 Tomography, 74, 91, 242 Tone, 58, 242 Tonicity, 211, 243 Tonsils, 50, 243 Tonus, 242, 243 Topical, 67, 243 Torsion, 215, 243

260

Sickle Cell Anemia

Toxic, iv, 12, 28, 37, 39, 45, 103, 129, 200, 213, 224, 243, 244 Toxicity, 13, 28, 33, 37, 39, 45, 163, 243 Toxicokinetics, 243 Toxicology, 170, 243 Toxin, 204, 242, 243 Trace element, 195, 243 Tracer, 123, 243 Trachea, 190, 242, 243 Transcription Factors, 42, 56, 138, 243 Transduction, 28, 64, 243 Transfection, 28, 58, 189, 208, 243 Transfer Factor, 214, 243 Transfusion, 17, 18, 19, 25, 63, 66, 70, 72, 77, 80, 82, 83, 91, 95, 96, 107, 180, 243 Transgenes, 26, 30, 56, 243 Translation, 34, 137, 138, 207, 243 Translational, 19, 55, 57, 58, 208, 243 Translocation, 40, 195, 243 Transmitter, 182, 188, 216, 220, 225, 244 Transplantation Conditioning, 33, 244 Transplantation Tolerance, 13, 244 Trans-Splicing, 58, 244 Trauma, 224, 227, 244 Treatment Outcome, 54, 244 Tricuspid Atresia, 198, 244 Trimetrexate, 33, 244 Trinucleotide Repeat Expansion, 152, 244 Trinucleotide Repeats, 244 Trisomy, 143, 185, 244 Tumor marker, 189, 244 Tumor Necrosis Factor, 65, 244 Tyrosine, 61, 245 U Ubiquitin, 34, 245 Ultraviolet radiation, 140, 245 Uracil, 233, 245 Uraemia, 227, 245 Uremia, 217, 245 Urethra, 228, 232, 245 Uridine Diphosphate, 93, 105, 245 Urinary, 77, 179, 192, 208, 225, 242, 245, 247 Urinary tract, 192, 245 Urine, 15, 177, 187, 190, 217, 225, 232, 245 Urogenital, 208, 245 Uterus, 157, 206, 218, 226, 245 V Vaccination, 65, 245 Vaccine, 64, 232, 245

Vacuoles, 226, 245 Valine, 9, 119, 245 Varicose, 218, 246 Varicose Ulcer, 218, 246 Vascular Resistance, 103, 246 Vasculitis, 227, 246 Vasoconstriction, 204, 246 Vasodilation, 35, 246 Vasodilator, 190, 212, 223, 246 Vector, 28, 33, 64, 162, 163, 243, 246 Vein, 185, 187, 216, 225, 229, 246 Venous, 77, 91, 108, 112, 187, 190, 193, 218, 232, 244, 246 Venous blood, 77, 112, 190, 193, 246 Ventilation, 109, 191, 246 Ventricle, 188, 198, 233, 241, 244, 246 Ventricular, 82, 94, 95, 103, 198, 223, 244, 246 Venules, 190, 191, 203, 221, 246 Veterinary Medicine, 170, 246 Viral, 33, 34, 109, 162, 207, 208, 225, 243, 246 Viral vector, 34, 246 Virulence, 243, 246 Virus, 28, 162, 193, 204, 208, 236, 243, 246 Viscera, 239, 247 Visceral, 101, 247 Viscosity, 236, 247 Vitreous, 235, 236, 247 Vitreous Body, 235, 247 Vitreous Humor, 236, 247 Vitro, 47, 48, 55, 157, 247 Vivo, 33, 34, 48, 58, 219, 247 W White blood cell, 31, 140, 179, 186, 219, 220, 224, 230, 247 Windpipe, 242, 247 Womb, 245, 247 Wound Healing, 192, 216, 247 X Xanthine, 35, 247 Xanthine Oxidase, 35, 247 Xenograft, 64, 185, 247 X-ray, 34, 179, 206, 217, 225, 233, 234, 247 Y Yeasts, 229, 247 Z Zygote, 197, 223, 247 Zymogen, 232, 247