Hemochromatosis - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

HEMOCHROMATOSIS A 3-in-1 Medical Reference A Bibliography and Dictionary for Physicians, Patients, and Genome Resea...

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HEMOCHROMATOSIS

A

3-in-1

Medical

Reference

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

HEMOCHROMATOSIS 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

ii

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., 1960Hemochromatosis: 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: 0-497-11228-0 1. Hemochromatosis-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 hemochromatosis. 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 HEMOCHROMATOSIS ................................................................................ 3 Overview........................................................................................................................................ 3 Genetics Home Reference ............................................................................................................... 3 What Is Hemochromatosis? ........................................................................................................... 3 How Common Is Hemochromatosis?............................................................................................. 4 What Genes Are Related to Hemochromatosis?............................................................................. 4 How Do People Inherit Hemochromatosis? ................................................................................... 5 Where Can I Find Additional Information about Hemochromatosis? ........................................... 5 References....................................................................................................................................... 7 What Is the Official Name of the HAMP Gene?............................................................................ 9 What Is the Normal Function of the HAMP Gene? ...................................................................... 9 What Conditions Are Related to the HAMP Gene? ...................................................................... 9 Where Is the HAMP Gene Located? .............................................................................................. 9 References..................................................................................................................................... 10 What Is the Official Name of the HFE Gene? .............................................................................. 11 What Is the Normal Function of the HFE Gene?......................................................................... 11 What Conditions Are Related to the HFE Gene? ........................................................................ 11 Where Is the HFE Gene Located? ................................................................................................ 12 References..................................................................................................................................... 13 What Is the Official Name of the HFE2 Gene? ............................................................................ 14 What Is the Normal Function of the HFE2 Gene?....................................................................... 14 What Conditions Are Related to the HFE2 Gene? ...................................................................... 14 Where Is the HFE2 Gene Located? .............................................................................................. 15 References..................................................................................................................................... 15 What Is the Official Name of the SLC40A1 Gene?...................................................................... 16 What Is the Normal Function of the SLC40A1 Gene? ................................................................ 16 What Conditions Are Related to the SLC40A1 Gene? ................................................................ 16 Where Is the SLC40A1 Gene Located? ........................................................................................ 16 References..................................................................................................................................... 17 What Is the Official Name of the TFR2 Gene? ............................................................................ 18 What Is the Normal Function of the TFR2 Gene? ....................................................................... 18 What Conditions Are Related to the TFR2 Gene?....................................................................... 19 Where Is the TFR2 Gene Located?............................................................................................... 19 References..................................................................................................................................... 19 Federally Funded Research on Hemochromatosis ........................................................................ 20 The National Library of Medicine: PubMed ................................................................................ 55 CHAPTER 2. ALTERNATIVE MEDICINE AND HEMOCHROMATOSIS .............................................. 100 Overview.................................................................................................................................... 100 National Center for Complementary and Alternative Medicine................................................ 100 Additional Web Resources ......................................................................................................... 105 General References ..................................................................................................................... 106 CHAPTER 3. PATENTS ON HEMOCHROMATOSIS........................................................................... 107 Overview.................................................................................................................................... 107 Patent Applications on Hemochromatosis ................................................................................. 107 Keeping Current ........................................................................................................................ 109 CHAPTER 4. BOOKS ON HEMOCHROMATOSIS .............................................................................. 110 Overview.................................................................................................................................... 110 Book Summaries: Online Booksellers......................................................................................... 110 The National Library of Medicine Book Index ........................................................................... 112 CHAPTER 5. MULTIMEDIA ON HEMOCHROMATOSIS ................................................................... 113

viii Contents

Overview.................................................................................................................................... 113 Bibliography: Multimedia on Hemochromatosis........................................................................ 113 APPENDIX A. HELP ME UNDERSTAND GENETICS ....................................................................... 115 Overview.................................................................................................................................... 115 The Basics: Genes and How They Work..................................................................................... 115 Genetic Mutations and Health................................................................................................... 126 Inheriting Genetic Conditions ................................................................................................... 132 Genetic Consultation ................................................................................................................. 140 Genetic Testing .......................................................................................................................... 142 Gene Therapy ............................................................................................................................. 148 The Human Genome Project and Genomic Research................................................................. 151 APPENDIX B. PHYSICIAN RESOURCES ........................................................................................... 154 Overview.................................................................................................................................... 154 NIH Guidelines.......................................................................................................................... 154 NIH Databases........................................................................................................................... 155 Other Commercial Databases..................................................................................................... 158 APPENDIX C. PATIENT RESOURCES .............................................................................................. 159 Overview.................................................................................................................................... 159 Patient Guideline Sources.......................................................................................................... 159 Finding Associations.................................................................................................................. 163 Resources for Patients and Families........................................................................................... 164 ONLINE GLOSSARIES................................................................................................................ 166 Online Dictionary Directories ................................................................................................... 169 HEMOCHROMATOSIS DICTIONARY................................................................................... 170 INDEX .............................................................................................................................................. 224

1

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 hemochromatosis 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 hemochromatosis, 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 hemochromatosis, 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 hemochromatosis. 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 hemochromatosis. 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 hemochromatosis, 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 hemochromatosis. The Editors

1

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

3

CHAPTER 1. STUDIES ON HEMOCHROMATOSIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on hemochromatosis. For those interested in basic information about hemochromatosis, 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 hemochromatosis 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 hemochromatosis is provided.2 The Genetics Home Reference has recently published the following summary for hemochromatosis:

What Is Hemochromatosis?3 Hemochromatosis is a disorder that causes the body to absorb too much iron from the diet. The excess iron is stored in the body's tissues and organs, particularly the skin, heart, liver, pancreas, and joints. Because humans cannot increase the excretion of iron, excess iron can overload and eventually damage tissues and organs. For this reason, hemochromatosis is also called an iron overload disorder. Early symptoms of hemochromatosis are nonspecific and may include fatigue, joint pain, abdominal pain, and loss of sex drive. Later signs and symptoms can include arthritis, liver 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=hemochromatosis.

4

Hemochromatosis

disease, diabetes, heart abnormalities, and skin discoloration. The appearance and progression of symptoms can be affected by environmental and lifestyle factors such as the amount of iron in the diet, alcohol use, and infections. Hemochromatosis is classified by type depending on the age of onset and other factors such as genetic cause and mode of inheritance. Hemochromatosis type 1, the most common form of the disorder, and type 4 (also called ferroportin disease) are adult-onset disorders. Men with type 1 or type 4 hemochromatosis typically develop symptoms between the ages of 40 and 60, and women usually develop symptoms after menopause. Type 2 hemochromatosis is a juvenile-onset disorder. Iron accumulation begins early in life, and symptoms may begin to appear in childhood. By age 20, decreased or absent secretion of sex hormones is evident. Females usually begin menstruation in a normal manner, but menses stop after a few years. Males may experience delayed puberty or sex hormone deficiency symptoms such as impotence. If the disorder is untreated, heart disease is evident by age 30. Onset of type 3 hemochromatosis is usually intermediate between types 1 and 2. Symptoms of type 3 hemochromatosis generally begin before age 30. In rare cases, iron overload begins before birth. These cases are called neonatal hemochromatosis. This type of hemochromatosis progresses rapidly and is characterized by liver damage that is apparent at birth or in the first day of life.

How Common Is Hemochromatosis? Type 1 hemochromatosis is one of the most common genetic disorders in the United States, affecting about 1 million people. It most often affects people of Northern European descent. The other types of hemochromatosis are considered rare and have been studied in only a small number of families worldwide.

What Genes Are Related to Hemochromatosis? Mutations in the HAMP (http://ghr.nlm.nih.gov/gene=hamp), HFE (http://ghr.nlm.nih.gov/gene=hfe), HFE2 (http://ghr.nlm.nih.gov/gene=hfe2), SLC40A1 (http://ghr.nlm.nih.gov/gene=slc40a1), and TFR2 (http://ghr.nlm.nih.gov/gene=tfr2) genes cause hemochromatosis. The HAMP, HFE, HFE2, SLC40A1, and TFR2 genes play an important role in regulating the absorption, transport, and storage of iron. Mutations in these genes impair the control of iron absorption during digestion and alter the distribution of iron to other parts of the body. As a result, iron accumulates in tissues and organs, which can disrupt their normal functions. Each type of hemochromatosis is caused by mutations in a specific gene. Type 1 hemochromatosis is caused by mutations in the HFE gene, and type 2 hemochromatosis is caused by mutations in either the HFE2 or HAMP gene. Mutations in the TFR2 gene cause type 3 hemochromatosis, and mutations in the SLC40A1 gene cause type 4 hemochromatosis. The cause of neonatal hemochromatosis is unknown.

Studies

5

How Do People Inherit Hemochromatosis? Hemochromatosis types 1, 2, and 3 are 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 are carriers of one copy of the altered gene but do not show signs or symptoms of the disorder. Type 4 hemochromatosis is distinguished by its autosomal dominant inheritance pattern. With this type of inheritance, one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition. The inheritance pattern of neonatal hemochromatosis is unknown.

Where Can I Find Additional Information about Hemochromatosis? You may find the following resources about hemochromatosis 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?rid=gnd.section.251

•

National Human Genome Research Institute: http://www.genome.gov/page.cfm?pageID=10001214

•

National Institute of Diabetes and Digestive and Kidney Diseases: http://digestive.niddk.nih.gov/ddiseases/pubs/hemochromatosis/index.htm

•

Office of Dietary Supplements: http://dietary-supplements.info.nih.gov/factsheets/iron.asp MedlinePlus - Health Information

•

Encyclopedia: Hemochromatosis: http://www.nlm.nih.gov/medlineplus/ency/article/000327.htm

•

Health Topic: Hemochromatosis: http://www.nlm.nih.gov/medlineplus/hemochromatosis.html Educational Resources - Information Pages

•

American Academy of Family Physicians: http://familydoctor.org/758.xml

•

Annals of Internal Medicine: http://www.annals.org/cgi/content/full/143/7/I-46

•

Centers for Disease Control and Prevention: http://www.cdc.gov/ncbddd/hemochromatosis/

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Hemochromatosis

•

Centre for Genetics Education (Australia): http://www.genetics.com.au/factsheet/36.htm

•

Human Genome Project Information, Department of Energy: http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/hh.shtml

•

Madisons Foundation: http://www.madisonsfoundation.org/content/3/1/display.asp?did=292

•

Mayo Clinic: http://www.mayoclinic.org/genetic-liver-diseases/hemochromatosis.html

•

Medical College of Wisconsin: http://healthlink.mcw.edu/article/974757337.html

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New York Online Access to Health (NOAH): http://www.noah-health.org/en/kidver/liver/diseases/hemochromatosis.html

•

Ohio State University Medical Center: http://medicalcenter.osu.edu/patientcare/healthinformation/otherhealthtopics/Hemato logyBloodDisorders/BloodDisorders/Hemochromatosis/

•

Orphanet: Hemochromatosis, familial: http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=445

•

Orphanet: Neonatal hemochromatosis: http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=446

•

The Wellcome Trust: http://genome.wellcome.ac.uk/doc_WTD020857.html

•

University of Washington: http://www.uwgi.org/hemochromatosis/noflash/ Patient Support - for Patients and Families

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American Hemochromatosis Society: http://www.americanhs.org/

•

American Liver Foundation: http://www.liverfoundation.org/db/articles/1013

•

Iron Disorders Institute: http://www.irondisorders.org/Disorders/Hemochromatosis.asp

•

Iron Overload Diseases Association: http://www.ironoverload.org/

•

National Organization for Rare Diseases: http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Hemochromato sis,+Hereditary

•

Neonatal Hemochromatosis Information Center: http://www.neonatalhemochromatosis.org/

Studies

7

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

Gene Reviews - Clinical summary: http://ghr.nlm.nih.gov/condition=hemochromatosis/show/Gene+Reviews;jsessionid= 0C5BFFE1EF63C5260D38AE8B3434C484

•

Gene Tests - DNA tests ordered by healthcare professionals: http://ghr.nlm.nih.gov/condition=hemochromatosis/show/Gene+Tests;jsessionid=0C5 BFFE1EF63C5260D38AE8B3434C484

•

Genetic Tools - Teaching cases: http://www.genetests.org/servlet/access?fcn=y&filename=/tools/cases/ironOverload25/

•

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

•

PubMed - Recent literature: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=PubMed&term=( Hemochromatosis[MAJR])+AND+(hemochromatosis[TI])+AND+(review[pt]+OR+rev iew+literature[mh])+AND+english[la]+AND+human[mh]&orig_db=PubMed&filters =ON&pmfilter_EDatLimit=1080+Days

•

Online Books - Medical and science texts: http://books.mcgrawhill.com/getommbid.php?isbn=0071459960&template=ommbid&c=127

•

OMIM - Genetic disorder catalog: http://ghr.nlm.nih.gov/condition=hemochromatosis/show/OMIM;jsessionid=0C5BFF E1EF63C5260D38AE8B3434C484

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

Alexander J, Kowdley KV. Hereditary hemochromatosis: genetics, pathogenesis, and clinical management. Ann Hepatol. 2005 Oct-Dec;4(4):240-7. Review. PubMed citation

•

Anderson GJ, Powell LW. HFE and non-HFE hemochromatosis. Int J Hematol. 2002 Oct;76(3):203-7. Review. PubMed citation

•

Beutler E. Hemochromatosis: genetics and pathophysiology. Annu Rev Med. 2006;57:331-47. Review. PubMed citation

•

Camaschella C, Roetto A, Cali A, De Gobbi M, Garozzo G, Carella M, Majorano N, Totaro A, Gasparini P. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000 May;25(1):14-5. PubMed citation

•

Camaschella C, Roetto A, De Gobbi M. Juvenile hemochromatosis. Semin Hematol. 2002 Oct;39(4):242-8. Review. PubMed citation

•

De Gobbi M, Roetto A, Piperno A, Mariani R, Alberti F, Papanikolaou G, Politou M, Lockitch G, Girelli D, Fargion S, Cox TM, Gasparini P, Cazzola M, Camaschella C.

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Hemochromatosis

Natural history of juvenile haemochromatosis. Br J Haematol. 2002 Jun;117(4):973-9. Review. PubMed citation •

Dolbey CH. Hemochromatosis: a review. Clin J Oncol Nurs. 2001 Nov-Dec;5(6):257-60. Review. PubMed citation

•

Heeney MM, Andrews NC. Iron homeostasis and inherited iron overload disorders: an overview. Hematol Oncol Clin North Am. 2004 Dec;18(6):1379-403. PubMed citation

•

Kelly AL, Lunt PW, Rodrigues F, Berry PJ, Flynn DM, McKiernan PJ, Kelly DA, MieliVergani G, Cox TM. Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism. J Med Genet. 2001 Sep;38(9):599-610. PubMed citation

•

Knisely AS, Mieli-Vergani G, Whitington PF. Neonatal hemochromatosis. Gastroenterol Clin North Am. 2003 Sep;32(3):877-89, vi-vii. Review. PubMed citation

•

Le Gac G, Ferec C. The molecular genetics of haemochromatosis. Eur J Hum Genet. 2005 Nov;13(11):1172-85. Review. PubMed citation

•

Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S, Trenor CC, Gasparini P, Andrews NC, Pietrangelo A. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest. 2001 Aug;108(4):619-23. PubMed citation

•

Njajou OT, Vaessen N, Joosse M, Berghuis B, van Dongen JW, Breuning MH, Snijders PJ, Rutten WP, Sandkuijl LA, Oostra BA, van Duijn CM, Heutink P. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet. 2001 Jul;28(3):2134. PubMed citation

•

Pietrangelo A. Hereditary hemochromatosis--a new look at an old disease. N Engl J Med. 2004 Jun 3;350(23):2383-97. Review. No abstract available. PubMed citation

•

Pietrangelo A. Non-HFE hemochromatosis. Hepatology. 2004 Jan;39(1):21-9. Review. No abstract available. PubMed citation

•

Pietrangelo A. Non-HFE hemochromatosis. Semin Liver Dis. 2005 Nov;25(4):450-60. Review. PubMed citation

•

Pietrangelo A. The ferroportin disease. Blood Cells Mol Dis. 2004 Jan-Feb;32(1):131-8. Review. PubMed citation

•

Wheeler CJ, Kowdley KV. Hereditary hemochromatosis: a review of the genetics, mechanism, diagnosis, and treatment of iron overload. Compr Ther. 2006 Spring;32(1):10-6. PubMed citation

•

Whitington PF. Fetal and infantile hemochromatosis. Hepatology. 2006 Apr;43(4):654-60. Review. No abstract available. PubMed citation

•

Yen AW, Fancher TL, Bowlus CL. Revisiting hereditary hemochromatosis: current concepts and progress. Am J Med. 2006 May;119(5):391-9. Review. PubMed citation

Studies

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A summary of the genes related to hemochromatosis is provided below:

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

What Is the Normal Function of the HAMP Gene? The HAMP gene provides instructions for the production of a protein called hepcidin. Hepcidin was originally identified as having antimicrobial properties, which refers to the ability of this protein to fight bacterial infections. Researchers have discovered that hepcidin plays a major role in maintaining iron balance in the body. They believe that hepcidin circulates in the blood and inhibits iron absorption by the small intestine when the body's supply of iron is too high. Researchers have proposed that hepcidin production in the liver increases when iron enters liver cells from the blood. Hepcidin is then released into the bloodstream and travels throughout the body. This protein interacts primarily with other proteins in the intestines, liver, and certain white blood cells to adjust iron absorption and storage. In this way, iron supplies are monitored and iron absorption is adjusted to reflect the needs of an individual's body.

What Conditions Are Related to the HAMP Gene? Hemochromatosis - Caused by Mutations in the HAMP Gene At least eight mutations in the HAMP gene have been identified that result in hemochromatosis. People who have mutations in the HAMP gene are affected by a severe type of juvenile hemochromatosis, sometimes called type 2 hemochromatosis, that begins between the ages of 10 years and 30 years. People with mutations in the HAMP gene are unable to make normal hepcidin and cannot inhibit iron absorption, even when the body has sufficient supplies of iron. The organs of affected people become overloaded with iron, especially the liver and the heart, leading to the organ damage characteristic of this disorder.

Where Is the HAMP Gene Located? Cytogenetic Location: 19q13.1 Molecular Location on chromosome 19: base pairs 40,465,249 to 40,467,885

4

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=hamp;jsessionid=05C2BA6232F541D2CEFF865200ED8E6E.

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Hemochromatosis

The HAMP gene is located on the long (q) arm of chromosome 19 at position 13.1. More precisely, the HAMP gene is located from base pair 40,465,249 to base pair 40,467,885 on chromosome 19.

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

Anderson GJ, Frazer DM, Wilkins SJ, Becker EM, Millard KN, Murphy TL, McKie AT, Vulpe CD. Relationship between intestinal iron-transporter expression, hepatic hepcidin levels and the control of iron absorption. Biochem Soc Trans. 2002 Aug;30(4):724-6. PubMed citation

•

Fleming RE, Sly WS. Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8160-2. Review. No abstract available. PubMed citation

•

Fleming RE, Sly WS. Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8160-2. Review. No abstract available. PubMed citation

•

Fleming RE, Sly WS. Mechanisms of iron accumulation in hereditary hemochromatosis. Annu Rev Physiol. 2002;64:663-80. Review. PubMed citation

•

Hunter HN, Fulton DB, Ganz T, Vogel HJ. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J Biol Chem. 2002 Oct 4;277(40):37597-603. PubMed citation

•

Leong WI, Lonnerdal B. Hepcidin, the recently identified peptide that appears to regulate iron absorption. J Nutr. 2004 Jan;134(1):1-4. Review. PubMed citation

•

McGregor J, McKie AT, Simpson RJ. Of mice and men: genetic determinants of iron status. Proc Nutr Soc. 2004 Feb;63(1):11-20. PubMed citation

•

Pietrangelo A. Hereditary hemochromatosis--a new look at an old disease. N Engl J Med. 2004 Jun 3;350(23):2383-97. Review. No abstract available. PubMed citation

Studies

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Roetto A, Papanikolaou G, Politou M, Alberti F, Girelli D, Christakis J, Loukopoulos D, Camaschella C. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003 Jan;33(1):21-2. PubMed citation

What Is the Official Name of the HFE Gene?5 The official name of this gene is “hemochromatosis.” HFE is the gene's official symbol. The HFE gene is also known by other names, listed below.

What Is the Normal Function of the HFE Gene? The HFE gene provides instructions for producing a protein that is located mainly on the surface of intestinal cells, liver cells, and some cells in the immune system. During digestion, this protein helps certain cells regulate the absorption of iron into the small intestine by interacting with other proteins located on the cell surface. The body uses this mechanism to help monitor its supply of iron. When the proteins involved in iron sensing and absorption are functioning properly, the body absorbs only about 10 percent of the iron ingested in the diet. Research suggests that the HFE protein also helps control levels of another important iron regulatory protein, hepcidin. Adequate levels of hepcidin are necessary to ensure that the body does not absorb and store too much iron in its tissues and organs.

What Conditions Are Related to the HFE Gene? Hemochromatosis - Caused by Mutations in the HFE Gene Researchers have identified more than 20 mutations in the HFE gene that cause type 1 hemochromatosis. These mutations alter the size of the HFE protein or disrupt its 3dimensional shape. As a result, the HFE protein cannot function properly. Two particular mutations are responsible for most cases of type 1 hemochromatosis. Each of these mutations changes one of the building blocks (amino acids) used to make the HFE protein. The most common mutation replaces the amino acid cysteine with the amino acid tyrosine at position 282 in the protein's chain of amino acids (written as C282Y or Cys282Tyr). The other mutation replaces the amino acid histidine with the amino acid aspartic acid at position 63 (written as H63D or His63Asp). As a result of these substitutions, the altered protein is not sent to the cell surface and does not interact with a cell surface receptor called the transferrin receptor. The transferrin receptor plays a critical role in regulating the amount of iron that enters the cell. When the HFE protein does not bind to the transferrin receptor, too much iron enters the body through the cells of the small intestine. This increased absorption of iron leads to the iron overload characteristic of this disorder.

5

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

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Hemochromatosis

Porphyria - Increased Risk from Variations of the HFE Gene Researchers have identified more than 20 mutations in the HFE gene that cause type 1 hemochromatosis. These mutations alter the size of the HFE protein or disrupt its 3dimensional shape. As a result, the HFE protein cannot function properly. Two particular mutations are responsible for most cases of type 1 hemochromatosis. Each of these mutations changes one of the building blocks (amino acids) used to make the HFE protein. The most common mutation replaces the amino acid cysteine with the amino acid tyrosine at position 282 in the protein's chain of amino acids (written as C282Y or Cys282Tyr). The other mutation replaces the amino acid histidine with the amino acid aspartic acid at position 63 (written as H63D or His63Asp). As a result of these substitutions, the altered protein is not sent to the cell surface and does not interact with a cell surface receptor called the transferrin receptor. The transferrin receptor plays a critical role in regulating the amount of iron that enters the cell. When the HFE protein does not bind to the transferrin receptor, too much iron enters the body through the cells of the small intestine. This increased absorption of iron leads to the iron overload characteristic of this disorder. X-Linked Sideroblastic Anemia - Course of Condition Modified by Mutations in the HFE Gene Mutations in the HFE gene that cause hemochromatosis are also believed to increase the risk of developing a form of porphyria called porphyria cutanea tarda. These mutations have been found more frequently in people with this condition than in unaffected people. Researchers are not certain how mutations in the HFE gene are related to the signs and symptoms of porphyria cutanea tarda. These mutations likely trigger this condition by increasing iron levels in the liver, as in hemochromatosis.

Where Is the HFE Gene Located? Cytogenetic Location: 6p21.3 Molecular Location on chromosome 6: base pairs 26,195,426 to 26,205,037

The HFE gene is located on the short (p) arm of chromosome 6 at position 21.3. More precisely, the HFE gene is located from base pair 26,195,426 to base pair 26,205,037 on chromosome 6.

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

Andrews NC. Molecular control of iron metabolism. Best Pract Res Clin Haematol. 2005 Jun;18(2):159-69. Review. PubMed citation

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Bennett MJ, Lebron JA, Bjorkman PJ. Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature. 2000 Jan 6;403(6765):46-53. PubMed citation

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Beutler E, Hoffbrand AV, Cook JD. Iron deficiency and overload. Hematology (Am Soc Hematol Educ Program). 2003;:40-61. Review. PubMed citation

•

Camaschella C, Roetto A, De Gobbi M. Genetic haemochromatosis: genes and mutations associated with iron loading. Best Pract Res Clin Haematol. 2002 Jun;15(2):261-76. PubMed citation

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CDC HuGE review: HFE Gene and Hereditary Hemochromatosis

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Deicher R, Horl WH. New insights into the regulation of iron homeostasis. Eur J Clin Invest. 2006 May;36(5):301-9. PubMed citation

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Egger NG, Goeger DE, Payne DA, Miskovsky EP, Weinman SA, Anderson KE. Porphyria cutanea tarda: multiplicity of risk factors including HFE mutations, hepatitis C, and inherited uroporphyrinogen decarboxylase deficiency. Dig Dis Sci. 2002 Feb;47(2):419-26. PubMed citation

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Fleming RE, Britton RS, Waheed A, Sly WS, Bacon BR. Pathogenesis of hereditary hemochromatosis. Clin Liver Dis. 2004 Nov;8(4):755-73, vii. Review. PubMed citation

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Fleming RE, Britton RS. Iron Imports. VI. HFE and regulation of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol. 2006 Apr;290(4):G590-4. Review. PubMed citation

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Fleming RE, Sly WS. Mechanisms of iron accumulation in hereditary hemochromatosis. Annu Rev Physiol. 2002;64:663-80. Review. PubMed citation

•

Fleming RE. Advances in understanding the molecular basis for the regulation of dietary iron absorption. Curr Opin Gastroenterol. 2005 Mar;21(2):201-6. Review. PubMed citation

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Kelleher T, Ryan E, Barrett S, Sweeney M, Byrnes V, O'Keane C, Crowe J. Increased DMT1 but not IREG1 or HFE mRNA following iron depletion therapy in hereditary haemochromatosis. Gut. 2004 Aug;53(8):1174-9. PubMed citation

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Kostler E, Wollina U. Therapy of porphyria cutanea tarda. Expert Opin Pharmacother. 2005 Mar;6(3):377-83. Review. PubMed citation

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Kowdley KV. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology. 2004 Nov;127(5 Suppl 1):S79-86. Review. PubMed citation

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McGregor J, McKie AT, Simpson RJ. Of mice and men: genetic determinants of iron status. Proc Nutr Soc. 2004 Feb;63(1):11-20. PubMed citation

•

NIDDK fact sheet on hemochromatosis

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Hemochromatosis

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Njajou OT, Alizadeh BZ, van Duijn CM. Is genetic screening for hemochromatosis worthwhile? Eur J Epidemiol. 2004;19(2):101-8. Review. PubMed citation

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Pietrangelo A. Hereditary hemochromatosis--a new look at an old disease. N Engl J Med. 2004 Jun 3;350(23):2383-97. Review. No abstract available. PubMed citation

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Roy CN, Andrews NC. Recent advances in disorders of iron metabolism: mutations, mechanisms and modifiers. Hum Mol Genet. 2001 Oct 1;10(20):2181-6. Review. PubMed citation

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Zaahl MG, Merryweather-Clarke AT, Kotze MJ, van der Merwe S, Warnich L, Robson KJ. Analysis of genes implicated in iron regulation in individuals presenting with primary iron overload. Hum Genet. 2004 Oct;115(5):409-17. Epub 2004 Aug 24. PubMed citation

What Is the Official Name of the HFE2 Gene?6 The official name of this gene is “hemochromatosis type 2 (juvenile).” HFE2 is the gene's official symbol. The HFE2 gene is also known by other names, listed below.

What Is the Normal Function of the HFE2 Gene? The HFE2 gene provides instructions for making a protein called hemojuvelin. This protein is made in the liver, heart, and muscles used for movement (skeletal muscles). Researchers recently discovered that hemojuvelin plays a role in maintaining iron balance in the body. Although its exact function is unclear, hemojuvelin appears to regulate the levels of another protein called hepcidin. Hepcidin also plays a key role in maintaining proper iron levels in the body.

What Conditions Are Related to the HFE2 Gene? Hemochromatosis - Caused by Mutations in the HFE2 Gene Researchers have identified more than 20 HFE2 mutations that cause type 2 hemochromatosis, a form of the disorder that begins during childhood or adolescence. Most HFE2 mutations change one of the protein building blocks (amino acids) used to make hemojuvelin. Most frequently, the amino acid glycine is replaced by the amino acid valine at protein position 320 (written as Gly320Val). Other mutations create a premature stop signal in the instructions for making the hemojuvelin protein. As a result, an abnormally small protein is made.

6

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=hfe2;jsessionid=05C2BA6232F541D2CEFF865200ED8E6E.

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Where Is the HFE2 Gene Located? Cytogenetic Location: 1q21 Molecular Location on chromosome 1: base pairs 144,124,634 to 144,128,901

The HFE2 gene is located on the long (q) arm of chromosome 1 at position 21. More precisely, the HFE2 gene is located from base pair 144,124,634 to base pair 144,128,901 on chromosome 1.

References These sources were used to develop the Genetics Home Reference gene summary on the HFE2 gene. •

Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006 May;38(5):5319. Epub 2006 Apr 9. PubMed citation

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Beutler L, Beutler E. Hematologically important mutations: iron storage diseases. Blood Cells Mol Dis. 2004 Jul-Aug;33(1):40-4. No abstract available. PubMed citation

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Lanzara C, Roetto A, Daraio F, Rivard S, Ficarella R, Simard H, Cox T, Cazzola M, Piperno A, Gimenez-Roqueplo AP, Grammatico P, Volinia S, Gasparini P, Camaschella C. The spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood. 2004 Feb 24 [Epub ahead of print]. PubMed citation

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Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP, Andres L, MacFarlane J, Sakellaropoulos N, Politou M, Nemeth E, Thompson J, Risler JK, Zaborowska C, Babakaiff R, Radomski CC, Pape TD, Davidas O, Christakis J, Brissot P, Lockitch G, Ganz T, Hayden MR, Goldberg YP. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 2004 Jan;36(1):77-82. Epub 2003 Nov 30. PubMed citation

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Pissia M, Polonifi K, Politou M, Lilakos K, Sakellaropoulos N, Papanikolaou G. Prevalence of the G320V mutation of the HJV gene, associated with juvenile hemochromatosis, in Greece. Haematologica. 2004 Jun;89(6):742-3. PubMed citation

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Roetto A, Totaro A, Cazzola M, Cicilano M, Bosio S, D'Ascola G, Carella M, Zelante L, Kelly AL, Cox TM, Gasparini P, Camaschella C. Juvenile hemochromatosis locus maps to chromosome 1q. Am J Hum Genet. 1999 May;64(5):1388-93. PubMed citation

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Hemochromatosis

What Is the Official Name of the SLC40A1 Gene?7 The official name of this gene is “solute carrier family 40 (iron-regulated transporter), member 1.” SLC40A1 is the gene's official symbol. The SLC40A1 gene is also known by other names, listed below.

What Is the Normal Function of the SLC40A1 Gene? The SLC40A1 gene provides instructions for making a protein called ferroportin 1. This protein plays an essential role in the regulation of iron levels in the body. Iron from the diet is absorbed through the walls of the small intestine. Ferroportin 1 then transports iron from the small intestine into the bloodstream. In the bloodstream, the iron binds to another transport protein called transferrin that carries it to the tissues and organs of the body. Ferroportin 1 also transports iron out of specialized immune system cells (called reticuloendothelial cells) that are found in the liver, spleen, and bone marrow. The iron balance in the body is regulated by the amount of iron stored and released from these cells. Research suggests that another iron regulatory protein, hepcidin, controls the amount of ferroportin 1 available to transport iron out of cells. Hepcidin binds to ferroportin and causes it to be broken down when the body's iron supplies are adequate. When the body is lacking iron, hepcidin levels drop and more ferroportin 1 is available to bring iron into the body and to release it from storage.

What Conditions Are Related to the SLC40A1 Gene? Hemochromatosis - Caused by Mutations in the SLC40A1 Gene Researchers have identified approximately 15 mutations that cause type 4 hemochromatosis. Almost all of these mutations change a single protein building block (amino acid) in ferroportin 1. Abnormal versions of ferroportin 1 do not permit the normal transport and release of iron from intestinal or reticuloendothelial cells. As a result, the regulation of iron levels in the body is impaired and iron overload results. One mutated copy of this gene in each cell is sufficient to cause type 4 hemochromatosis, sometimes referred to as ferroportin disease.

Where Is the SLC40A1 Gene Located? Cytogenetic Location: 2q32 Molecular Location on chromosome 2: base pairs 190,133,560 to 190,153,857

7

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=slc40a1.

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The SLC40A1 gene is located on the long (q) arm of chromosome 2 at position 32. More precisely, the SLC40A1 gene is located from base pair 190,133,560 to base pair 190,153,857 on chromosome 2.

References These sources were used to develop the Genetics Home Reference gene summary on the SLC40A1 gene. •

Beutler E, Hoffbrand AV, Cook JD. Iron deficiency and overload. Hematology (Am Soc Hematol Educ Program). 2003;:40-61. Review. PubMed citation

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Beutler E. Hemochromatosis: genetics and pathophysiology. Annu Rev Med. 2006;57:331-47. Review. PubMed citation

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De Domenico I, Ward DM, Musci G, Kaplan J. Iron overload due to mutations in ferroportin. Haematologica. 2006 Jan;91(1):92-5. Review. PubMed citation

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De Domenico I, Ward DM, Nemeth E, Vaughn MB, Musci G, Ganz T, Kaplan J. The molecular basis of ferroportin-linked hemochromatosis. Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):8955-60. Epub 2005 Jun 13. PubMed citation

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Deicher R, Horl WH. New insights into the regulation of iron homeostasis. Eur J Clin Invest. 2006 May;36(5):301-9. PubMed citation

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Devalia V, Carter K, Walker AP, Perkins SJ, Worwood M, May A, Dooley JS. Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). Blood. 2002 Jul 15;100(2):695-7. PubMed citation

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Fleming RE, Sly WS. Ferroportin mutation in autosomal dominant hemochromatosis: loss of function, gain in understanding. J Clin Invest. 2001 Aug;108(4):521-2. No abstract available. PubMed citation

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Fleming RE. Advances in understanding the molecular basis for the regulation of dietary iron absorption. Curr Opin Gastroenterol. 2005 Mar;21(2):201-6. Review. PubMed citation

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Kelleher T, Ryan E, Barrett S, Sweeney M, Byrnes V, O'Keane C, Crowe J. Increased DMT1 but not IREG1 or HFE mRNA following iron depletion therapy in hereditary haemochromatosis. Gut. 2004 Aug;53(8):1174-9. PubMed citation

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McGregor J, McKie AT, Simpson RJ. Of mice and men: genetic determinants of iron status. Proc Nutr Soc. 2004 Feb;63(1):11-20. PubMed citation

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Hemochromatosis

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McKie AT, Barlow DJ. The SLC40 basolateral iron transporter family (IREG1/ferroportin/MTP1). Pflugers Arch. 2004 Feb;447(5):801-6. Epub 2003 Jun 27. Review. PubMed citation

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McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW, Simpson RJ. A novel duodenal ironregulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell. 2000 Feb;5(2):299-309. PubMed citation

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Pietrangelo A. Hereditary hemochromatosis--a new look at an old disease. N Engl J Med. 2004 Jun 3;350(23):2383-97. Review. No abstract available. PubMed citation

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Pietrangelo A. Non-HFE hemochromatosis. Semin Liver Dis. 2005 Nov;25(4):450-60. Review. PubMed citation

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Thomas C, Oates PS. Ferroportin/IREG-1/MTP-1/SLC40A1 modulates the uptake of iron at the apical membrane of enterocytes. Gut. 2004 Jan;53(1):44-9. PubMed citation

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Wallace DF, Pedersen P, Dixon JL, Stephenson P, Searle JW, Powell LW, Subramaniam VN. Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis. Blood. 2002 Jul 15;100(2):692-4. PubMed citation

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Zaahl MG, Merryweather-Clarke AT, Kotze MJ, van der Merwe S, Warnich L, Robson KJ. Analysis of genes implicated in iron regulation in individuals presenting with primary iron overload. Hum Genet. 2004 Oct;115(5):409-17. Epub 2004 Aug 24. PubMed citation

What Is the Official Name of the TFR2 Gene?8 The official name of this gene is “transferrin receptor 2.” TFR2 is the gene's official symbol. The TFR2 gene is also known by other names, listed below.

What Is the Normal Function of the TFR2 Gene? The TFR2 gene provides instructions for making a protein called transferrin receptor 2. Studies suggest that this receptor helps iron enter liver cells (hepatocytes). In the blood, iron binds to a protein called transferrin for transport and delivery to the liver and other tissues. On the cell surface, transferrin binds to transferrin receptor 2, and iron is allowed to enter the cell. Additionally, this receptor helps sense and regulate iron storage levels in the body by controlling the levels of another protein called hepcidin. Hepcidin is a protein that determines how much iron is absorbed from the diet and released from storage sites in the body in response to iron levels.

8

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=tfr2;jsessionid=05C2BA6232F541D2CEFF865200ED8E6E.

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What Conditions Are Related to the TFR2 Gene? Hemochromatosis - Caused by Mutations in the TFR2 Gene At least nine different mutations that cause type 3 hemochromatosis have been identified in the TFR2 gene. Some mutations in the TFR2 gene prevent the production of transferrin receptor 2. Other mutations result in proteins that have an incorrect sequence of protein building blocks (amino acids) or proteins that are too short to function normally. These mutations likely impair the ability to regulate importation of iron into certain cells.

Where Is the TFR2 Gene Located? Cytogenetic Location: 7q22 Molecular Location on chromosome 7: base pairs 100,055,974 to 100,077,094

The TFR2 gene is located on the long (q) arm of chromosome 7 at position 22. More precisely, the TFR2 gene is located from base pair 100,055,974 to base pair 100,077,094 on chromosome 7.

References These sources were used to develop the Genetics Home Reference gene summary on the TFR2 gene. •

Beutler E, Hoffbrand AV, Cook JD. Iron deficiency and overload. Hematology (Am Soc Hematol Educ Program). 2003;:40-61. Review. PubMed citation

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Camaschella C, Roetto A, Cali A, De Gobbi M, Garozzo G, Carella M, Majorano N, Totaro A, Gasparini P. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000 May;25(1):14-5. PubMed citation

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Camaschella C. Why do humans need two types of transferrin receptor? Lessons from a rare genetic disorder. Haematologica. 2005 Mar;90(3):296. No abstract available. PubMed citation

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Deaglio S, Capobianco A, Cali A, Bellora F, Alberti F, Righi L, Sapino A, Camaschella C, Malavasi F. Structural, functional, and tissue distribution analysis of human transferrin

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Hemochromatosis

receptor-2 by murine monoclonal antibodies and a polyclonal antiserum. Blood. 2002 Nov 15;100(10):3782-9. PubMed citation •

Deicher R, Horl WH. New insights into the regulation of iron homeostasis. Eur J Clin Invest. 2006 May;36(5):301-9. PubMed citation

•

Fleming RE, Sly WS. Mechanisms of iron accumulation in hereditary hemochromatosis. Annu Rev Physiol. 2002;64:663-80. Review. PubMed citation

•

Fleming RE. Advances in understanding the molecular basis for the regulation of dietary iron absorption. Curr Opin Gastroenterol. 2005 Mar;21(2):201-6. Review. PubMed citation

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Frazer DM, Anderson GJ. The orchestration of body iron intake: how and where do enterocytes receive their cues? Blood Cells Mol Dis. 2003 May-Jun;30(3):288-97. Review. PubMed citation

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Le Gac G, Mons F, Jacolot S, Scotet V, Ferec C, Frebourg T. Early onset hereditary hemochromatosis resulting from a novel TFR2 gene nonsense mutation (R105X) in two siblings of north French descent. Br J Haematol. 2004 Jun;125(5):674-8. PubMed citation

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McGregor J, McKie AT, Simpson RJ. Of mice and men: genetic determinants of iron status. Proc Nutr Soc. 2004 Feb;63(1):11-20. PubMed citation

•

Pietrangelo A. Hereditary hemochromatosis--a new look at an old disease. N Engl J Med. 2004 Jun 3;350(23):2383-97. Review. No abstract available. PubMed citation

•

Pietrangelo A. Non-HFE hemochromatosis. Semin Liver Dis. 2005 Nov;25(4):450-60. Review. PubMed citation

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Roetto A, Daraio F, Alberti F, Porporato P, Cali A, De Gobbi M, Camaschella C. Hemochromatosis due to mutations in transferrin receptor 2. Blood Cells Mol Dis. 2002 Nov-Dec;29(3):465-70. PubMed citation

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SwissProt for TFR2

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Trinder D, Baker E. Transferrin receptor 2: a new molecule in iron metabolism. Int J Biochem Cell Biol. 2003 Mar;35(3):292-6. Review. PubMed citation

Federally Funded Research on Hemochromatosis The U.S. Government supports a variety of research studies relating to hemochromatosis. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.9 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 9

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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perform targeted searches by various criteria, including geography, date, and topics related to hemochromatosis. 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 hemochromatosis. The following is typical of the type of information found when searching the CRISP database for hemochromatosis: •

Project Title: ACHIEVING IRON BALANCE IN MEN & WOMEN WITH HEMOCHROMATOSIS Principal Investigator & Institution: Phatak, Pradyumma D.; Associate Professor of Medicine; Iron Disorders Institute, Inc. 2722 Wade Hampton Blvd Greenville, Sc 29615 Timing: Fiscal Year 2006; Project Start 15-MAY-2006; Project End 14-MAY-2007 Summary: (provided by applicant): Genetic hemochromatosis is one of the most prevalent conditions among Caucasians. In the US, more than one million have the genetic makeup for this disorder. Though hemochromatosis remains underdiagnosed in much of the USA, it is being diagnosed with greater frequency in some communities. A rising concern is that following diagnosis, clinicians vary how they employ therapeutic phlebotomy treatments. There is discrepancy in the frequency and amount of blood removed, which iron tests are appropriate and dietary recommendations. This has resulted in patients who are underbled, overbled or treatment that is postponed for "observation". These patients are at increased risk for pain, suffering and unnecessary death due and consequential anemia or diabetes, heart trouble, liver and joint disease or hormonal insufficiencies. The Iron Disorders Institute's (IDI) Conference, May 18-19, 2006 "Achieving Iron Balance in Men & Women with Hemochromatosis" addresses these critical issues. It is imperative that the most recent findings and best practices are imparted to the medical community promptly so that treatment plans are being administered within scientifically and medically recognized parameters developed for the optimal health benefit. The primary aim of this conference is to strengthen the capacity of healthcare professionals to make effective use of evidence-based information in the treatment of patients with classic type I hereditary hemochromatosis. A secondary goal is to promote interaction and awareness of methods and concepts developed by the various disciplines. This conference will provide continuing education for the physician and healthcare teams through the collaboration of strategic alliances such as NIH, CDC and the institution affiliations of the clinicians and scientists on the IDI Scientific Advisory Board (SAB). This one and half day event is primarily for physicians involved in the treatment or anticipated treatment of patients with hemochromatosis. A period of time on the second day is open to patients. The subject matter is multi-fold and concentrates on the standardization of the therapy for the "typical" hemochromatosis patient as well as translating this into meeting the treatment challenge presented by patients with multiple disorders that might accompany hemochromatosis, such as anemia, cancer, heart, lung and liver disease.

•

Project Title: BELGRADE RAT: A MUTATION IN A CRITICAL METAL TRANSPORTER Principal Investigator & Institution: Garrick, Laura M.; Biochemistry; State University of New York at Buffalo Sponsored Projects Services Buffalo, Ny 14260 Timing: Fiscal Year 2005; Project Start 01-MAR-2001; Project End 31-DEC-2006 Summary: (Adapted from the applicant's abstract): The Belgrade (b/b) rat has a G185R mutation in DMT1, resulting in a hypochromic, microcytic anemia that is inherited as a

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Hemochromatosis

recessive. DMT1 is a Fe2+/H+ symporter, transporting iron into the duodenum and out of the erythroid endosome. In an expression assay in ooctyes, DMT1 also appears to transport other divalent metals. This proposal is designed to preserve and make available a valuable animal model that is at risk of disappearing just after its mutational basis has been identified. One aim of the proposed research is to understand the role of DMT1 in iron flux and homeostasis and its role in the flux and homeostasis of other metals. The applicants plan to determine metal uptake activity of wild type (185G) and mutant (185R) constructs in a HEK293T cell assay to learn if the mutation affects uptake of each of eight metals (Fe, Mn, Co, Ni, Zn, Cu, Cd and Pb). The applicants will also measure tissue levels of these eight metals in +/+, +/b and b/b rats to see if the levels correlate with mutations in the DMT1 gene itself. A second aim is to learn the role of two isoforms of DMT1 mRNA encoding isoforms of DMT1 that differ in their Cterminal regions. The mutant also provides an opportunity to begin to understand how iron flux and the flux of other metals can continue sufficient for survival of the rat with DMT1 function "knocked out." These aims will also be evaluated relative to systemic iron status, and in other mutants affecting the HFE gene and beta2-microglobulin, a protein complex recently shown to play a regulatory role in iron uptake. The proposed research should have a significant bearing on understanding the basis of iron deficiency, the most prevalent disorder in the world; on iron overload including hereditary hemochromatosis, the most prevalent genetic disease in the US; and on nutrition and toxicity of the other seven metals, of which several, including lead and manganese, have important public health relevance. •

Project Title: BIOIRON RESEARCH CONFERENCE 2005 Principal Investigator & Institution: Kaplan, Jerry; Professor; Pathology; University of Utah 75 South 2000 East Salt Lake City, Ut 84112 Timing: Fiscal Year 2005; Project Start 15-APR-2005; Project End 31-MAR-2006 Summary: (provided by applicant): This application requests support for travel expenses to enable young U.S. investigators to attend and participate in the biennial Bioiron World Congress on Iron Metabolism (Bioiron 2005). The application also requests support provide travel expenses for senior investigators whose expertise may not be in iron but whose participation in the meeting would be of benefit to the field. A special emphasis will be given to the support of women, members of minority subpopulations, persons with disabilities and other individuals who have been traditionally underrepresented in science. Bioiron 2005 is recognized as the premier international conference on iron in physiology and medicine. The Bioiron conferences bring together clinicians and researchers in a meeting that combines state-of-the-art sessions and symposia given by the world's leading investigators with peer-reviewed presentations and posters of the latest research results. Recent progress in this field, especially the discovery of genes whose products are involved in the regulation of cellular iron uptake and distribution in humans, has made participation in this meeting essential for the development of young U.S. investigators working in this area. Conference abstracts are published in full and distributed to all participants. Major topics to be considered in Bioiron 2005 include, animal models of disorders of iron metabolism, mechanisms and regulation of iron transport and storage, analysis of genes that lead to iron overload disease including both HFE and non-HFE hereditary hemochromatosis. Sessions will focus on the role of iron in the cardiovascular and pulmonary systems. Special attention will be given to clinical issues such as treatment of iron overload disorders and anemia, and the potential role of iron-chelator therapy in disease prevention and management. Bioiron 2005 will be held in Prague Czech Republic from May 22 to May 28 2005. The overall goal of the Bioiron (2005) World

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Congress is the international dissemination of important new research results to investigators working in the field of iron metabolism. •

Project Title: BMP SIGNALING AND IRON METABOLISM Principal Investigator & Institution: Babitt, Jodie L.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2006; Project Start 01-JUL-2006; Project End 30-JUN-2011 Summary: (provided by applicant): The applicant proposes a program to prepare for a career in academic medicine and basic science research in the field of TGF-beta superfamily signaling and iron metabolism. Research will be conducted in the laboratory of Dr. Dennis Brown at MGH. Iron homeostasis is tightly regulated to provide this critical element for growth and survival, but to prevent the toxicity of iron excess. Hemojuvelin (HJV), was recently identified as the gene mutated in most cases of juvenile hemochromatosis, a severe disorder of iron overload. Although the function of HJV is unknown, hepcidin levels are depressed in persons with HJV mutations, suggesting that HJV positively regulates hepcidin expression. A soluble protein secreted by the liver, hepcidin is a critical regulator of systemic iron homeostasis whose levels are inversely correlated with iron uptake from the intestine and release from macrophages and hepatocytes. Preliminary data is presented that 1) HJV, a member of the repulsive guidance molecule (RGM) family, is a co-receptor that enhances bone morphogenetic protein (BMP) signaling; 2) mutations in HJV which cause iron overload impair its BMP signaling ability; 3) BMP-2 upregulates hepcidin expression; 4) BMP-2 induction of hepcidin expression is blunted in Hjv-/- hepatocytes. These data reveal a novel link between the BMP signaling pathway and iron metabolism and suggest a mechanism by which HJV mutations cause hemochromatosis: HJV dysfunction decreases BMP-2 signaling, thereby lowering hepcidin expression. This proposal aims to: 1) Characterize the molecular mechanisms by which BMP-2 regulates hepcidin expression, including the interaction between this pathway and other known modulators of hepcidin expression such as inflammatory mediators, HFE, TfR2, iron overload, and anemia; 2) Determine the effects of BMP-2 signaling via HJV in vivo on hepcidin expression, ferroportin expression, serum iron, and tissue iron levels; 3) Determine the role of other TGF- beta superfamily members on hepcidin expression and iron metabolism. Relevance: Disorders of iron balance represent a significant public health problem affecting over a billion people worldwide. This proposal aims to investigate a novel regulatory pathway, which appears to play a key role in iron balance. It is hoped that this work will provide clues leading to new treatment strategies for disorders of iron overload such as hemochromatosis and disorders of iron deficiency such as anemia of chronic disease.

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Project Title: LYMPHOMA

CELLULAR

TARGETS

FOR

GALLIUM

COMPOUNDS

IN

Principal Investigator & Institution: Chitambar, Christopher R.; Professor of Medicine; Medicine; Medical College of Wisconsin 8701 Watertown Plank Rd Milwaukee, Wi 532260509 Timing: Fiscal Year 2005; Project Start 01-APR-2005; Project End 31-MAR-2009 Summary: (provided by applicant): The mortality from lymphoma is high; thus, there is a great need to not only develop new therapeutic agents for this disease but to also further develop agents that have already shown promise in prior investigations. In early clinical trials, gallium nitrate (NSC15200) demonstrated significant clinical activity in lymphoma but its use in lymphoma was never rigorously pursued and information

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regarding its mechanisms of action has remained largely incomplete. There is now a renewed clinical interest in using gallium for lymphoma and clinical trials are in progress. The long-term objectives of this project are to optimally develop gallium compounds for the treatment of lymphoma by understanding its mechanisms of action. Our preliminary data suggest that the hemochromatosis (HFE) gene influences gallium uptake and cytotoxicity in lymphoblastoid cells and that gallium targets the mitochondria. HFE mutations, C282Y and H63D, occur with high frequency in the population. Specific Aim 1 will further investigate the role of HFE [wild type (wt) and mutant] as modulators of transferrin receptor-targeted gallium uptake and cytotoxicity in lymphoma cells. This Aim will investigate why lymphoblastic cells with the HFE C282Y mutation are more sensitive to gallium than cells with wt HFE. Studies will investigate the effects of HFE on gallium transport, gallium-induced apoptosis, gallium's action on iron homeostasis and ribonucleotide reductase. Specific Aim 2 will examine the effects of gallium on the generation of reactive oxygen species (ROS), mitochondrial function, and apoptosis induction. The effect of HFE mutations on gallium's antineoplastic action will be investigated with immortalized cell lines developed from individuals with wt HFE and HFE mutations. Lymphoma cells transfected with an inducible HFE gene (wt or mutant) will also be utilized. Ga-67 and Fe-59-transferrin will be used for uptake studies. mRNA and protein levels of transferrin receptor, ferritin, and HFE will be measured by Northern blotting, ligand binding, immunoblotting and immunoassays. Iron regulatory protein-RNA binding and ribonucleotide reductase R2 subunit will be studied by bandshift assay and ESR spectroscopy, respectively. ROS in cells will be detected using fluorescent probes and HPLC. Mitochondria-targeted antioxidants will be employed to investigate the source of gallium-induced ROS production. Mitochondrial electron transport enzymes will be assayed by measuring oxygen consumption and ATP production in cells and isolated mitochondria using substrates and inhibitors. Assays will measure aconitase and glucose consumption and caspase activity. Our studies will provide new information regarding: a) the impact of HFE mutations on the response of lymphoma to gallium, and, b) the mechanism of action of gallium at the mitochondrial level. •

Project Title: CHARACTERIZING A RECEPTOR FOR RGMC/HEMOJUVELIN Principal Investigator & Institution: Kuns, Robin E.; Biochem and Molecular Biology; Oregon Health & Science University 3181 Sw Sam Jackson Pk Rd Portland, or 972393098 Timing: Fiscal Year 2006; Project Start 01-AUG-2006; Project End 31-JUL-2009 Summary: (provided by applicant): RGMc (Repulsive Guidance Molecule c), or hemojuvelin, has been genetically linked with the iron overloading disorder juvenile hemochromatosis. Patients with juvenile hemochromatosis and RGMc knockout mice exhibit iron overloading in the liver, heart, and pancreas, and have decreased hepatic expression of the key iron regulatory protein, hepcidin. These observations suggest that RGMc plays a critical role in the regulation of systemic iron homeostasis, although its mechanisms of action are unknown. Initial studies have shown that RGMc binds to the transmembrane protein neogenin. The focus of this application is to test the hypothesis that neogenin functions as a receptor for RGMc. The following Specific Aims are proposed to test this hypothesis: 1. to define the nature of the interaction between RGMc and neogenin, 2; to determine whether neogenin mediates the biological actions of RGMc.

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Project Title: CHEMICAL GENETICS OF IRON TRANSPORT Principal Investigator & Institution: Wessling-Resnick, Marianne; Professor; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2005; Project Start 15-JUL-2004; Project End 30-JUN-2008 Summary: (provided by applicant): Chemical genetics is an emerging field that takes advantage of combinatorial chemical and small molecule libraries to dissect complex biological processes. Small molecules can act very fast, can be very specific, and can help to distinguish the temporal order of molecular steps and the hierarchical regulation of biological processes. Because small molecules can alter the function of a specific gene product, they can be used in a manner analogous to the use of inducible dominant or homozygous recessive genetic mutations. A large body of biochemical literature is based on the past use of small molecule antagonists that were employed in "reverse chemical genetics" approaches to conditionally eliminate protein function, and on that basis to subsequently identify the target, its mechanism of action, and its regulation. Thus, ouabain helped to define the catalytic cycle of the NaK-ATPase, cytochalasin B was instrumental in defining the molecular basis for insulin's action to stimulate glucose uptake, and analogs of amiloride were used to purify and define the epithelial Na channel. There is a need to develop "forward chemical genetics" in order to discover small molecules that partner with key elements in a pathway of interest. This proposal is supported by preliminary data that establish a fluorescence-based assay to screen for inhibitors of iron uptake by mammalian cells. Iron deficiency remains the most prevalent nutritional problem in our country, yet recent identification of the gene responsible for hereditary hemochromatosis indicates that 1 in 20 Caucasians carry the defective allele and thus 1 in 400 may be susceptible to iron overload. Increased knowledge about the transport factors and how they protect against iron deficiency and overload is essential to more broadly address these significant health problems. Using the cell-based fluorescence assay, we propose to: 1) Perform chemical genetic screens for selective inhibitors of different pathways of iron transport using combinatorial libraries; 2) Characterize the compounds identified to block iron uptake with highest potency; 3) Develop structure-activity profiles on compounds of interest and identify their targets. The goals of this project are to discover small molecule inhibitors of iron transport using chemical genetics and to use these reagents to advance our understanding of the factors, mechanisms, and regulation of different pathways of iron uptake.

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Project Title: COPPER HOMEOSTASIS IN YEAST Principal Investigator & Institution: Thiele, Dennis J.; Professor; Pharmacology and Cancer Biology; Duke University 2424 Erwin Rd. Durham, Nc 27705 Timing: Fiscal Year 2005; Project Start 01-APR-1989; Project End 30-NOV-2008 Summary: (provided by applicant): The trace metals copper (Cu) and iron (Fe) are nutrients that are essential to life, serving as catalytic cofactors in a wide variety of enzymatic reactions involved in blood clotting, energy generation, DMA replication, peptide hormone maturation, oxygen transport and a variety of other essential processes. Defects in Cu or Fe balance cause severe human diseases that include Menkes and Wilson diseases, hemochromatosis, anemia and others, and are implicated in Alzheimer's, Parkinson's and prion diseases and in cancer and aging. The essentiality of both Cu and Fe, and the functional interactions of these two metals require that organisms possess fine-tuned homestatic mechanisms to ensure that sufficient levels of Cu and Fe are acquired, distributed and utilized to drive biochemical reactions. Furthermore, cells must respond to changes that limit Cu or Fe availability to mobilize stores of these metals, or to reprogram cellular metabolism to cope with metal

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limitation. This proposal describes avenues of investigation, using yeast as a model system, to understand fundamental mechanisms whereby eukaryotic cells regulate Cu and Fe availability. In the first specific aim experiments are outlined to understand the physiological role, regulation and mechanism by which the yeast Ctr2 protein mobilizes intracellular Cu stores under conditions of Cu deprivation. The second specific aim outlines experiments to understand the function, mechanism of action and role of the Cth2 protein in targeting specific mRNA molecules for degradation under conditions of Cu or Fe deficiency, as a means of prioritizing Fe utilization. Given the importance of proper homeostatic control of Cu and Fe in human health, and the presence of potential functional orthologues of both Ctr2 and Cth2 in humans, the studies described in this proposal will provide fundamentally important information on the mechanisms whereby cells maintain Cu and Fe homeostasis in health and disease. •

Project Title: DERMATOREMEDIATION OF IRON OVERLOAD Principal Investigator & Institution: Milstone, Leonard M.; Professor; Dermatology; Yale University 47 College Street, Ste 203 New Haven, Ct 065208047 Timing: Fiscal Year 2005; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: The goal of this work is to demonstrate that the normal process of epidermal desquamation can be harnessed to eliminate systemic toxins from the body. The central hypothesis is that if epidermal keratinocytes can be manipulated to accumulate a systemic toxin, then that toxin will be removed from the body by the eventual desquamation of those keratinocytes. This proposal focuses on remediating iron overload. Iron is essential for life, but too much iron causes the disease hemochromatosis. Four key questions need to be answered. First, are there pharmacological or genetic ways to increase iron content of epidermis? Second, can keratinocytes accumulate sufficient iron to expect that enough iron could be eliminated through epidermis to ease the burden of excess iron expected in hemochromatosis? Third, can sufficient iron be delivered from the circulation to the epidermis to reduce systemic iron in a model of iron overload? Fourth, how much excess iron can the epidermis tolerate before showing signs of local toxicity? We believe our preliminary data have answered the first two questions in the affirmative. This proposal focuses on the third question and has two specific aims: 1) to devise methods to increase iron accumulation in mouse epidermis a) genetically by creating a transgenic mouse that overexpresses the transferrin receptor in epidermis b) pharmacologically by topical application of nitrosopine, a derivative of nifedipine. 2) to test whether these methods of increasing iron in epidermis are able to reduce the iron burden in a mouse model of iron overload a) by breeding the transgenic, transferrin receptor overexpressor mouse to Hfe null mice; b) by topical application of nitrosopine, a derivative of nifedipine, to Hfe null mice.

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Project Title: DIABETES MECHANISMS

IN

HEMOCHROMATOSIS:

PREVALENCE

AND

Principal Investigator & Institution: Mcclain, Donald A.; Professor; Internal Medicine; University of Utah 75 South 2000 East Salt Lake City, Ut 84112 Timing: Fiscal Year 2005; Project Start 01-MAR-2002; Project End 30-NOV-2006 Summary: Although the hemochromatosis gene (HFE) has been identified there is little information about the diabetes that often accompanies the disease. We hypothesize nondiabetic homozygotes for mutations in HFE will exhibit a defect in insulin secretion as iron overload develops. This notion is supported by preliminary data obtained in HFE mutant mice. The insulin deficiency will progress to type 2 diabetes only if insulin

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resistance also occurs, either from cirrhosis or inheritance of type 2 diabetes genes. Insulin resistance from cirrhosis is hypothesized to result from excess carbohydrate delivery to peripheral tissues, resulting in excess hexosamine generation, an established cause of insulin resistance. Our specific aims are to: 1. Determine the prevalence of impaired glucose intolerance (IGT) and diabetes in clinically unselected individuals with hemochromatosis by oral glucose tolerance criteria. 2. Determine if a defect in insulin secretion exists in nondiabetic homozygotes with or without iron overload. This will be accomplished using the frequently sampled intravenous glucose tolerance test (FSIVGTT) with insulin levels. Reversibility of the defect will be examined after subjects have undergone phlebotomy. The hypothesis will be verified in studies of isolated islets from mice carrying disrupted or mutant HFE genes. 3. Using animal models, determine if diabetes in hemochromatosis results only when insulin resistance is superimposed on an iron- mediated defect in insulin secretion. 4. Determine the sequence and relative contributions of insulin resistance and hepatic glucose production (HGP) in the evolution of diabetes in human hemochromatosis. Insulin resistance and HGP will be quantified by the hyperinsulinemic euglycemic clamp and stable isotope techniques in subjects with hemochromatosis who have normal or IGT, with or without hepatic involvement. •

Project Title: EPIDEMIOLOGY AND INCIDENCE OF BARRETT'S ESOPHAGUS Principal Investigator & Institution: Corley, Douglas A.; Investigator; Kaiser Foundation Research Institute 1800 Harrison St, 16Th Fl Oakland, Ca 94612 Timing: Fiscal Year 2005; Project Start 30-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Although the incidence of esophageal adenocarcinoma is rising more rapidly than that of any other malignancy, little is known about its pathogenesis. In particular, little population-based information is known about its main precursor lesion, Barrett's esophagus. The presence of Barrett's esophagus, a metaplastic esophageal columnar epithelium, effectively identifies persons at risk for esophageal adenocarcinoma. Thus, there is a compelling rationale for characterizing the incidence and major modifiable risk factors for Barrett's esophagus, and how these relate to purported risk factors for esophageal adenocarcinoma. Specific Aims/Methods: A. Evaluate the association between obesity/body fat distribution and Barrett's esophagus using a nested case-control study in the Northern California Kaiser Permanente (NCKP) population. The NCKP population contains approximately 3 million people, and is representative of the gender and ethnic distribution of Northern California. The study would use 313 cases, 313 population-based controls, and 313 controls with gastroesophageal reflux disease (who do not have Barrett's esophagus). We would employ a supplementary dietary questionnaire to evaluate for potential dietary confounders of the obesity-Barrett's esophagus relationship. B. Evaluate the association between serum antibody status for Helicobacter Pylori (including the virulent cagA+ strain) and Barrett's esophagus using a case-control study. C. Assay Barrett's esophagus patients and controls for iron stores and heterozygosity for the C282Y hemochromatosis gene mutation. D. Use the patients identified in these case-control studies to estimate the annual population-based incidence of Barrett's esophagus diagnosis. Obesity and body fat distribution, H.pylori infection, and iron stores represent potentially major, modifiable risk factors for Barrett's esophagus and esophageal adenocarcinoma. Our proposed study will: substantially extend current knowledge regarding the epidemiology of Barrett's esophagus; may partially explain why Barrett's esophagus/esophageal adenocarcinoma occurs predominantly in Caucasian males; estimate the population-based incidence of Barrett's esophagus diagnosis in the United States; and provide information for future intervention trials.

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Project Title: EPIDEMIOLOGY OF HEPATOCELLULAR CARCINOMA Principal Investigator & Institution: Ko, Cynthia W.; Medicine; University of Washington Office of Sponsored Programs Seattle, Wa 98105 Timing: Fiscal Year 2005; Project Start 06-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): The goals of the proposed research project are: 1) to prepare and train the candidate for a career in academic gastroenterology by providing the necessary environment, education, and research support, and 2) to gain insight into the epidemiology of hepatocellular carcinoma in the United States. The candidate is a clinically trained gastroenterologist with additional training in basic epidemiology and biostatistics. As part of this proposal, she will be provided with more advanced training in both general and applied epidemiology and biostatistics. The candidate will be supported and mentored by Dr. John Potter. Her progress will be monitored by the sponsor and the Division of Gastroenterology. The Department of Medicine and Division of Gastroenterology will provide full commitment and support toward the development of the candidate's independent research career. The focus of the scientific portion of this proposal is on hepatocellular carcinoma, a common tumor worldwide the incidence of which is also rising in the United States. Much of this increase can be attributed to the current epidemic of hepatitis C. The epidemiology of hepatocellular carcinoma has not been extensively studied in this country, and few studies have recruited population-based cases and controls. Well-recognized environmental risk factors for hepatocellular carcinoma include chronic viral hepatitis, other chronic liver diseases, and exposure to aflatoxins. However, risk factors that predispose patients with chronic liver disease to hepatocellular carcinoma are not well defined. It is likely that genetic risk factors for hepatocellular carcinoma exist, since familial and ethnic clustering of the tumor are well documented, iron is a recognized co-factor for the development of malignancy in other sites. Hemochromatosis is an inherited disorder in which excess iron accumulates in the liver, heart, pancreas, and other organs. A gene for hemochromatosis, HFE, has recently been identified. Patients with hemochromatosis are at up to 200-fold increased risk of developing hepatocellular carcinoma. We hypothesize that HFE mutations are risk factors for HCC in patients either with or without underlying liver disease. Thus, the specific aims of tills proposal are: 1) to determine whether mutations in the HFE gene are a risk factor for hepatocellular carcinoma; and 2) to recruit a cohort of patients with chronic hepatitis C for prospective studies of the epidemiology of hepatocellular carcinoma.

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Project Title: FERRITIN AND IRON NUTRITION IN HEALTH AND DISEASE Principal Investigator & Institution: Theil, Elizabeth C.; Senior Scientist; Children's Hospital & Res Ctr at Oakland 747 52Nd St Oakland, Ca 946091809 Timing: Fiscal Year 2005; Project Start 18-JUN-1998; Project End 30-NOV-2005 Summary: Alternatives to current management strategies for managing dietary iron deficiency can help compensate for the relative expense of food supplementation, for noncompliance with specific therapies and for interactions between supplements and endogenous food components such as phytate. Dietary iron deficiency and anemia afflict an estimated 1.5 billion people world. In the United States estimates of iron deficiency in women of reproductive age are approximately 6.6 percent and for children and adolescents, approximately 11 percent. The link between slow cognitive development and iron deficiency makes the potential economic impact great. Certain disease states such as Sickle Cell Disease (SCD), hereditary hemochromatosis (HH), and beta-thalassemia (beta-thal) have altered gut iron uptake that is poorly characterized. In addition, the consequences of Fe overload are different for SCD, beta-thal and HH. Such

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observations illustrate disease-dependent variations in handling iron. With more information, recommendations for different dietary iron sources in each disease states might need to be developed. Ferritin is a major source of iron in the early development of humans, other animals and plants. Legume seeds consumed by humans are rich in iron and ferritin. Soybean seed iron (largely ferritin) and horse spleen ferritin are available iron sources for iron deficient rats. During the last grant period soybean iron has been shown to be readily available to humans and horse spleen ferritin iron was shown to be taken up by cultured cells. However, there is little information about the molecular mechanism of iron uptake from ferritin. The impact of ferritin iron on expression of iron uptake and export proteins in normal or the disease states SCD, HH and beta-thal is not known, and the nutritional impact of differences in the mineral structure of plants (high phosphate) and animals (low phosphate) has not been explored. Proposed are three sets of experiments: 1. Uptake, metabolism and transport of iron from ferritin in Caco-2 cells and the fate of ferritin during digestion. 2. Comparison of ferritin and iron salts for of red cell iron, in mouse models of human disease. 3. Ferritin with high (plant) and low (animal) phosphate mineral for dietary iron in humans-whole body analyses. The results will clarify mechanisms of ferritin iron uptake and characterize molecular genetic differences in iron uptake for improving dietary iron sources in health and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FERROPORTIN 1 IN VERTEBRATE IRON UTILIZATION Principal Investigator & Institution: Zon, Leonard I.; Professor; Children's Hospital Boston 300 Longwood Ave Boston, Ma 021155737 Timing: Fiscal Year 2005 Summary: Efficient uptake and utilization of iron is essential to normal hematopoiesis. In mammals, dietary iron absorption is carried out by specialized enterocytes in the proximal small intestine. Iron is taken up through the apical transmembrane iron transport, DMT1, Homozygous mutant mice carrying a mutation in DMT1 are severely iron deficient and poorly viable. Until recently, it was not known host iron exists the basolateral surface of the enterocyte to reach the circulation. We recently identified a transmembrane protein, ferroportin1, which as an iron exporter. The ferroportin1 gene is defective in the zebrafish mutant weissherbst. Weissherbst embryos die from severe iron deficiency anemia, resulting from defective iron transport between the yolk sac and the developing embryo. The mammalian ortholog of ferroportin1 is expressed in the basolateral membrane of intestinal enterocytes, and at other sites requiring active iron expert. We hypothesize that ferroportin1 is the basolateral iron transporter in enterocytes and an iron exporter in other cell types In this grant we propose to study the conservation of vertebrate ferroportin1 function and the role of ferroportin1 in vivo. Gene targeting will be used to generate mice lacking ferroportin1 in selected tissues and these animals will be analyzed for defects in iron absorption and homeostasis. Ferroportin1 expression and activity will be analyzed in a panel of mouse mutants with defects in iron metabolism, and in a murine model of human hemochromatosis. Zebrafish studies will investigate the relationship between erythropoiesis and ferroportin1 by studying mRNA expression in known hematopoietic mutants. A mutagenesis screen will also be done to find zebrafish mutants with defects in ferroportin1 mRNA expression. Finally, we plan to do also be done to find zebrafish mutants with defects in ferroportin1 mRNA expression. Finally, we plan to do a suppressor-enhancer screen for ferroportin1 to define factors that genetically coordinate iron metabolism with ferroportin1 in the developing zebrafish embryo. Our findings

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will improve our understanding of vertebrate iron biology and may be relevant to human patients with iron deficiency and iron overload disorders. •

Project Title: FERROPORTIN AND IRON EXPORT FROM THE MACROPHAGE Principal Investigator & Institution: Knutson, Mitchell D.; Assistant Professor; Food Science & Human Nutrition; University of Florida 219 Grinter Hall Gainesville, Fl 32611 Timing: Fiscal Year 2005; Project Start 15-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): This application is for further training of the candidate, Mitchell Knutson, who has a Ph.D. in Nutrition and post-doctoral experience in the molecular biology of iron metabolism. Dr. Knutson's immediate career goal is to acquire new skills and knowledge that will enable him to study iron metabolism in macrophages. To accomplish this task, Dr. Knutson will be mentored by Dr. Lester Kobzik, an expert in macrophage biology at the Harvard School of Public Health (HSPH), and co-mentored by Dr. Marianne Wessling-Resnick, his current mentor at HSPH. The research proposal will investigate the function of the newly identified protein, ferroportin, FPN1 (also known as MTP1 or IREG1), in iron metabolism in the macrophage. The hypothesis to be tested is that FPN1 plays a role in iron export from the macrophage after phagocytosis of red blood cells. Erythrophagocytosis by macrophages, with the subsequent release of iron into the circulation, constitutes the largest flux of iron within the body. The mechanism for this, however, is unknown. To investigate the role of FPN1 in the macrophage, immunofluorescence experiments will determine the subcellular localization of this protein. Cytolocalization will be assessed before and after erythrophagocytosis. FPN1 mRNA and protein expression will be measured after erythrophagocytosis, and the changes will be compared to changes in rates of iron release, as measured by the efflux of 59Fe after phagocytosis of 59Fe-labeled erythrocytes. To test the hypothesis that FPN1 plays a role in iron release, efflux of erythrocyte-derived 59Fe will be measured after overexpressing FPN1 in macrophages using retroviral vector transduction, as well as after suppressing FPN1 using antisense techniques. The proximity of experts in macrophage biology, retroviral transduction, and antisense technology at HSPH, combined with the local expertise of investigators in the iron field, offers Dr. Knutson a highly suitable environment for learning the necessary skills required to carry out the proposed experiments. Successful completion of these experiments will contribute significantly to our understanding of iron metabolism in the macrophage and will enable Dr. Knutson to advance towards his long-term career goal of becoming an independent investigator and Assistant Professor of Nutrition. Moreover, a better understanding of iron release from the macrophage is of considerable clinical importance given the disturbances in macrophage iron metabolism characteristic of hereditary hemochromatosis and the anemia of chronic disease.

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Project Title: FUNCTION OF THE HEMOCHROMATOSIS PROTEIN Principal Investigator & Institution: Enns, Caroline; Associate Professor; Cell and Developmental Biology; Oregon Health & Science University 3181 Sw Sam Jackson Pk Rd Portland, or 972393098 Timing: Fiscal Year 2005; Project Start 01-MAR-2000; Project End 28-FEB-2010 Summary: (provided by applicant): Hereditary hemochromatosis (HH) is the most common inherited disorder in people of Northern European descent. Over 83% of the cases of HH result from a single mutation of a Cys to Tyr in the HH protein, HFE. This mutation causes a recessive disease resulting in an accumulation of iron in selected tissues. Iron overload damages these organs leading to cirrhosis of the liver, diabetes, cardiomyopathy, and arthritis. The mechanism by which HFE influences iron

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homeostasis in cells and in the body remains elusive. Lack of functional HFE in humans produces the opposite effects in different cell types in the body. In the early stages of the disease, Kupffer cells in the liver and enterocytes in the intestine cells are iron depleted and have low intracellular ferritin levels, whereas hepatocytes in the liver are iron overloaded and have high intracellular iron levels. Whether these are direct or indirect effects of HFE function is not known. In order to address this question and to understand the molecular mechanisms by which HFE influences iron homeostasis, cell lines have been developed that when transfected with HFE show either increases or decreases in iron levels. The aims of this proposal are focused on finding the basis of the opposite effects of HFE function in different cell types. The hypothesis that HFE alters iron homeostasis by interacting different proteins in different cell lines will be tested. Chimeric HFE proteins will be made to define the domains of HFE responsible for the alterations in iron homeostasis and site-directed mutagenesis will be used for finer mapping of the domains. The HFE protein complex could be directly regulating intracellular iron levels or signaling independently of intracellular iron levels. New genes that functionally couple to HFE will be identified in a high throughput screen. The hypothesis that HFE alters gene expression in an iron-dependent manner will be tested by microarray analysis of cells expressing and not expressing HFE. Finally, the hypothesis that HFE acts to regulate iron homeostasis in hepatocytes solely through controlling intracellular iron levels will be tested using a hepatic cell line and orimary hepatocytes. The long term goal of this work is to understand the function of HFE. •

Project Title: GENETIC ANALYSIS OF IRON HOMEOSTASIS IN ZEBRAFISH Principal Investigator & Institution: Fraenkel, Paula Goodman.; Instructor; Beth Israel Deaconess Medical Center 330 Brookline Avenue, Br 264 Boston, Ma 02215 Timing: Fiscal Year 2005; Project Start 01-JUL-2002; Project End 30-JUN-2007 Summary: (provided by applicant) Maintaining iron homeostasis is essential for normal hematopoiesis and the prevention of organ damage due to iron overload. Although the C282Y mutation in the HFE gene is commonly found in the Caucasian population, the penetrance of hereditary hemochromatosis is quite variable (1), suggesting that other genes also participate in the regulation of iron homeostasis. The zebrafish, Danio rerio, provides an excellent genetic system for the identification of novel genes involved in iron metabolism, as evidenced by the recent identification of the novel iron transporter ferroportin1 by positional cloning of the mutation responsible for the hypochromic zebrafish mutant, weissherbst (2). Analyzing mutants generated in a large scale chemical mutagenesis screen, I have identified another mutant with hypochromic anemia, HF107, that maps to a novel locus on zebrafish chromosome 20. I propose to clone the gene responsible for this mutant and to characterize the gene product. Complementation studies and low-resolution mapping of another mutant with hypochromic anemia, HM007, resulted in the identification of a new allele of weissherbst that appears to have less severe anemia than the previously identified alleles. Determining the genetic basis for this new allele may provide insight into the regulation and function of ferroportin1. Furthermore, I propose to place ferroportin1 in a genetic pathway governing iron homeostasis by performing a screen for zebrafish mutations that overcome a defect in ferroportin1 function. We hypothesize that ferroportin1 plays a critical role in maintaining iron homeostasis and that its regulation and function depend on specific genes which are likely to be identified in the suppressor screen. These may include (1) hephaestin (2) HFE (3) transferrin receptor (4) novel genes including the postulated iron stores regulator and erythropoietic regulator (5) alternative iron transporters. In addition we expect to find gain of function mutations in the ferroportin1 gene itself. Performing a mutagenesis screen facilitates evaluation of the

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interactions of all these factors simultaneously and may result in the identification of novel genes involved in iron homeostasis. These novel genes may become molecular targets for the treatment of iron overload conditions, such as hereditary hemochromatosis. •

Project Title: GENETIC MODIFIERS IN CHILDREN WITH SICKLE CELL ANEMIA Principal Investigator & Institution: Ware, Russell E.; Director; St. Jude Children's Research Hospital 332 N Lauderdale St Memphis, Tn 381052794 Timing: Fiscal Year 2005; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: (provided by applicant) The beta6 (Glu toVal) mutation in the beta globin gene that leads to sickle cell anemia (SCA) has been known for many years, and the biophysical characteristics of intracellular sickling are well described, but the clinical heterogeneity in patients with SCA is poorly understood. Patients with SCA have a wide variability of clinical disease expression that is puzzling, despite efforts to identify globin gene modifiers such as alpha thalassemia, beta globin haplotype, or enhanced gamma globin expression. Our preliminary data suggest that genetic modifiers outside the globin gene loci can alter clinical disease expression in SCA, and we hypothesize that these genetic modifiers can predict the development of cerebrovascular and hepatobiliary disease in children with SCA. To test our hypothesis, we will analyze DNA samples from over 400 pediatric patients enrolled in two completed NHLBIsponsored multicenter trials: (1) the Cooperative Study of Sickle Cell Disease (CSSCD) and (2) the Study to Prevent Stroke (STOP). We also include the upcoming Phase III infant hydroxyurea trial (BABY-HUG) that will add 200 additional DNA samples and the opportunity for direct patient contact and clinical research experience by trainees. We will test DNA samples from these unique pediatric cohorts for genetic polymorphisms (DNA mutations) in genes that collectively are important in thrombosis (e.g. methylenetetrahydrofolate reductase, platelet glycoprotein IIIa, plasminogen activator inhibitor, prothrombin, Factor V, and Factor VII genes), brain injury repair (apolipoprotein E), bilirubin metabolism (the UDP-glucuronosyltransferase), and iron accumulation (hereditary hemochromatosis gene). After determining the prevalence of each DNA mutation, we will correlate specific polymorphisms with patient data including laboratory measurements, clinical events, and radiological studies. The longterm goal is to identify genetic risk factors that influence the development of cerebrovascular and hepatobiliary disease, and to develop a prospective interventional clinical trial for children with SCA. Trainees will study laboratory techniques, statistical analysis, IRB protocol design, informed consent, ethical issues related to participation in clinical trials, and have direct patient contact with families participating in BABY-HUG.

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Project Title: GENETIC MODIFIERS OF HEMOCHROMATOSIS PHENOTYPE Principal Investigator & Institution: Gertig, Dorota M.; University of Melbourne Level 5 Melbourne, 3010 Timing: Fiscal Year 2005; Project Start 01-MAR-2004; Project End 28-FEB-2007 Summary: (provided by applicant): Hereditary hemochromatosis (HH) is a common disorder of iron overload and over 80% of patients are homozygous for the C282Y mutation in the HFE gene. Clinical manifestations of HH vary widely from non-specific symptoms associated with mild iron overload to severe organ damage due to iron deposition in the liver, heart, joints and pancreas. Penetrance is age-dependent and it is estimated that only about half of all C282Y homozygotes will express clinical disease. A number of factors may modify expression of disease in HH and both genetic and environmental factors are potentially important. There are several promising candidate

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genes in the iron transport pathway that could modify the effect of HFE mutations. The overall aim of this project is to evaluate genetic modifiers of phenotypic variability in HH. We hypothesize that haplotypes in genes involved in iron transport and storage, and regulation of iron homeostasis, modify iron overload as measured by serum ferritin and transferrin saturation, in HFE mutation carriers. This study will use the resources of an existing unique Australian general population cohort of 41,500 men and women aged 40-69 years at enrollment. Initial HFE mutation testing will be conducted on the entire cohort. Participants have been followed for almost 10 years and extensive epidemiologic and dietary data and a blood specimen were collected at baseline. A sub cohort (n=1,150) that includes all C282Y homozygotes and an age-matched stratified random sample of other HFE genotypes and wild-type individuals will be selected for clinical follow-up. Siblings of C282Y homozygotes will also be invited for clinical follow-up. For this sub-cohort, serum ferritin and transferrin saturation will be measured on follow-up samples as well as on the samples collected at baseline approximately 10 years earlier. Variants in potential modifier genes in the pathways described above will be systematically identified and haplotypes will be determined using a computational algorithm. Individuals in the subcohort will be tested for variants to define these haplotypes and we will look for interaction with HFE mutations using measures of iron overload as the outcome. In addition, we will utilize the epidemiologic and dietary data on the cohort to evaluate whether dietary and lifestyle factors modify HH phenotype and how these factors may interact with the genetic modifiers described above. Finally, the functional significance of variants that are associated with iron overload will be determined. The identification of genetic and environmental modifiers of HH phenotype in this study has potentially important implications for clinical management of genetically susceptible people and for public health decision-making regarding screening for HH. HH is a model disease for studying gene-gene interaction due to the availability of intermediate markers of iron overload and promising candidate modifier genes in iron transport pathways. •

Project Title: HEMOCHROMATOSIS -- EPIDEMIOLOGY AND MOLECULAR MECHANISMS Principal Investigator & Institution: Beutler, Ernest; Chairman; Scripps Research Institute 10550 North Torrey Pines Road La Jolla, Ca 920371000 Timing: Fiscal Year 2005; Project Start 28-APR-1998; Project End 31-JAN-2007 Summary: This abstract is not available.

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Project Title: HEMOCHROMATOSIS MODIFIER GENES Principal Investigator & Institution: Kushner, James P.; Professor of Medicine; Internal Medicine; University of Utah 75 South 2000 East Salt Lake City, Ut 84112 Timing: Fiscal Year 2005; Project Start 15-FEB-2004; Project End 31-JAN-2007 Summary: (provided by applicant): Homozygosity for a single mutation (HFE C282Y) is responsible for the vast majority of cases of hemochromatosis, yet phenotypic expression in homozygotes varies widely. The hypothesis to be tested in this application is that modifier genes are responsible for the phenotypic variability. To test this hypothesis, we propose two specific aims. Specific Aim 1: Utilize murine chromosome substitution strains (CSSs) to identify chromosomes that influence the iron phenotype. Iron metabolism in inbred mice varies in a strain-specific manner. We have established that mice of the A/J strain have a "high iron" phenotype. They absorb twice the amount of iron than C57BL/6J mice absorb and also deposit more newly absorbed iron in the liver, have higher transferrin saturation, higher liver iron content and transfer more iron

34

Hemochromatosis

from macrophages to hepatocytes. The CSSs we will utilize are on a C57BL/6J background, but each strain is homozygous for one chromosome (1-19, X,Y) donated from A/J. A CSS strain in which the iron phenotype differs from C57BL/6J will immediately identify a chromosome containing a modifier gene(s). CSSs of interest will be crossed with Hfe mutant C57BL/6J mice to establish that the chromosome identified modifies the Hfe phenotype. Specific Aim 2: Identify candidate modifier genes by narrowing the regions of interest on the chromosomes identified in Specific Aim1. Recombinant congenic strains (RCS) have been generated from the C57BL/6J an A/J strains. RCS containing segments of chromosomes identified in Specific Aim 1 will be phenotyped to narrow the candidate modifier region. Genes localized to the candidate region will be considered candidates for genes that modify the iron phenotype and hence affect expression of hemochromatosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEPHAESTIN: A COPPER PROTEIN INVOLVED IN IRON METABOLISM Principal Investigator & Institution: Vulpe, Christopher D.; Assistant Professor; Nutritional Scis & Toxicology; University of California Berkeley 2150 Shattuck Avenue, Room 313 Berkeley, Ca 947045940 Timing: Fiscal Year 2005; Project Start 01-AUG-1999; Project End 30-APR-2007 Summary: (provided by applicant): Iron deficiency adversely affects over one-third of the world's population. Conversely, iron overload disease hemochromatosis is one of the commonest genetic defects in man. In order to maintain a balance between deficiency and toxicity, multiple regulatory systems exist to optimize iron levels in the human body. The absorption of iron by the intestine is central to this regulation because no physiologic means exists to excrete excess iron. Our long-term goal is to understand how changes the body communicates its iron needs to the intestine and how the intestine controls iron absorption into the body. We previously identified, hephaestin, which oxidizes iron from ferrous to ferric iron and is required for moving iron from gut cells into the body. We are studying its function and role in intestinal iron transport and whole body iron homeostasis. Remarkable changes occur in response to iron deficiency, the expression of iron transport proteins increase and some proteins including hephaestin move from intracellular locations to the cell surface to facilitate iron transport. In systemic iron deficiency, the intestinal enterocyte is poised for maximal absorption but is also capable of buffering the uptake of iron in case of potentially toxic dietary levels. In this study, we will ask three questions. 1) How is hephaestin regulated in response to local and systemic iron status? We will independently manipulate dietary and systemic iron status in mice to define the dietary versus systemic effects on hephaestin and other iron transport proteins. We will use cell culture studies to define the regulatory mechanisms. 2) What regulates the movement of hephaestin? We will define the dietary conditions for movement and the rate at which it occurs. We will use a cell culture system to identify the parts of hephaestin that are necessary for movement. We will try to identify the proteins that play a role in the movement of hephaestin. Finally, we will ask 3) how iron oxidation by hephaestin facilitates iron transport ? Hephaestin could be directly required in order to release iron from the iron transporter or alternatively it could create a gradient of ferrous iron which would drive the transport of iron. Iron transport assays using a buffer system that allows us to very tightly control the amount of ferrous and ferric iron will allow us to distinguish between these possibilities.

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Project Title: HFE HOMEOSTASIS

TRANSFERRIN

RECEPTOR

INTERACTION

IN

35

IRON

Principal Investigator & Institution: Schmidt, Paul; Children's Hospital Boston 300 Longwood Ave Boston, Ma 021155737 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-MAR-2011 Summary: (provided by applicant): The objective of this study is to elucidate the role of the hereditary hemochromatosis gene (HFE) - Transferrin receptor (TFR1) interaction in vivo. HFE is a major histocompatibility complex (MHC) class l-like gene that forms a protein-protein complex with TFR soon after synthesis and is transported to the cell membrane. This interaction causes a conformational change in TFR1, reducing the affinity of the receptor for holo-transferrin (Fe-TF). Mutations in HFE disrupt its conformation and interaction with (2-microglobulin, and cause a decrease in cell surface expression of the HFE protein. Previous studies have investigated the HFE/TFR interaction interface by co-crystallization of HFE and TFR1, by site-directed mutagenesis and by in vitro binding studies. We chose to introduce two mutations into the murine Tfr1, L622A and R654A, to study the role of the Hfe/Tfr1 interaction in vivo. The L622A mutation disrupts a leucine residue that is essential for interaction between Hfe and Tfr1, but is not crucial for the Tfr1/Tf interaction. Conversely, the R654A substitution greatly decreases the affinity of Tfr1 for Tf but has no impact on the Hfe/Tfr1 interaction. Several parameters will be analyzed to define the phenotype of the genetically engineered mice. Liver iron stores will be used as an index of intestinal iron absorption, and serum transferrin saturation and spleen iron stores will be used to assess macrophage iron recycling and stores. The resulting data will give new insight into the function of the Hfe/Tfr1 complex and aid in distinguishing among competing models for how Hfe regulates iron homeostasis. The specific aims of this proposal are: 1) to generate mouse models where Tfr1 is unable to interact with Tf, but its ability to bind to Hfe is unaffected, 2) to generate a mouse model where Tfr1 is able to interact with Tf, but its ability to bind to Hfe has been abrogated, and 3) to generate transgenic mouse models to examine putative signaling portions of the Hfe molecule. Knowledge gained through this study will add to our understanding of human iron disorders including hereditary hemochromatosis, iron-limited anemia, and anemia caused by chronic disease. It may inform new therapeutic strategies. The KO1 award will allow the candidate to undertake an extensive mentorship with Dr. Nancy Andrews. During this period he will have the opportunity to increase the technical skills and the knowledge base necessary for the successful generation of both transgenic and gene-targeted mice. The candidate will also learn to effectively employ this information and skill set to test complex hypotheses in iron metabolism and homeostasis. He will also have ample opportunities to interact and collaborate with leading investigators in the field through attendance at meetings and the writing of articles for publication. Most importantly, this award will assist in the transition of the candidate to become a fully independent investigator in the field of iron metabolism. •

Project Title: HFE/TRANSFERRIN RECEPTOR/TRANSFERRIN INTERACTIONS Principal Investigator & Institution: Bjorkman, Pamela J.; Professor and Howard Hughes Investigator; None; California Institute of Technology Office of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125 Timing: Fiscal Year 2005; Project Start 01-MAR-2002; Project End 31-JAN-2007 Summary: We seek to understand the structural basis for negatively cooperative3 ligand binding by transferrin receptor (TfR). TfR is a membrane-bound homodimer that binds two ligands: iron loaded transferrin (Fe-Tf) and HFE, the protein mutated in the iron

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Hemochromatosis

overload disease hereditary. hemochromatosis. Binding of HFE to one TfR chain lowers the affinity for binding Fe-Tf or another HFE to the other chain. We solved crystal structures of HFE alone and a 2:2 TfR/HFE complex in which one HFE is bound to each chain of the TfR homodimer. The TfR/HFE structure reveals that HFE binding induces changes at the TfR dimer interface, suggesting that binding to one polypeptide chain of the TfR dimer transmits structural changes to the other TfR chain that influence binding of Fe-Tf or another HFE. To elucidate how structural changes influencing binding are transmitted, we will characterize the biochemical and structural properties of a 2:1 TfR/HFE complex (TfR dimer binding only one HFE) and a Fe-TfR/HFE ternary complex. These complexes will be prepared using a heterodimeric version of TfR in which mutations have been introduced such that one polypeptide chain can bind HFE but not Fe-Tf, and the other polypeptide chain can bind Fe-Tf but not HFE. We will first identify residues that eliminate binding of HFE or Fe-Tf by measuring the affinities of site-directed TfR mutants for Fe-Tf or HFE using a quantitative biosensor assay. Since HFE and Fe-Tf bind to an overlapping site on TfR, residues within or near the HFE binding site on TFR (which is known from the TfR/HFE crystal structure) should form part of the Fe-Tf binding site. Upon identification of TfR mutants that retain binding for one ligand, but not the other, we will produce TfR heterodimers by expressing both mutant TfR chains in the same cell. TfR heterodimers will be purified from homodimers using different affinity tags attached to each TfR chain. Heterodimeric TfR will be used to solve crystal structures of a 2:1 TfR/HFE complex and a 1:2:1 Fe-Tf/TfR/HFE complex. Comparisons with the structures of TfR alone and the 2:2 TfR/HFE complex will elucidate the structural effects of ligand binding to one side of the TfR dimer. Other TfR mutants will be analyzed to elucidate the structural mechanism for TfR's sharply pH dependent binding behavior. TfR binds apo-Tf at the acidic pH of endosomes (greater than or equal to pH 6.5), but not at the slightly basic pH of the cell surface (pH 7.4) and binds to HFE with the opposite pH dependence. Results from these studies will be critical for understanding how interactions between TfR, HFE, and Fe-Tf are involved in regulating iron homeostasis. •

Project Title: HIGH TC SUSCEPTOMETER FOR MAGNETIC MEASURE OF BODY IRON Principal Investigator & Institution: Brittenham, Gary M.; Professor of Medicine; Pediatrics; Columbia University Health Sciences Columbia University Medical Center New York, Ny 100323702 Timing: Fiscal Year 2005; Project Start 30-SEP-2001; Project End 30-APR-2007 Summary: (provided by applicant): The proposed Bioengineering Research Partnership will integrate bioengineering, basic science and clinical efforts in the design, development and clinical validation of a high-transition-temperature (high Tc; operating at 77oK) superconducting susceptometer for the direct, non-invasive measurement of hepatic iron stores in patients with iron overload from hereditary hemochromatosis, thalassemia major, sickle cell disease and other disorders. Our laboratories originally proposed that storage iron (ferritin and hemosiderin) could be non-invasively assessed in vivo because of its paramagnetic properties. We subsequently developed lowtransition-temperature (low Tc; operating at 4.2oK) superconducting quantum interference device (SQUID) biosusceptometry as a clinical method for the measurement of hepatic iron stores. Non-invasive magnetic measurements of hepatic storage iron in patients with iron overload are quantitatively equivalent to biochemical determinations on tissue obtained by biopsy but the cost and complexity of the low-Tc instrument has restricted clinical adoption of the method. Our low-Tc susceptometer has three elements which utilize superconductivity: (i) the SQUID, (ii) the field coils that produce a

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localized steady magnetic field near the liver, and (iii) the detection coils and flux transformer. Recent technological advances make possible replacement of each of these low-Tc elements, cooled by liquid helium, with components able to function when cooled by liquid nitrogen. To provide "proof-of-principle," we have constructed and operated a prototype high-Tc susceptometer with (i) a high-Tc SQUID, (ii) a NdBFe permanent magnet providing a strong localized magnetic field, and (iii) detection coils and flux transformer fashioned from a high-Tc Y1Ba2Cu3O7-delta film deposited on a flexible substrate. The proposed Partnership will now optimize and integrate these components into a series of liquid nitrogen-cooled clinical devices, and then validate and certify the high Tc-susceptometers in studies of adult and pediatric patients. Magnetic studies permit accurate, direct, and repeated measurements of hepatic iron stores not possible with any other method. The development of an affordable, readily usable instrument for the non-invasive measurement of hepatic iron - a high priority goal of both the NIDDK and the NHLBI - would be a major advance in the diagnosis and management of patients with iron overload that would find immediate and widespread clinical use both in the U.S. and worldwide. •

Project Title: IMPROVED SUSCEPTOMETRY TO MEASURE BODY IRON STORES Principal Investigator & Institution: Kumar, Sankaran; Senior Scientist; Quantum Magnetics, Inc. San Diego, Ca 92128 Timing: Fiscal Year 2005; Project Start 01-AUG-2005; Project End 31-MAY-2008 Summary: (provided by applicant): This R21 program will fundamentally improve the precision and reduce the cost of magnetic susceptometry for noninvasive measurements of body iron stores. Where existing susceptometers use expensive SQUID sensors that require liquid helium, the new susceptometer will use inexpensive magnetic sensors working at room temperature. In preliminary studies, a first-generation susceptometer with room-temperature sensors showed a good correlation (r=0.98) with an existing SQUID system. The next-generation susceptometer will resolve lower iron levels, in fatter patients, than any existing susceptometer. As a model system, this program focuses on liver iron measurements, which are the best indicator of total body iron. Innovative susceptometer coil geometry will minimize errors due to the susceptibility responses of the lung and abdominal wall. Additional errors in current measurement systems will be further reduced, after correcting for lung and abdominal-wall susceptibilities, as well as by improving the water bag that compensates for the diamagnetic background response of the body. These improved susceptometry techniques may ultimately be used to measure iron in the brain, heart and other organs, and to detect tissue-specific magnetic tracers that highlight certain molecules and cell types, signal the presence of cancers, or indicate the function of the lymph nodes, liver and spleen.

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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

38

Hemochromatosis

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. •

Project Title: INTESTINAL ABSORPTION

FERROPORTIN

1

EXPRESSION

AND

IRON

Principal Investigator & Institution: Yeh, Kwo-Yih; Medicine; Louisiana State Univ Hsc Shreveport 1501 Kings Hwy Shreveport, La 71103 Timing: Fiscal Year 2005; Project Start 01-FEB-2005; Project End 30-NOV-2009 Summary: (provided by applicant): Iron deficiency and iron overload are prevalent conditions around the world with various adverse consequences. The need of iron as a critical nutrient and the necessity for iron homeostatic regulation is well appreciated. Iron homeostasis is solely regulated through intestinal iron absorption through incompletely understood mechanisms. Ferroportin 1 (FPT1) is the iron transporter exporting iron across the basal-lateral membrane of enterocytes to the systemic circulation. Mutations of human FPT1 are associated with type 4 hereditary hemochromatosis suggesting that FPT1 plays a specific role in iron homeostatic regulation. The long-term goal of this proposal is to elucidate the mechanism by which the function and the expression of FPT1 are regulated. The specific aims are to determine the effect of iron and hepcidin on the expression and subcellular localization of FPT1 in relation to intestinal iron absorption. Iron and/or Hepcidin induced changes in the expression, migration and function of FPT1 will be determined in rat intestine and in Caco2 cells including Caco2 cells transfected with vectors expressing wild-type or mutant FPT1 and its interacting proteins. Confocal microscopy and velocity sedimentation will be used to analyze differences in the migration of wild-type and mutant FPT1. Changes in intestinal iron absorption and iron transport across Caco2 cells will be monitored in relation to subcellular FPT1 sites. Hepcidin suppression of FPT1 expression and function will be examined to determine the mechanism of FPT1 regulation by hepcidin. Finally, the interactions among FPT1, liver fatty acid biding protein, heme oxygenase and hephaestin will be verified by confocal immunofluorescent microscopy, co-immunoprecipitation, and mammalian two hybrid assay and the function of these protein-protein interactions in intestinal iron absorption will be determined by iron transport across the Caco2 cell layer. The results should

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reveal mechanisms involved in the regulation and function of FPT1 and extend our understanding of intestinal iron absorption and body iron homeostatic regulation. •

Project Title: INVESTIGATION HOMEOSTASIS

OF

HEPCIDIN

IN

MAMMALIAN

IRON

Principal Investigator & Institution: Roy, Cindy N.; Children's Hospital Boston 300 Longwood Ave Boston, Ma 021155737 Timing: Fiscal Year 2005; Project Start 15-FEB-2004; Project End 30-NOV-2008 Summary: (provided by applicant): Hepcidin is an antimicrobial peptide that is synthesized by the liver in response to inflammation and iron overload. Emerging data implicate hepcidin as a major regulator of iron homeostasis in mouse and man. Inappropriate hepcidin expression is associated with diseases such as hereditary hemochromatosis and the anemia of chronic disease. This proposal is designed to test the hypothesis that hepcidin is an essential regulator of iron balance that binds to enterocytes, macrophages, and placental syncytiotrophoblasts where it negatively regulates iron egress. Only in the context of the whole animal can the communication between the immune system and sites of iron storage and utilization be adequately characterized. The Specific Aims of this proposal are: 1) to develop a tetracyclineregulated hepcidin transgenic mouse to investigate the role of hepcidin activity in iron homeostasis and distribution, 2) to determine whether over expression of hepcidin in mice produces a faithful model of the anemia of chronic disease in humans, 3) to identify the putative hepcidin receptor to investigate how hepcidin regulates cellular iron egress. The KO1 award will provide mentored research experience to the candidate under the guidance of Dr. Nancy Andrews, an expert in iron metabolism and mouse genetics. Under Dr. Andrews' mentorship, the candidate will develop the technical skills and the knowledge base necessary for developing transgenic and knock out mice and then testing hypotheses that investigate the physiology of iron metabolism. The candidate will also have the opportunity to develop her reputation as an independent contributor to the field by meeting with prominent scientists, delivering talks, and writing scientific articles about her findings for peer reviewed journals. The KO1 award will facilitate the candidate's transition to an independent research career at the interface of immunology and iron metabolism. Future work will focus on investigating the role of the hepcidin receptor and its homologs in iron metabolism and the anemia of chronic disease •

Project Title: IRON AND PATHOGENESIS IN INFECTIONS BY VIBRIO VULNIFICUS Principal Investigator & Institution: Crosa, Jorge H.; Professor; Molecular Microbiology and Immunology; Oregon Health & Science University 3181 Sw Sam Jackson Pk Rd Portland, or 972393098 Timing: Fiscal Year 2007; Project Start 01-MAR-2007; Project End 29-FEB-2012 Summary: (provided by applicant): Vibrio vulnificus is an opportunistic human pathogen capable of causing fatal primary septicemias or necrotizing wound infections. Septicemia occurs in patients that are immunocompromised or suffering from hemochromatosis or with other underlying liver disorders such as cirrhosis and alcoholic liver disease. The common theme in most of these patients is that iron is present at higher than physiological level. We believe that gene regulation of V. vulnificus CMCP6 depends on many factors according to the changes in environmental conditions i.e. high iron, nutrients concentration, and oxygen availability during the process of infection. In this application we propose to dissect the specific mechanisms

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Hemochromatosis

that govern their expression in V. vulnificus, in vitro and in vivo. The specific aims to achieve these goals are: 1) In vitro regulation of genes whose expression is affected by the iron concentration of the medium and/or components of human serum of compromised patients. In this aim we identify factors in addition to the high iron concentration of the serum play a role in the expression of virulence genes expressed in patient sera. 2) Analysis of HlyU, a global transcription regulator and virulence factor of V. vulnificus expressed at both high and iron limiting conditions. We demonstrate that HlyU in addition to being an important virulence factor is also a global transcriptional regulator that at both iron-rich and iron limiting conditions controls the expression of many virulence-genes, some of them highly expressed only at high iron conditions. In this aim we propose to use a combination of transcriptional and translational fusions as well as gel shift and DNAsel protection experiments with the purified HlyU protein. 3) Analysis of the in vivo expression of V. vulnificus genes in two different mouse models. In this specific aim we propose to use recombination-based in vivo technology (RIVET) to identify V. vulnificus genes that are expressed specifically in vivo during infection of the iron-overloaded mouse model as compared to those induced after infecting the normal mouse. The genes identified using both mouse models as well as those identified in vitro will be characterized by mutagenesis and virulence experiments. Thus, we expect to obtain a comprehensive picture of the physiology of this bacterium during in vivo as compared to in vitro growth. These studies will lead to an enhanced understanding of the pathogenesis of V. vulnificus infections in particular and of bacterial virulence in general. •

Project Title: IRON AS NUTRITIONAL MODIFIER TOXIC NEUROPATHY HIV/AIDS Principal Investigator & Institution: Kallianpur, Asha R.; Medicine; Vanderbilt University Medical Center Nashville, Tn 372036869 Timing: Fiscal Year 2006; Project Start 27-SEP-2006; Project End 31-JUL-2008 Summary: (provided by applicant): Access to highly active anti-retroviral drug therapy has markedly reduced morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). Although the incidence of most of the neurological complications of HIV infection has declined dramatically with the use of these drug regimens, peripheral neuropathy (PN), a devastating complication of nucleoside reverse transcriptase inhibitor (NRTI) therapy, is increasingly common among persons living with HIV/AIDS. The precise mechanisms of nerve damage in PN are unclear, but important factors include: nerve inflammation caused by HIV-infected macrophages, drug-induced mitochondrial abnormalities leading to oxidative stress, and poor nutrition. Iron metabolism is abnormal in HIV infection, but the role of iron, a micronutrient critical for mitochondrial and neuronal function, has not been directly explored in HIV-associated PN. A common variant in the hemochromatosis (HFE) gene, C282Y, causes increased dietary iron absorption and defects in cellular iron transport and immunity. Expression of the HFE-encoded iron-transport protein on macrophages has recently been shown to decrease as result of HIV-1 infection. We previously used clinical data and stored DNA from a large, prospective cohort study conducted by the AIDS Clinical Trials Group (ACTG) to make the seminal observation that HFE C282Y protects against the development of PN during NRTI therapy in HIV/AIDS. Since this iron-loading variant is protective against PN, and iron deficiency is endemic in many populations devastated by HIV/AIDS, it is critical to define the mechanism underlying this protective effect in order to benefit patients globally. The goals of our study are therefore to use cryopreserved serum samples in the same HIV cohort to determine 1) if reduced PN in HFE C282Y carriers is due to increased body iron stores, 2) if time to

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onset of PN during NRTI therapy is related to iron levels before or soon after starting treatment, 3) if a statistical model incorporating iron stores, early changes in iron levels during NRTI therapy; HFE genotype, and certain high-risk mitochondrial DNA variants can be created to predict the development of PN. Conventional regression as well as newer statistical modeling tools will be used. These studies will generate critical preliminary data for an R01 grant application to fund in-depth mechanistic studies that we hope will ultimately enable clinicians to reduce the incidence of this debilitating complication of HIV/AIDS treatment. •

Project Title: IRON CHELATORS PREDICATED ON DESFERRITHIOCIN Principal Investigator & Institution: Bergeron, Raymond J.; Professor; Medicinal Chemistry; University of Florida 219 Grinter Hall Gainesville, Fl 32611 Timing: Fiscal Year 2005; Project Start 01-FEB-1995; Project End 31-JAN-2010 Summary: (provided by applicant): The proposed research project will focus on the design, synthesis, evaluation, and development of targeted desferrithiocin analogues for the treatment of iron overload. Physicians have a pressing clinical need for new, more effective iron-chelating agents which selectively remove iron from the liver, heart, and pancreas, the organs at greatest risk of iron-induced injury in patients with thalassemia major, sickle cell disease, hereditary hemochromatosis and other forms of iron overload. Desferrithiocin (DFT), a natural product iron chelator (siderophore) isolated from Streptomyces antibioticus, is one of the most orally effective iron chelating agents yet identified but renal toxicity precludes its clinical use. Our systematic structure-activity studies have allowed the design and synthesis of analogues and derivatives, which retain the exceptional iron-chelating activity of DFT without adverse effects on the kidneys or other organs. Our lead compound, the orally active DFT analogue (S)-2-(2,4dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT (28)], which is nearly three times as effective as sc DFO in the C. apella primate model, has been licensed to a commercial sponsor and currently is in Phase I/II clinical trials. We now hypothesize that the DFT platform can be structurally programmed to target delivery to organs at greatest risk of iron induced injury and to further enhance iron clearance. To test these hypotheses, our research plan has three specific aims: Aim 1: to design and synthesize partition-variant desferrithiocin analogues with enhanced access to organs vulnerable to iron-induced injury (eg, liver, heart, pancreas) and/or increased iron clearing efficiency; Aim 2: to design and synthesize polyamine-vectored desferrithiocin analogues that use the polyamine transport apparatus to gain entry into cells; and Aim 3: to assess these new desferrithiocin analogues in physiochemical, cellular and animal models to identify safe and effective compounds for GLP preclinical evaluation in preparation for human studies. The development of safe, effective, and well-tolerated iron-chelating agents based on DFT would be a major advance in the treatment of iron overload that would greatly enhance both the quality and length of life of affected patients in the United States and worldwide.

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Project Title: IRON OVERLOAD AND HEREDITARY HEMOCHROMATOSISN01HC5192-268005192 Principal Investigator & Institution:; Wake Forest University 1834 Wake Forest Road Winston-Salem, Nc 27106 Timing: Fiscal Year 2005 Summary: This abstract is not available.

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Project Title: PATIENTS

IRON

SIGNALING/MONOCYTES/ALCOHOLIC

HEPATITIS

Principal Investigator & Institution: Xiong, Shigang; Medicine; University of Southern California Department of Contracts and Grants Los Angeles, Ca 90033 Timing: Fiscal Year 2005; Project Start 10-SEP-2004; Project End 31-AUG-2007 Summary: (provided by applicant): Heightened expression of TNFalpha by hepatic macrophages (HM) and peripheral blood monocytes (PBM) is a hallmark pathogenetic event in alcoholic hepatitis (AH). Although several hypotheses have been proposed, the precise molecular mechanism underlying the dysregulated TNFalpha expression in AH is still elusive. We have recently disclosed a novel signaling event involving a transient rise in the intracellular level of low molecular weight iron complex(es) ([LMW-Fe]i) for LPS-induced activation of IkB kinase and NF-kB, and TNFalpha expression in HM. We further demonstrated that [LMW-Fe]I signaling was accentuated, in parallel to increased non-heme iron content and heightened TNFalpha expression, in HM from rats with experimental alcoholic liver disease. The identical phenotype was also disclosed by us in the murine macrophage cell line (RAW.264.7) that is deficient in Nrampl, the protein that controls iron flux from endosomes, due to its G169D mutation. Finally, the treatment with a lipophilic iron chelator corrected both accentuated [LMW-Fe]i signaling and heightened TNFalpha expression in both examples. The present exploratory study will test the demonstrated novel link between [LMW-Fe]i signaling and TNFalpha expression, in PBM of AH patients to determine whether the [LMW-Fe]i signaling is primed as the molecular basis for the heightened TNFalpha response. The study will also examine in PBM of AH patients, the expression of Nrampl and other putative genes known to be involved in iron metabolism and homeostasis in order to search for the mechanisms of iron accumulation and consequent enhancement in [LMWFe]I signaling. To address these two specific aims, we will isolate PBM from patients with stable acute AH and gender and age-matched healthy subjects as the proven surrogate marker for HM. Iron content, [LMW-Fe]I signaling, and TNFalpha expression will be examined ex vivo. Real-time PCR and Western blot analysis will be performed on PBM to determine the expression of Nrampl, DMT1 (divalent metal transporter), ferroportin, TfR1 (transferrin receptor 1), HFE (a hemochromatosis gene product), ferritin H and L chains to correlate them with observed changes in iron content and [LMW-Fe]i signaling. Additional longitudinal comparison will be made between the acute AH phase and the remission phase in the same patients to determine whether they have inherent abnormalities in [LMW-Fe]i signaling or expression of iron regulatory molecules. In summary, the current proposal is the first exploratory study to test dysregulation of the novel [LMW-Fe]I signaling in AH patients as the molecular basis for heightened TNFalpha expression. •

Project Title: LEAD-GENE INTERACTIONS AND CONGNITION Principal Investigator & Institution: Hu, Howard; Professor; Brigham and Women's Hospital Research Administration Boston, Ma 02115 Timing: Fiscal Year 2005; Project Start 01-FEB-1991; Project End 31-JUL-2008 Summary: (provided by applicant) Cognitive decline is a common, but not inevitable, accompaniment to aging. While much research is currently being directed at Alzheimer' s Disease -- one of the most severe expressions of cognitive decline -- relatively little work is currently aimed at identifying risk factors and mechanisms associated with early (i.e., subclinical) cognitive decline, even though this may be the stage most amenable to prevention. An important issue that needs to be clarified in relation to the etiology of cognitive decline is the role of environmental lead exposure and the

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interaction of lead with specific candidate genes. In this application we discuss how four candidate genes -- APOE, the HFE (hemochromatosis) gene, transferrin, and Tau protein -- may interact with lead burden to increase the risk for oxidative cell damage leading to neuronal cell loss and cognitive deficits. We review the last 11 years of our research on low-level lead toxicity and describe compelling preliminary data. We then propose a new study that calls for new data collection in our established Bostonarea cohorts [Normative Aging Study (NAS), Nurses Health Study (NHS), and Community Lead Study (CLS)]. Our specific aims are to test hypotheses related to the impact on cognition of lead burden and its potential interaction with our four polymorphisms of interest. We will look at cognition cross-sectionally and longitudinally, using a validated battery of telephone cognitive function assessment tools as well as a battery of in-person cognitive tests that we have been administering in person since 1993. Results of this research promise to shed further light on lead's potential impact on society and may also give rise to tools for identifying susceptible individuals as well as early brain effects. •

Project Title: MECHANISMS OF ACTION OF HEMOJUVELIN Principal Investigator & Institution: Lin, Herbert Y.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2005; Project Start 01-AUG-2005; Project End 31-JUL-2010 Summary: (provided by applicant): Juvenile hemochromatosis is a severe variant of hemochromatosis that is caused by mutations in two genes which give indistinguishable phenotypes. One gene encodes hepcidin (HAMP, 19q13.1), a peptide synthesized by the liver in response to inflammation and iron overload. The second gene has recently been identified as hemojuvelin (HJV, 1q21). Although the function of HJV is unknown, hepcidin levels are depressed in persons with HJV mutations, indicating that HJV may be a hepcidin modulator. HJV is also a member of the RGM family of proteins originally described by our group and others as neural adhesion molecules. We present preliminary studies in vitro in liver cells that 1) HJV can induce BMP but not TGF-beta signals, 2) HJV signaling can be blocked by Noggin, a wellknown BMP inhibitor, 3) HJV can bind directly to radiolabeled BMP-2 ligand, 4) HJV signals via the BMP type I receptors, ALK3 and ALK6, 5) HJV signals via the R-Smad, Smad1, 6) an HJV mutant known to cause juvenile hemochromatosis has decreased BMP signaling ability, and 7) BMP can increase, while Noggin can decrease, hepcidin expression in liver cells. We believe that HJV is a novel BMP co-receptor whose BMP signaling ability is important in regulating iron metabolism. Loss of BMP signaling by mutations in HJV could lead to decreased BMP signaling in liver cells, which would cause decreased hepcidin expression, and would thus explain why persons with HJV mutations also have depressed hepcidin levels. We propose to: 1) Determine the molecular mechanism of HJV action in the BMP signaling pathway in liver cells in vitro, including characterizing the physical interaction of HJV with the known BMP receptors and determining the binding affinities of HJV for different BMP ligands; 2) Study the role of key structural features of HJV on its function, including HJV's RGD motif, GPI anchor and its proteolytic cleavage site; 3) Determine the role of HJV and BMP signaling in iron metabolism in vitro and in vivo in HJV knock-out mice. Knowledge gained regarding the mechanism of action of HJV would be important in furthering our understanding of BMP signaling and of iron metabolism, and could lead to novel treatments of disorders of iron metabolism such as hemochromatosis and anemias of chronic disease.

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Project Title: MODIFIERS OF IRON LOADING IN MICE Principal Investigator & Institution: Andrews, Nancy Catherine.; Associate Professor; Children's Hospital Boston 300 Longwood Ave Boston, Ma 021155737 Timing: Fiscal Year 2005; Project Start 01-FEB-2004; Project End 31-JAN-2009 Summary: (provided by applicant): Hemochromatosis is characterized by a chronic increase in intestinal iron absorption, leading to excessive iron deposition in the liver, heart, pancreas and other organs. Patients who are homozygous for mutations in the HFE gene or heterozygous for mutations in the FPN gene are at risk for these complications, but there is variability in disease severity. This has been particularly well studied for HFE hemochromatosis; some individuals have severe complications in the third decade of life, whereas others reach old age with little or no evidence of iron toxicity. The severity of the disease correlates with the extent of tissue iron loading. The goal of this proposal is to identify genes that modify iron-loading phenotypes. This will be done using mice, because mice are similar to humans in their iron metabolism, and mouse models of both HFE hemochromatosis and FPN hemochromatosis are available in the laboratory. Preliminary studies show that two inbred mouse strains, C57BL/10 and SWR, differ markedly in their tissue iron loading phenotypes. C57BL/10 mice accumulate little iron in the liver and spleen, while SWR mice accumulate large iron burdens in both tissues. Quantitative liver and spleen iron loading data were used in a quantitative trait locus (QTL) analysis to identify chromosomal regions that have a high probability of accounting for differences in iron loading between the two strains. In the analysis of 96 N2 backcross animals from a cross between these strains, at least 4 QTLs (LOD scores 2.9 - 4.0) were identified for liver iron loading, and one QTL (LOD 8.3) was identified for spleen iron loading. The aims described in this proposal are (1) to identify the genes responsible for these QTLs, and (2) to determine whether these and other potential modifiers of iron loading also modify the phenotypes of mice with Hfe and Fpn hemochromatosis.

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Project Title: MOLECULAR MECHANISMS OF INTESTINAL IRON TRANSPORT Principal Investigator & Institution: Glass, Jonathan; Professor; Medicine; Louisiana State Univ Hsc Shreveport 1501 Kings Hwy Shreveport, La 71103 Timing: Fiscal Year 2005; Project Start 01-JAN-1989; Project End 30-APR-2007 Summary: Iron deficiency is still endemic in many parts of the developing world with significant physical and economic consequences. Iron overload seen in association with common hemoglobinpathies such as sickle cell disease and the thalassemias contributes to the pathophysiology of these disease. To properly regulate the absorption of iron in these states requires a detailed knowledge of the mechanisms of intestinal iron transport. Recently, proteins have been described that are involved in the regulation of iron uptake. These proteins include HFE, which when harboring a C282Y mutation causes hemochromatosis, a disease characterized by increased iron absorption. Two iron transporters have been described: NRAMP2, an iron transporter expressed on brush border membrane, and ferroportinl, a basal membrane iron transporter. Hephaestin, a multicopper ferrioxidase and a homologue of cerruloplasm, oxidizes newly absorbed iron, an event required for iron release from intestinal epithelium. Our data has demonstrated that exposure of the small intestine epithelium to iron stimulates the internalization of NRAMP2 from the brush border membrane. We have also demonstrated that NRAMP2 when internalized meets apo-Tf internalized from the basolateral surface in a perinuclear compartment. Based on our data and the work of others, we hypothesize that iron is transported through the intestinal cell via transcytosis. The specific aims of the current proposal are directed to substantiating this

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hypothesis. In the first speck aim, we will examine the kinetics of NRAMP2 internalization after exposure to iron. In the second specific aim, we will determine if newly absorbed iron and NRAMP2 are in the same vesicles or if NRAMP2 is internalized separtely as a regulatory mechanism. In the third specific aim, we use confocal microscopy to determine if NRAMP2 and apo-Tf, hephaestin, or ferroportin 1 meet and share the same compartment. The fourth specific aim will also use the yeast two-hybrid system to find proteins that interact with NRAMP2. In addition, we will determine the specificity of NRAMP2 internalization and interaction with other proteins for Fe versus other divalent cations. •

Project Title: MRI METHOD FOR IN VIVO IRON QUANTIFICATION Principal Investigator & Institution: Jensen, Jens H.; Professor; Radiology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2005; Project Start 01-AUG-2005; Project End 31-JUL-2008 Summary: (provided by applicant): The broad goal of the research is to develop a new magnetic resonance imaging (MRI) technique for quantifying body iron stores. Elevated body iron levels can develop in a variety of disorders, including hereditary hemochromatosis, thalassemia major, myelodysplasia, and sickle cell anemia. Excess body iron or "iron overload" can be toxic and may lead to a variety of iron-induced complications, such as diabetes, cirrhosis, and heart disease. In diagnosing and managing iron overload, it is important to quantify body iron excess. The two generally available clinical methods for doing this, liver biopsy and blood serum ferritin measurement, suffer from significant shortcomings. Liver biopsy is invasive and may be inaccurate for liver with cirrhosis, while the serum ferritin level correlates poorly with total body iron. The research would develop a method for iron quantification based on the effect of iron on MRI signal decay. The research would optimize and validate the technique for liver tissue, since liver iron concentration is considered the best single indicator of iron overload. A major advantage of MRI quantification of iron overload is that this method is completely non-invasive, which allows the frequent monitoring of iron levels during therapy. The proposed approach differs markedly from prior attempts to use MRI for iron quantification, in that two independent MRI quantities, rather than one, are measured. This is critical for obtaining a high accuracy, as iron in the liver comes in two forms, ferritin iron and hemosiderin iron, which affect MRI signal decay in significantly different ways. Our research will be divided into two stages. First, we will develop and test the necessary MRI pulse sequences using a tissue model (phantom) consisting of a gel with suspended iron particles. Second the method will be applied to 150 iron overload patients. As validation, the MRI predictions will be correlated to results of needle biopsy of the liver, the current clinical gold standard. We will also compare the MRI data to iron measurements obtained with SQUID biosusceptometry.

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Project Title: MRI QUANTITATION OF TISSUE IRON IN HEMATOLOGIC DISORDERS Principal Investigator & Institution: Song, Hee Kwon; Radiology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2005; Project Start 15-SEP-2003; Project End 30-JUN-2007 Summary: (provided by applicant): Chronic iron overload leads to increased iron deposition in tissues. In chronically-transfused thalassemia patients, exogenous iron is stored in the spleen, liver, endocrine organs and heart. By contrast, in hereditary hemochromatosis iron overload occurs as a result of excessive absorption of iron from

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the diet. In both diseases, control of iron levels below the toxic threshold is essential. Further, since serum ferritin levels do not parallel tissue iron levels, periodic liver biopsies have to be performed. The invasive nature of this procedure calls for alternative, less traumatic approaches for multi-organ iron screening. Here we propose to implement, validate and apply to patients with thalassemia, a MRI-based quantitative tissue iron mapping technique focusing on the liver and heart, to evaluate the hypothesis that tissue iron levels can be measured accurately and reproducibly. The method is based on the GESFIDE imaging technique developed in the investigators' laboratory. This method allows efficient measurement of T2'and T2, the RF-reversible and RF-irreversible transverse relaxation times, both known to be reduced at elevated tissue iron levels. The following specific aims will be pursued: 1. We shall fully develop and implement improved GESFIDE MRI iron mapping technique at 1.5 and 3T and examine its performance in human volunteers. 2. We shall evaluate the method's accuracy on specimens of a murine model of thalassemia in comparison to chemical assay. 3. We shall, in a pilot study of 30 patients with thalassemia, measure iron levels in the heart and liver at three time points during a three-year observation period and compare the results with liver biopsy data and to results in age- and gender-matched controls. 4. We shall, in the patients of specific aim #3, evaluate cardiac function by MR to test the hypothesis that the severity of impaired function is associated with the degree of cardiac iron overload. •

Project Title: NEW BIOMARKERS OF NEUROTOXICITY Principal Investigator & Institution: Weisskopf, Marc G.; Environmental Health; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2005; Project Start 09-APR-2004; Project End 28-FEB-2009 Summary: (provided by applicant) This proposal will allow the Principal Investigator (PI) to gain knowledge and skills in Environmental Epidemiology under the direct supervision of a highly qualified sponsor, which will build on and extend his previous expertise in neurobiology, further enhancing his potential to develop into an independent investigator. The PI is trained in cellular and molecular aspects of neurobiology, and has had some exposure to epidemiology, including some classes at the Harvard School of Public Health taken on a part-time basis. During the first 3 years of this proposal, course work is proposed to attain needed skills in statistical methods for environmental epidemiology, molecular and genetic epidemiology, and neuroepidemiology. This course work, combined with the research to be conducted during this proposal will enable the principal investigator to obtain a doctorate in environmental epidemiology from the Harvard School of Public Health, thus enabling him to be a very competitive candidate for a tenure-track faculty position, which is the long-term goal of the candidate. The environment at the Harvard School of Public Health is an excellent one to accomplish the candidate's goals. The mentor is a recognized leader in the field of environmental epidemiology who has mentored other K-awardees. The school has a vibrant community of epidemiologists of all types, including genetic and neuro-epidemiologists with whom the candidate can interact. Ongoing seminar series in, among other topics, statistical methods and chronic (including neurologic) disease, provide fertile ground for learning, intellectual interactions, and development of ideas. The overall scientific goal of this study is to explore the use of novel biomarkers of neurotoxicity. In particular, the candidate proposes to build on his past neurobiology research to examine the effects of lead exposure on psychophysiologic measures of learning in the context of fear and anxiety, as well as the effects of lead on fine motor control as manifested through a new device for sophisticated analyses of handwriting and on autonomic nervous system control of

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cardiac function. This proposal focuses on lead not only because of the important public health consequences of lead exposure, but also because the extensive research experience with aspects of low-level lead exposure provides a solid foundation from which to explore these relatively new biomarkers of neurotoxicity. •

Project Title: PEDIATRIC CLINICAL RESEARCH SCHOLAR PROGRAM WASHINGTON Principal Investigator & Institution: Luban, Naomi L.; Director, Transfusion Medicine; Children's Research Institute 111 Michigan Avenue, Nw Washington, Dc 20010 Timing: Fiscal Year 2005; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (Provided by the applicant): This application proposes to develop an NCRR Pediatric Clinical Research Scholars (PCRS) Program in Washington, D.C. as a consortium effort between Children's National Medical Center/George Washington University School of Medicine and Health Sciences (CNMC/GW), Georgetown University Medical Center (GUMC), and Howard University Hospital (HUH). CNMC will serve as the lead institution and is the applicant for this grant. The goal of the PCRS program is to increase the number of well-trained and innovative pediatric clinical investigators who are able to design and conduct all phases of patient-oriented research and who will become leaders of multidisciplinary clinical research efforts. The Scholars will be guaranteed 75-90% protected time throughout the program (2-5 years) and will be provided training in patient-oriented research, with the goal of achieving independent NIH funding by the end of their participation in the program. With the infrastructure provided by the three NCRR-funded GCRCs at CNMC, GUMC and HUH, it is believed that a successful career as an independent pediatric clinical investigator is an achievable goal for each Scholar. The applicants will enroll a total of 12 Scholars during the first five years award period. In addition, they will enroll two additional "Scholars" using institutional CNMC funds as a matching grant. Both internal and external recruitment of PCRS candidates will be pursued, with an emphasis on women, underrepresented minorities, and individuals with disabilities. The individualized and structured PCRS training program will include: 1) Fundamental and comprehensive mentored training in clinical research methodology; 2) Mandatory courses relevant to clinical research that can lead to a post-graduate degree; 3) Training in the responsible conduct of research; and 4) An intensive supervised clinical research project involving one or more of the three GCRCs. Individual programs of study will be performed under the guidance of one of the 21 Lead Mentors with the help of other mentors and support faculty if required, and will be integrated across the three institutions. Mentors have been selected in a wide range of disciplines in order to be able to train Scholars with diverse research interests. The applicants also present eight potential PCRS candidates from the consortium, five of whom are women, five are from minority groups and one has a disability. Available clinical research training areas include: Behavioral medicine and clinical neuroscience with research interests in attention deficit hyperactivity disorder (ADHD), language disorders, feeding disorders, and depression; Genetic medicine with research in sickle cell disease, hemochromatosis, inborn errors of metabolism, hypertension and muscular dystrophies; Oncology, with studies in brain tumors and leukemia; Hematology, immunology and infectious diseases with research in HIV, transfusion and Hepatitis C, iron overload and vaccine development; Experimental therapeutics with drug trials in cancer, infectious diseases, and neurological disorders; and Health services and Public Health research with research in infant mortality, violence prevention, HIV prevention in adolescents, and prediction of outcome following injury or severe illness.

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Project Title: REGULATION OF HEME UPTAKE IN INTESTINAL EPITHELIAL CELLS Principal Investigator & Institution: Uc, Aliye; Pediatrics; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2006; Project Start 01-MAR-2006; Project End 28-FEB-2008 Summary: (provided by applicant): Project Summary: In this proposal, Dr. Aliye Uc is seeking a RO3 award to expand on her studies of intestinal heme uptake and transport mechanisms initiated under her KO8 grant, DK-63135. With the support of her KO8 funding, Dr. Uc started to examine heme-intestinal epithelial cell interactions through course work and laboratory investigations. Heme provides the majority of body's iron, but little is known about its intestinal absorption. Dr. Uc's observations so far suggest that enterocytes actively control heme uptake and transport, a phenomeon that can have an important role in the regulation of body iron stores. In the current R03 application, Dr. Uc proposes to begin investigating vesicular transport mechanisms involved in heme absorption and metabolism. Based on her preliminary data, Dr. Uc hypothesizes that heme is acquired by intestinal epithelial cells via an active and tightly regulated process that involves vesicular transport. Basolateral membrane heme uptake occurs via clathrin-dependent endocytosis; apical (lumen) heme is acquired via a membrane protein-dependent, cholesterol-sensitive, caveolar/lipid raft endocytosis. The specific aims are to: 1) Determine the vesicular transport mechanisms involved in intestinal heme uptake by using electron microscopy and cell fractionation techniques and colocalization with proteins that are trasported via clathrin or caveolae/lipid raft dependent pathways; 2) Determine the regulatory mechanisms involved in intestinal heme uptake by studying the role of a membrane heme binding protein and heme oxygenase-1. The current RO3 application, if approved will give Dr. Uc the opportunity to expand on her KO8-related goals and objectives as she approaches a full transition to an independent investigator status. The supportive environment at the University of Iowa will provide a perfect medium for Dr. Uc to accomplish her goal to become a fully independent clinician scientist. Relevance: Heme, found in red meat provides the majority of body's iron, but it can also cause injury by producing toxic free radicals. Because of its dual effects, intestinal heme absorption should be carefully regulated. However, it is not clear how intestinal epithelial cells take up heme from the diet or if they regulate its absorption. Defining intestinal heme uptake pathways will have a great impact in understanding disorders associated with iron overload (hereditary hemochromatosis, iron overload secondary to blood transfusions) and nutritional iron deficiency

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Project Title: REGULATION OF IRON METABOLISM GENES IN EUKARYOTES Principal Investigator & Institution: Walden, William E.; Associate Professor; Microbiology and Immunology; University of Illinois at Chicago 310 Aob, M/C 672 Chicago, Il 60612 Timing: Fiscal Year 2005; Project Start 01-JAN-1995; Project End 31-JAN-2007 Summary: Iron is an essential element for nearly all forms of life. One of the challenges for organisms is the acquisition of iron due to its propensity to oxidize in aerobic environments and the extreme insolubility of ferric iron. As a result, organisms have evolved elaborate mechanisms for acquiring and storing iron. These mechanisms must be tightly regulated, however, due to the toxicity of free iron through its ability to catalyze the generation of free radicals through the Fenton reaction. In fact, aberrant iron regulation is associated with a variety of diseases and disorders in humans, including hemochromatosis, sideroblastic anemias, and Friedrich's ataxia, to name a few. Animals

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regulate iron uptake and storage primarily through the action of iron regulatory proteins (IRP), a family of sequence- specific, RNA binding proteins. IRPs regulate the synthesis of ferritin and transferrin receptor, proteins that serve in iron storage and iron transport, respectively. Through this regulation, animal cells are able to maintain iron homeostasis. IRPs also regulate the synthesis of proteins that are involved in heme biosynthesis and energy production. Thus the role of IRPs in cellular physiology is broader than simply iron regulation. There are two IRP family members, called IRP1 and IRP2. IRP1 is a bifunctional protein having the aforementioned activity as a RNA binding, gene regulator, or as the cytosolic isoform of aconitase. These activities are mutually exclusive and require the assembly and disassembly of a [4Fe-4S] cluster in the protein. Therefore, the activity of IRP1 and the regulation of iron in animals is dependent on the reversible assembly of an Fe- S cluster in this protein. In the proposed studies, we will define the mechanism and factors involved in the assembly/disassembly of the Fe-S cluster in IRP1. We will use a combination of molecular genetic, genetic and biochemical techniques in the yeast, Saccharomyces cerevisiae, to accomplish our goals. Our specific aims are to: 1) Define the mechanism of Fe-S cluster assembly in IRP1; 2) Determine the mechanism by which iron disrupts IRE/IRP1 complexes; 3) Investigate the process of Fe-S cluster disassembly in IRP1. The completion of these studies will help us to understand how organisms utilize Fe-S clusters as sensors of cellular iron status and oxidant levels as well as giving us insight into the fundamental question of Fe-S cluster assembly. •

Project Title: SEALING LIVER BIOPSY TRACTS WITH HYDROGELS Principal Investigator & Institution: Hronowski, Lucjan J J.; Director of Chemistry; Biopsy Sciences, Llc Suite 103 Tucson, Az 85716 Timing: Fiscal Year 2006; Project Start 01-JUL-2006; Project End 30-JUN-2007 Summary: (provided by applicant): Many experts consider the liver biopsy to be the most specific diagnostic tool used to assess the nature and severity of liver disease. There are many important reasons for performing liver biopsies, such as accurate diagnosing or ruling out any coexisting liver disease, staging and grading the severity of HCV disease, treatment decisions, patient and provider reassurance, and as a benchmark to gauge or measure future disease progression. Furthermore, diagnosis of hemochromatosis, occult hepatitis B and non-alcoholic steatosis can only be made by a liver biopsy and can have an important impact on the treatment and prognosis of hepatitis C. The most common type of liver biopsy is a percutaneous (through the skin) needle biopsy. Ultrasonography or Computed Tomography (CT) scans may be used to aid in the procedure to identify lesions in the liver and pinpoint the exact point in which the needle will be inserted. Approximately 30% of people biopsied experience mild and moderate pain during and after the procedure. Complications for the procedure are another area of concern, but are generally uncommon. It is estimated that 3 biopsies per 1,000 have complications and 3 per 10,000 result in death. Also, there is an immeasurable but substantial population that need a liver biopsy performed, but cannot because of high risk of hemorrhaging. The risk of post-biopsy hemorrhagic complications is particularly great in patients with coagulopathy or therapeutic anticoagulation, such as patients undergoing dialysis, those with hepatic failures or those with transplants. The severe bleeding complications are related to the puncture of the liver capsule during biopsy, thereby allowing blood to escape into the peritoneal space, which can result in life threatening bleeding and even death. The deployment of a dehydrated hydrogel plug (Bio-Seal) into the biopsy tract across the liver capsule which expands in vivo rapidly to mechanically seal the biopsy tract may benefit all patients that need and have been denied a liver biopsy. This Phase I proposal will explore the

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feasibility of using Bio-Seal biopsy tract sealant as an effective plug following a liver biopsy in the porcine model (for both acute and chronic studies). The long-term objectives are to obtain FDA clearance and commercially sell the Bio-Seal system to seal biopsy tracts after liver and kidney biopsies. Bio-Seal has already been granted FDA clearance for the lung. •

Project Title: STRUCTURAL RECOGNITION

PARAMETERS

INVOLVED

IN

METAL

Principal Investigator & Institution: Maroney, Michael J.; Professor; Chemistry; University of Massachusetts Amherst 70 Butterfield Terrace Amherst, Ma 010039242 Timing: Fiscal Year 2005; Project Start 15-SEP-2004; Project End 31-JUL-2008 Summary: (provided by applicant): The mechanisms by which organisms control transition metal ions and the roles of these metals in cellular regulation have emerged as key areas of investigation in metallobiochemistry. Specific metal binding and responses are required by biological systems in order to avoid cross talk between metals in the expression of proteins, in the uptake of specific metals, and for the incorporation of the correct metal into enzyme active sites. The details of how the metalloproteins recognize, bind and respond to the presence of the requisite metal ion is not well established. This is particularly true for transition metal ions, many of which have similar charges and ionic radii. Thus, it seems likely that coordination geometry and ligand preferences (at least among the ligands provided by amino acids) play important roles in distinguishing transition metals. This proposal seeks to use biophysical methods aimed at delineating structural parameters that are involved in determining metal specificity. The overall objective of this research project is to understand the structural parameters that underlie metal specific binding, and the related protein structural responses to specific metal binding, in metalloproteins involved in metal trafficking. Toward this goal, we plan to examine the structural parameters involved in a metalloregulator (NikR), a metallotransporter (NikABCDE) and a metallochaperone (HypB)--proteins all involved in nickel trafficking in E. coli. The viability of bacteria, including human pathogens, is linked to the acquisition of required metals, and several human diseases have been shown to result from a breakdown in metal trafficking (e.g., Wilson's and Menkes' diseases for copper, genetic hemochromatosis and other hereditary iron overload disorders for iron). A detailed understanding of metal trafficking is thus important to understanding metal metabolism and its effect on human health, and requires an understanding of mechanisms by which metalloregulators, metal transporters and chaperones specific to each required metal operate. In addition, a detailed understanding of the structural parameters involved in metal-trafficking may lead to the design of new antibiotics that interfere with bacterial metal metabolism, which is frequently essential for pathogenesis, and the development of plants that are resistant to metals and useful in bioremediation. •

Project Title: STUDY HOMEOSTASIS

OF

FERROPORTIN

1

IN

MAMMALIAN

IRON

Principal Investigator & Institution: Donovan, Adriana; Children's Hospital Boston 300 Longwood Ave Boston, Ma 021155737 Timing: Fiscal Year 2005; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): The long-term research objective of this KO1 application is to define the role of the iron exporter Ferroportin 1 (Fpn1) in mammalian iron homeostasis. Fpn1 functions as a transmembrane iron exporter, and is important for normal development in zebrafish, where it is needed for transfer of iron from the yolk

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sac to developing erythrocytes. In contrast, the role of Fpn1 in mammals has not been established. We have previously demonstrated that Fpn1 is expressed in tissues that are key players in mammalian iron absorption and storage, including placenta, intestine, liver and reticuloendothelial macrophages. In addition, we have identified a missense mutation in Fpn1 that is associated with the iron overload disorder autosomaldominant hemochromatosis. Based upon our studies of Fpn1 in humans and mice, and the requirement for Fpn1 in zebrafish, we hypothesize that Fpn1 is critically involved in the export of iron from mammalian cells functioning in iron transport and storage. We plan to test our hypothesis by using gene-targeting strategies. The specific aims of this proposal are: 1) to employ a Fpn1 knock-out mouse model to characterize the requirement for Fpn1 in mice and the interaction of Fpn1 with other iron metabolism genes, 2) to define the role of Fpn1 in individual tissues using a conditional knockout strategy, and 3) to create and characterize a mouse model of the human iron overload disorder autosomal dominant hemochromatosis. In the long term, knowledge generated from the study of these mouse models could help us to better understand and treat diseases of iron homeostasis such as hemochromatosis, iron deficiency anemia and the anemia of chronic disease. The candidate's overall career goal is to study mammalian iron homeostasis as an independent academic scientist. This award will provide the candidate with a period of mentored research experience during which she will develop an independent research program. Dr. Nancy Andrews will mentor the candidate during the period of the award. As an expert in the field of iron metabolism, Dr. Andrews is well equipped to assist the candidate with the development of both the knowledge base and the resources required for her transition to full independence. During the period of the award the candidate will also expand her technical skills in the areas of mouse genetics, iron metabolism and developmental biology. •

Project Title: THE BIOLOGY OF GASTRIN-FERRIC ION COMPLEXES Principal Investigator & Institution: Baldwin, Graham S.; University of Melbourne Level 5 Melbourne, 3010 Timing: Fiscal Year 2006; Project Start 01-AUG-2002; Project End 31-MAR-2010 Summary: (provided by applicant): The long-term objective of this project is to understand the biological significance of the complex between ferric ions and nonamidated gastrins (NAGs). This laboratory has shown that NAGs selectively bind 2 ferric ions that ferric ion binding is essential for biological activity in vitro, and that gastrin interacts with transferrin. The specific aims of the project are: (1) to determine whether or not ferric ions are essential for the stimulation of colorectal carcinoma (CRC) development by NAGs in vivo, (2) to develop NAG antagonists, (3) to establish the role of NAGs in iron homeostasis, and (4) to define the role of the NAG-transferrin complex in cellular ion uptake and determine its structure. The health significance of the project lies in the facts that NAGs act as growth factors for the normal gastric and colonic mucosa, accelerate the development of both gastric and colorectal cancer, and may be involved in disorders of iron homeostasis. The research design mirrors the specific aims, and utilizes the unique combination of skills of the principal investigators. Firstly, agents known to block the binding of ferric ions to NAGs will be tested as NAG inhibitors in four animal models of CRC development. Secondly, exchange inert metal ion-NAG complexes and structurally modified gastrin fragments will be tested as NAG inhibitors in CRC cell lines and in animal CRC models. Thirdly, patterns of progastrin expression and processing will be measured by radioimmunoassy in mice with altered dietary iron uptake, and in patients with hemochromatosis. Iron status will also be measured in hypergastrinemic and gastrin-deficient transgenic mice with altered dietary iron uptake, and in patients with hypergastrinemia. Fourthly, the role of the

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gastrin/transferrin complex in cellular iron trafficking will be investigated, and covalent cross-linking and X-ray crystallography with a panel of NAG and transferrin mutants will be used to define the structural requirements for formation of the complex. These studies are expected to demonstrate an unexpected role for ferric ions in gastrin bioactivity in vivo, and for gastrins in ferric ion homeostasis. Recognition that metal ions are essential for the biological activity of NAGs may permit the development of novel therapies for colon cancer. •

Project Title: THE LYSOSOMAL-MITOCHONDRIAL AXIS IN NONALCOHOLIC FATTY LIVER DISEASE Principal Investigator & Institution: Feldstein, Ariel; Medicine; Cleveland Clinic Lerner Col/Med-Cwru 9500 Euclid Avenue Cleveland, Oh 44195 Timing: Fiscal Year 2007; Project Start 01-MAR-2007; Project End 31-JAN-2012 Summary: (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide, yet its pathogenesis remains poorly understood. Impaired mitochondrial function is largely thought to be a core abnormality responsible for disease progression in this condition. The central question extant is what events link excessive lipid accumulation in liver cells to mitochondrial dysfunction. Thus, the overall objective of this proposal is to define the cellular and molecular mechanisms contributing to mitochondrial dysfunction and disease progression in NAFLD. Based on extensive preliminary data, we propose the novel CENTRAL HYPOTHESIS that excessive free fatty acids accumulation in the liver results in impaired mitochondrial function and NAFLD progression by triggering lysosomal permeabilization via regulation of the Bcl-2 family members We will now employ current and complementary, molecular, biochemical and cell biological approaches to further explore the lysosomal - mitochondrial axis in NAFLD. Our proposal has three SPECIFIC AIMS. FIRST, we will identify and manipulate novel intracellular targets that initiate lysosomal permeabilization in in-vitro and in-vivo models of NAFLD as well as human specimens of NAFLD and control individuals. SECOND, we will molecularly define the lysosomal - mitochondrial axis in models of NAFLD and cell free systems. FINALLY, we will determine if inhibition of lysosomal permeabilization and cathepsin B activation prevent liver injury and fibrosis in an in-vitro tissue model and in-vivo dietary murine models of NAFLD. The proposal is innovative technically and conceptually as it tests new concepts for lipid induced hepatotoxicity using sophisticated technologies. Moreover, because lipotoxicity as a result of overaccumulation of free fatty acids in non-adipose tissues has been implicated in the pathogenesis of other human liver diseases including chronic hepatitis C infection, alcoholic steatohepatitis and hemochromatosis, as well as other diseases such as type II diabetes and obesity associated heart disease the results of this proposal may not only bring new insights to the mechanisms underlying these conditions, but also could translate into new therapeutic strategies to treat them (e.g. the use of pharmacological Bax or cathepsin B inhibitors).

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Project Title: THE ROLE OF HEMOJUVELIN IN THE REGULATION OF IRON METABOLISM Principal Investigator & Institution: Ganz, Tomas; Professor; Medicine; University of California Los Angeles Office of Research Administration Los Angeles, Ca 90024 Timing: Fiscal Year 2006; Project Start 15-FEB-2006; Project End 31-JAN-2008 Summary: (provided by applicant): Iron overload diseases are among the most common genetic disorders worldwide. This proposal analyzes the molecular pathways that lead

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to iron overload diseases, including hereditary hemochromatosis. Recent discoveries created new opportunities for fundamental molecular understanding of iron metabolism and the diseases of iron overload. The peptide hormone hepcidin emerged as the principal regulator of systemic iron homeostasis. Hepcidin synthesis is induced by inflammation and by iron loading in vivo, and is suppressed by hypoxia and anemia. In turn, hepcidin inhibits the intestinal absorption of dietary iron, as well as iron recycling by macrophages and iron release from hepatic stores. Hepcidin deficiency and the resulting dysregulation of iron absorption are the common pathogenetic features of most hereditary hemochromatoses, except for those caused by mutations in the hepcidin target, ferroportin. The molecular pathways that sense iron and regulate hepcidin synthesis in response to iron loading are not known. It is also not clear how the specific genes mutated in hemochromatosis cause hepcidin deficiency. We reason that the hemochromatosis genes HFE, transferrin receptor 2 and hemojuvelin, whose homozygous disruption causes partial or complete deficiency of hepcidin, encode proteins that regulate hepcidin production. Of these genes, hemojuvelin appears to be the "closest" to hepcidin because its homozygous disruption causes the absence or near absence of hepcidin. Moreover, the disruption of hemojuvelin is the main cause of juvenile hemochromatosis, and phenotypically completely mimics homozygous disruption of the hepcidin gene itself. Furthermore, hemojuvelin belongs to a family of receptor ligands, repulsive guidance molecules (RGM), indicating that it may function in a signal transduction pathway. By focusing on hemojuvelin and identifying its partners and function, this R21 proposal will lay the groundwork for understanding how iron regulates hepcidin production. Specifically, we will: 1. Prepare and characterize human hemojuvelin and generate anti-hemojuvelin antibodies. 2. Identify the hemojuvelin receptor(s). 3. Analyze the regulation of hemojuvelin synthesis and processing by iron and inflammation 4. Identify the biological effects of hemojuvelin in vivo. The results of this work will form the foundation of a comprehensive R01 proposal to elucidate how iron load is sensed and how it regulates hepcidin production, processes that constitute the afferent arc of systemic regulation of iron absorption and transport. •

Project Title: THE ROLE OF IRON AND HFE GENOTYPE IN LIVER DISEASE Principal Investigator & Institution: Kowdley, Kris V.; Professor of Medicine; Medicine; University of Washington Office of Sponsored Programs Seattle, Wa 98105 Timing: Fiscal Year 2005; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: The candidate is currently an Associate Professor of Medicine at the University of Washington and is nationally recognized for his work in hepatology, in particular hepatic iron overload disorders. He has reached a stage of rapid and productive growth in his career. Heavy clinical responsibilities have limited his ability to focus on patient-oriented research. This award will protect his time and help him sustain the momentum and productivity he has generated. He will also strengthen and build on his knowledge of biostatistics, epidemiology and molecular biologic techniques. The candidate will be able, with the protected time afforded by this award, to achieve the following career goals: 1. Conduct excellent patient-oriented research in liver disease. 2. Develop into a leader in his field and make significant scientific contributions that will improve clinical care. 3. Serve as a mentor and role model in the training of new and junior patient-oriented investigators. During the period of funding, the candidate will develop and expand a multidisciplinary research program in two broad areas: 1. The role of iron and HFE mutations in liver disease and 2. Genotype/phenotype correlations in hereditary hemochromatosis. The candidate will lead studies examining the relationship between hepatic iron stores, HFE genotype and disease severity in hepatitis C and nonalcoholic steatohepatitis (NASH). He will

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continue and expand a current study funded by an NIH planning grant to examine the effect of iron overload on outcome after liver transplantation. These studies will provide definitive data on the role of iron and HFE mutations in the expression and clinical severity of hepatitis C, NASH and in end-stage liver disease. Hereditary hemochromatosis is a genetic disease caused by an autosomal recessive defect in the recently identified HFE gene. There is currently much debate about the clinical expression (penetrance) of HFE mutations in hemochromatosis, the natural history of this disease, and the appropriate use of genetic testing and liver biopsy in this condition. The candidate has established the only multidisciplinary clinic in the region dedicated to the care and study of patients with iron overload. The large patient database that will be generated from this clinic will be used to answer current important clinical questions about the relationship between genotype and phenotype in hemochromatosis. The University of Washington, as the only referral center for liver disease and iron overload in a five-state region, is uniquely positioned to enable the candidate to achieve these patient oriented research goals. The candidate has strong institutional support, facilities and resources to help him achieve these goals. •

Project Title: THERAPEUTIC MULTIDENTATE IRON SEQUESTERING AGENTS Principal Investigator & Institution: Raymond, Kenneth N.; Professor; Chemistry; University of California Berkeley 2150 Shattuck Avenue, Room 313 Berkeley, Ca 947045940 Timing: Fiscal Year 2005; Project Start 01-JUN-2000; Project End 30-JUL-2008 Summary: (provided by applicant): Human iron overload as a consequence of betathalassemia, hemochromatosis, or sickle cell anemia is a serious clinical problem. Iron chelation therapy is effective, but the goal of developing readily available, orally-active, effective and non-toxic sequestering agents have proven to be remarkably difficult to achieve. Desferrioxamine (Desferal(r)), a trihydroxamate ligand, remains the iron chelator of clinical use in the United States. Desferal(r) is expensive, has a short half-life in vivo, does not efficiently remove iron from transferrin, must be given on a regular, frequent basis by a subcutaneous or intravenous route, and its use can result in significant, irreversible toxicity. While there are other agents being investigated and developed as potential successors to Desferal(r), there is no established chelator that has yet met this target. The goal of this project is to develop new sequestering agents that would meet that need. In the previous period of support, in collaboration with the Children's Hospital of Oakland Research Institute (CHORI) and Dr. Patricia DurbinHeavey at the Lawrence Berkeley National Laboratory (LBNL), both new ligand systems and new screening protocols have been developed. The radioactive tracer mouse model at LBNL has been found to be accurate and reliable and has been selected as this project's routine screening protocol. Several promising new multidentate ligands have been developed based on the continuing hypothesis that multidentate, rather than bidentate or tridentate, hydroxypyridonate ligands will be effective as oral chelating agents effective at concentrations below toxic levels. A kinetic animal model has been developed for the metabolism of these agents that accurately fits the observed behavior. It is now proposed to extend these animal studies and to develop the chelators to the point where they can be accepted for large-scale testing, with the ultimate goal being the production of a safe, orally-active iron chelating agent that will prevent the toxicity of iron accumulation in patients who require chronic red cell transfusions. Several new ligand types are proposed with specific hypotheses about structural function relationships.

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

A case of neonatal hemochromatosis-like liver failure with spontaneous remission. Author(s): Inui A, Fujisawa T, Kubo T, Sogo T, Komatsu H, Kagata Y. 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=15735497&query_hl=19&itool=pubmed_docsum

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A diagnostic approach to hemochromatosis. Author(s): Tavill AS, Adams PC. Source: Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16955151&query_hl=19&itool=pubmed_docsum

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A foundation for hemochromatosis. Author(s): Krikker MA. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7137745&query_hl=19&itool=pubmed_docsum

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A juvenile hemochromatosis patient homozygous for a novel deletion of cDNA nucleotide 81 of hemojuvelin. Author(s): Lee P, Promrat K, Mallette C, Flynn M, Beutler E. Source: Acta Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16424663&query_hl=19&itool=pubmed_docsum

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

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A lack of association of variants in Hemochromatosis gene with ischemic stroke. Author(s): Saleheen D, Farooq U, Frossard P. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16127372&query_hl=19&itool=pubmed_docsum

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A liver fibrosis cocktail? Psoriasis, methotrexate and genetic hemochromatosis. Author(s): Mathew J, Leong MY, Morley N, Burt AD. Source: Bmc Dermatology [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16316460&query_hl=19&itool=pubmed_docsum

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A mouse model of juvenile hemochromatosis. Author(s): Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC. Source: The Journal of Clinical Investigation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16075059&query_hl=19&itool=pubmed_docsum

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A novel ferroportin mutation in a Canadian family with autosomal dominant hemochromatosis. Author(s): Morris TJ, Litvinova MM, Ralston D, Mattman A, Holmes D, Lockitch G. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16111902&query_hl=19&itool=pubmed_docsum

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A study of 82 extended HLA haplotypes in HFE-C282Y homozygous hemochromatosis subjects: relationship to the genetic control of CD8+ T-lymphocyte numbers and severity of iron overload. Author(s): Cruz E, Vieira J, Almeida S, Lacerda R, Gartner A, Cardoso CS, Alves H, Porto G. Source: Bmc Medical Genetics [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16509978&query_hl=19&itool=pubmed_docsum

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Absorption of iron and lead in hereditary hemochromatosis. Author(s): Conrad ME, Umbreit JN. 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=8051476&query_hl=19&itool=pubmed_docsum

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An HLA-All association with the hemochromatosis allele? Author(s): Le Mignon L, Simon M, Fauchet R, Edan G, Le Reun M, Brissot P, Genetet B, Bourel M. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6578890&query_hl=19&itool=pubmed_docsum

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An unusual case of ulcerative colitis with concurrent extraintestinal manifestations of primary sclerosing cholangitis, thromboembolism, hemolytic anemia, and hemochromatosis. Author(s): Wu CH, Wong JM, Hsieh SC, Yu CL. Source: J Microbiol Immunol Infect. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15986075&query_hl=19&itool=pubmed_docsum

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Analysis of hemochromatosis gene mutations in 52 consecutive patients with polycythemia vera. Author(s): Franchini M, de Matteis G, Federici F, Solero P, Veneri D. Source: Hematology (Amsterdam, Netherlands). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15763983&query_hl=19&itool=pubmed_docsum

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Analysis of the hemochromatosis mutations C282Y and H63D in infertile men. Author(s): Peterlin B, Kunej T, Hruskovicova H, Ferk P, Gersak K, Zorn B. Source: Fertility and Sterility. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17067586&query_hl=19&itool=pubmed_docsum

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Ankle arthropathy of hemochromatosis: a case series and review of the literature. Author(s): Davies MB, Saxby T. Source: Foot & Ankle International / American Orthopaedic Foot and Ankle Society [and] Swiss Foot and Ankle Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17144950&query_hl=19&itool=pubmed_docsum

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Antisense gene delivered by an adenoassociated viral vector inhibits iron uptake in human intestinal cells: potential application in hemochromatosis. Author(s): Ezquer F, Nunez MT, Israel Y. Source: Biochemical Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15896335&query_hl=19&itool=pubmed_docsum

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Articular cartilage in the degenerative arthropathy of hemochromatosis. Author(s): Schumacher HR. Source: Arthritis and Rheumatism. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7150378&query_hl=19&itool=pubmed_docsum

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Association of myeloperoxidase promotor polymorphism with cirrhosis in patients with hereditary hemochromatosis. Author(s): Osterreicher CH, Datz C, Stickel F, Hellerbrand C, Penz M, Hofer H, Wrba F, Penner E, Schuppan D, Ferenci P. Source: Journal of Hepatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15885363&query_hl=19&itool=pubmed_docsum

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Association of the H63D polymorphism in the hemochromatosis gene with sporadic ALS. Author(s): Goodall EF, Greenway MJ, van Marion I, Carroll CB, Hardiman O, Morrison KE. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16186539&query_hl=19&itool=pubmed_docsum

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Autosomal dominant hereditary hemochromatosis associated with two novel Ferroportin 1 mutations in Spain. Author(s): Bach V, Remacha A, Altes A, Barcelo MJ, Molina MA, Baiget M. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16257244&query_hl=19&itool=pubmed_docsum

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Bacteremic cellulitis caused by Non-01, Non-0139 Vibrio cholerae: report of a case in a patient with hemochromatosis. Author(s): Fernandez JM, Serrano M, De Arriba JJ, Sanchez MV, Escribano E, Ferreras P. Source: Diagnostic Microbiology and Infectious Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10794945&query_hl=19&itool=pubmed_docsum

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Benefit of population-based screening for phenotypic hemochromatosis in young men. Author(s): Asberg A, Tretli S, Hveem K, Bjerve KS. Source: Scandinavian Journal of Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12408528&query_hl=19&itool=pubmed_docsum

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Beta(+)-thalassemia with hemochromatosis. Author(s): Uchihara M, Nouchi T, Harano T, Yamane M, Sakai H, Takabe K, Mae S, Maekawa S, Fukuma T, Miyahara Y, et al. Source: Intern Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1362099&query_hl=19&itool=pubmed_docsum

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beta-thalassemia trait might increase the severity of hemochromatosis in subjects with the C282Y mutation in the HFE gene. Author(s): Arruda VR, Agostinho MF, Cancado R, Costa FF, Saad ST. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10706769&query_hl=19&itool=pubmed_docsum

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Beware of multiple comparisons: a study of symptoms associated with mutations of the HFE hemochromatosis gene. Author(s): Waalen J, Beutler E. 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=15993396&query_hl=19&itool=pubmed_docsum

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Biliary excretion of iron and ferritin in idiopathic hemochromatosis. Author(s): Hultcrantz R, Angelin B, Bjorn-Rasmussen E, Ewerth S, Einarsson K. Source: Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2714579&query_hl=19&itool=pubmed_docsum

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Biochemical liver profile in hemochromatosis. A survey of 100 patients. Author(s): Lin E, Adams PC. Source: Journal of Clinical Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2066547&query_hl=19&itool=pubmed_docsum

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Bioelectronic sensor technology for detection of cystic fibrosis and hereditary hemochromatosis mutations. Author(s): Bernacki SH, Farkas DH, Shi W, Chan V, Liu Y, Beck JC, Bailey KS, Pratt VM, Monaghan KG, Matteson KJ, Schaefer FV, Friez M, Shrimpton AE, Stenzel TT. Source: Archives of Pathology & Laboratory Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14632577&query_hl=19&itool=pubmed_docsum

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Biventricular diastolic behaviour in patients with hypertrophic and hereditary hemochromatosis cardiomyopathies. Author(s): Palka P, Lange A, Atherton J, Stafford WJ, Burstow DJ. Source: European Journal of Echocardiography : the Journal of the Working Group on Echocardiography of the European Society of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15341871&query_hl=19&itool=pubmed_docsum

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Blood donation by patients with hemochromatosis. Author(s): Penning HL. 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=8254851&query_hl=19&itool=pubmed_docsum

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Blood donation by patients with hemochromatosis. Author(s): Friedrich C. 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=8254850&query_hl=19&itool=pubmed_docsum

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Blood donation from patients with hemochromatosis. Author(s): Grindon AJ. 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=8133632&query_hl=19&itool=pubmed_docsum

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Blood from patients with hereditary hemochromatosis--a wasted resource. Author(s): Jeffrey G, Adams PC. Source: Transfusion. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10378831&query_hl=19&itool=pubmed_docsum

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Blood lead concentrations in hereditary hemochromatosis. Author(s): Barton JC, Patton MA, Edwards CQ, Griffen LM, Kushner JP, Meeks RG, Leggett RW. 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=8051482&query_hl=19&itool=pubmed_docsum

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Bone and joint involvement in genetic hemochromatosis: role of cirrhosis and iron overload. Author(s): Sinigaglia L, Fargion S, Fracanzani AL, Binelli L, Battafarano N, Varenna M, Piperno A, Fiorelli G. Source: The Journal of Rheumatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9292808&query_hl=19&itool=pubmed_docsum

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Bone involvement in primary hemochromatosis and alcoholic cirrhosis. Author(s): Conte D, Caraceni MP, Duriez J, Mandelli C, Corghi E, Cesana M, Ortolani S, Bianchi PA. Source: The American Journal of Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2801672&query_hl=19&itool=pubmed_docsum

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Bone mineral density in men with genetic hemochromatosis and HFE gene mutation. Author(s): Guggenbuhl P, Deugnier Y, Boisdet JF, Rolland Y, Perdriger A, Pawlotsky Y, Chales G. Source: Osteoporosis International : a Journal Established As Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the Usa. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15928800&query_hl=19&itool=pubmed_docsum

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Broadsheet number 54. Hereditary hemochromatosis. Author(s): Powell LW. Source: Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10740801&query_hl=19&itool=pubmed_docsum

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By the way, doctor. I have phlebotomies every six months to manage my hemochromatosis. At my most recent bloodletting, a fibrous clot came out after the nurse removed the needle from my forearm. It seems to me that such clotting presents an unnecessary risk for ischemic stroke. What do you think? Author(s): Komaroff AL. Source: Harvard Health Letter / from Harvard Medical School. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15496379&query_hl=19&itool=pubmed_docsum

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Cardiac hemochromatosis in an HFE His63Asp (187C->G) heterozygote. Author(s): Winer D, Silversides C, Israel N, Rinne C, Chang WS, Butany J. Source: The Canadian Journal of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15332145&query_hl=19&itool=pubmed_docsum

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Cardiac hemochromatosis. Author(s): Templin C, Pertschy S, Schaefer A. Source: International Journal of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17134777&query_hl=19&itool=pubmed_docsum

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Cardiac hemochromatosis: beneficial effects of iron removal therapy. An echocardiographic study. Author(s): Candell-Riera J, Lu L, Seres L, Gonzalez JB, Batlle J, Permanyer-Miralda G, Garcia-del-Castillo H, Soler-Soler J. Source: The American Journal of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6624673&query_hl=19&itool=pubmed_docsum

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Case 75: erythropoietic hemochromatosis. Author(s): Ben Salem D, Cercueil JP, Ricolfi F, Krause D. Source: Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15454619&query_hl=19&itool=pubmed_docsum

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CD14-positive hepatic monocytes/macrophages increase in hereditary hemochromatosis. Author(s): Leicester KL, Olynyk JK, Brunt EM, Britton RS, Bacon BR. Source: Liver International : Official Journal of the International Association for the Study of the Liver. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15482341&query_hl=19&itool=pubmed_docsum

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Changes in erythropoiesis in hereditary hemochromatosis are not mediated by HFE expression in nucleated red cells. Author(s): Feeney GP, Carter K, Masters GS, Jackson HA, Cavil I, Worwood M. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15710569&query_hl=19&itool=pubmed_docsum

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Chronic inflammation does not appear to modify the homozygous hereditary hemochromatosis phenotype. Author(s): Beutler E, Waalen J, Gelbart T. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16154780&query_hl=19&itool=pubmed_docsum

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Chronic inflammatory demyelinating polyneuropathy associated with idiopathic hemochromatosis. Author(s): Misawa S, Kuwabara S, Matsuda S, Sakakibara Y, Ogawa Y, Tashiro J, Hattori T. Source: Intern Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16908945&query_hl=19&itool=pubmed_docsum

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Circulating gastrin is increased in hemochromatosis. Author(s): Smith KA, Kovac S, Anderson GJ, Shulkes A, Baldwin GS. Source: Febs Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17064691&query_hl=19&itool=pubmed_docsum

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Clinical aspects of hemochromatosis. Author(s): O'Neil J, Powell L. Source: Seminars in Liver Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16315132&query_hl=19&itool=pubmed_docsum

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Clinical consult: iron overload--hereditary hemochromatosis. Author(s): Matthews AL, Grimes SJ, Wiesner GL, Acheson LS. Source: Primary Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15331258&query_hl=19&itool=pubmed_docsum

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Combined segregation and linkage analysis of genetic hemochromatosis using affection status, serum iron, and HLA. Author(s): Borecki IB, Lathrop GM, Bonney GE, Yaouanq J, Rao DC. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2393027&query_hl=19&itool=pubmed_docsum

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Common heterozygous hemochromatosis gene mutations are risk factors for inflammation and fibrosis in chronic hepatitis C. Author(s): Geier A, Reugels M, Weiskirchen R, Wasmuth HE, Dietrich CG, Siewert E, Gartung C, Lorenzen J, Bosserhoff AK, Brugmann M, Gressner AM, Matern S, Lammert F. Source: Liver International : Official Journal of the International Association for the Study of the Liver. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15287851&query_hl=19&itool=pubmed_docsum

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Comparison of genotypic and phenotypic strategies for population screening in hemochromatosis: assessment of anxiety, depression, and perception of health. Author(s): Patch C, Roderick P, Rosenberg W. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16247293&query_hl=19&itool=pubmed_docsum

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Comparison of the unsaturated iron-binding capacity with transferrin saturation as a screening test to detect C282Y homozygotes for hemochromatosis in 101,168 participants in the hemochromatosis and iron overload screening (HEIRS) study. Author(s): Adams PC, Reboussin DM, Leiendecker-Foster C, Moses GC, McLaren GD, McLaren CE, Dawkins FW, Kasvosve I, Acton RT, Barton JC, Zaccaro D, Harris EL, Press R, Chang H, Eckfeldt JH. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15833784&query_hl=19&itool=pubmed_docsum

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Compound heterozygous hemochromatosis genotype predicts increased iron and erythrocyte indices in women. Author(s): Rossi E, Olynyk JK, Cullen DJ, Papadopoulos G, Bulsara M, Summerville L, Powell LW. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10657371&query_hl=19&itool=pubmed_docsum

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Congenital diserythropoietic anemia type I. Report on monozygotic twins with associated hemochromatosis and short stature. Author(s): Facon T, Mannessier L, Lepelley P, Weill J, Fenaux P, Dupriez B, Morel P, Jouet JP. Source: Blut. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2224147&query_hl=19&itool=pubmed_docsum

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Correction for Stott et al.: simple multiplex PCR for the simultaneous detection of the C282Y and H63D hemochromatosis (HFE) gene mutations. Author(s): Stott MK, Fellowes AP, Upton JD, Burt MJ, George PM. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10657401&query_hl=19&itool=pubmed_docsum

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Cost-effectiveness analysis for evaluation of screening programs: hereditary hemochromatosis. Author(s): Buffone GJ, Beck JR. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8045021&query_hl=19&itool=pubmed_docsum

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Cost-effectiveness of screening for hereditary hemochromatosis. Author(s): Phatak PD, Guzman G, Woll JE, Robeson A, Phelps CE. Source: Archives of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8147681&query_hl=19&itool=pubmed_docsum

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Denaturing gradient gel electrophoresis analysis of the hemochromatosis (HFE) gene: impact of HFE gene mutations on the manifestation of porphyria cutanea tarda. Author(s): Christiansen L, Bygum A, Thomsen K, Brandrup F, Horder M, Petersen NE. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10545080&query_hl=19&itool=pubmed_docsum

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Detection of the hereditary hemochromatosis gene mutation by real-time fluorescence polymerase chain reaction and peptide nucleic acid clamping. Author(s): Kyger EM, Krevolin MD, Powell MJ. Source: Analytical Biochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9657870&query_hl=19&itool=pubmed_docsum

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Diagnosis and management of hemochromatosis. Author(s): Tavill AS; American Association for the Study of Liver Diseases; American College of Gastroenterology; American Gastroenterological Association. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11343262&query_hl=19&itool=pubmed_docsum

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Diagnosis of hemochromatosis in family members of probands: a comparison of phenotyping and HFE genotyping. Author(s): Barton JC, Rothenberg BE, Bertoli LF, Acton RT. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11336458&query_hl=19&itool=pubmed_docsum

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Diagnosis of hemochromatosis. Author(s): Gollan JL. Source: Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6336710&query_hl=19&itool=pubmed_docsum

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Diagnosis of neonatal hemochromatosis with MR imaging and duplex Doppler sonography. Author(s): Oddone M, Bellini C, Bonacci W, Bartocci M, Toma P, Serra G. Source: European Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10602969&query_hl=19&itool=pubmed_docsum

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Differential diagnosis of hereditary hemochromatosis from other liver disorders by genetic analysis: gene mutation analysis of patients previously diagnosed with hemochromatosis by liver biopsy. Author(s): Bartolo C, McAndrew PE, Sosolik RC, Cawley KA, Balcerzak SP, Brandt JT, Prior TW. Source: Archives of Pathology & Laboratory Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9674544&query_hl=19&itool=pubmed_docsum

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Differential HFE allele expression in hemochromatosis heterozygotes. Author(s): Bergamaschi G, Rolandi V, Cazzola M. Source: Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11288747&query_hl=19&itool=pubmed_docsum

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Discordant hepatic uptake of 99mTc sulfur colloid and 99mTc-DISIDA in hemochromatosis. Author(s): Knopf DR, McClees EC, Fajman WA, Sones PJ. Source: Ajr. American Journal of Roentgenology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6603771&query_hl=19&itool=pubmed_docsum

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Discussion of the role of hemochromatosis susceptibility gene mutation in protecting against iron deficiency in celiac disease. Author(s): Ravine D, Darke C. Source: Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12744240&query_hl=19&itool=pubmed_docsum

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Discussion of the role of hemochromatosis susceptibility gene mutation in protecting against iron deficiency in celiac disease. Author(s): Bowlus CL, Lie BA. Source: Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12744238&query_hl=19&itool=pubmed_docsum

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Disease-related conditions in relatives of patients with hemochromatosis. Author(s): Grosse SD, Morris JM, Khoury MJ. 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=11357841&query_hl=19&itool=pubmed_docsum

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Disparate clinical presentation of neonatal hemochromatosis in twins. Author(s): Ekong UD, Kelly S, Whitington PF. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16291733&query_hl=19&itool=pubmed_docsum

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Distribution of the C282Y and H63D polymorphisms in hereditary hemochromatosis patients from the French Basque Country. Author(s): Bauduer F, Scribans C, Degioanni A, Renoux M, Dutour O. Source: Annals of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15503019&query_hl=19&itool=pubmed_docsum

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DMT1 genetic variability is not responsible for phenotype variability in hereditary hemochromatosis. Author(s): Kelleher T, Ryan E, Barrett S, O'Keane C, Crowe J. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15223008&query_hl=19&itool=pubmed_docsum

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Does bilirubin protect against hemochromatosis gene (HFE) related mortality? Author(s): Alizadeh BZ, Njajou OT, Houwing-Duistermaat JJ, de Jong G, Vergeer JM, Hofman A, Pols HA, van Duijn CM. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15266614&query_hl=19&itool=pubmed_docsum

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Does the hepatic iron index differentiate hereditary hemochromatosis from secondary hemochromatosis? Author(s): van Deursen CT, Fickers MM, Brombacher PJ. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2373479&query_hl=19&itool=pubmed_docsum

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Duodenal cytochrome b and hephaestin expression in patients with iron deficiency and hemochromatosis. Author(s): Zoller H, Theurl I, Koch RO, McKie AT, Vogel W, Weiss G. Source: Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12949720&query_hl=19&itool=pubmed_docsum

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Duodenal expression of a putative stimulator of Fe transport and transferrin receptor in anemia and hemochromatosis. Author(s): Barisani D, Parafioriti A, Armiraglio E, Meneveri R, Conte D. Source: Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11313310&query_hl=19&itool=pubmed_docsum

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Duration of hepatic iron exposure increases the risk of significant fibrosis in hereditary hemochromatosis: a new role for magnetic resonance imaging. Author(s): Olynyk JK, St Pierre TG, Britton RS, Brunt EM, Bacon BR. Source: The American Journal of Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15784029&query_hl=19&itool=pubmed_docsum

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Early diagnosis of hemochromatosis-related cardiomyopathy with magnetic resonance imaging. Author(s): Ptaszek LM, Price ET, Hu MY, Yang PC. Source: Journal of Cardiovascular Magnetic Resonance : Official Journal of the Society for Cardiovascular Magnetic Resonance. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16136860&query_hl=19&itool=pubmed_docsum

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Early onset hereditary hemochromatosis resulting from a novel TFR2 gene nonsense mutation (R105X) in two siblings of north French descent. Author(s): Le Gac G, Mons F, Jacolot S, Scotet V, Ferec C, Frebourg T. Source: British Journal of Haematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15147384&query_hl=19&itool=pubmed_docsum

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Educational outcomes of a workplace screening program for genetic susceptibility to hemochromatosis. Author(s): Nisselle AE, Collins VR, Gason AA, Flouris A, Delatycki MB, Allen KJ, Aitken MA, Metcalfe SA. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16433697&query_hl=19&itool=pubmed_docsum

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Effect of Native American ancestry on iron-related phenotypes of Alabama hemochromatosis probands with HFE C282Y homozygosity. Author(s): Barton JC, Barton EH, Acton RT. Source: Bmc Medical Genetics [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16533407&query_hl=19&itool=pubmed_docsum

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Establishment of a cell line from a hepatocellular carcinoma from a patient with hemochromatosis. Author(s): Sing GK, Pace R, Prior S, Scott JS, Shield P, Martin N, Searle J, Battersby C, Powell LW, Cooksley WG. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8020907&query_hl=19&itool=pubmed_docsum

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Evaluation of a diagnostic algorithm for hereditary hemochromatosis in 3,500 patients with diabetes. Author(s): Hahn JU, Steiner M, Bochnig S, Schmidt H, Schuff-Werner P, Kerner W. Source: Diabetes Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16443912&query_hl=19&itool=pubmed_docsum

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Evaluation of HFE (hemochromatosis) mutations as genetic modifiers in sporadic AD and MCI. Author(s): Berlin D, Chong G, Chertkow H, Bergman H, Phillips NA, Schipper HM. Source: Neurobiology of Aging. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15013567&query_hl=19&itool=pubmed_docsum

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Evidence for an association between compound heterozygosity for germ line mutations in the hemochromatosis (HFE) gene and increased risk of colorectal cancer. Author(s): Robinson JP, Johnson VL, Rogers PA, Houlston RS, Maher ER, Bishop DT, Evans DG, Thomas HJ, Tomlinson IP, Silver AR. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15941956&query_hl=19&itool=pubmed_docsum

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Evidence for non-HFE linked hemochromatosis in Asian Indians. Author(s): Panigrahi I, Ahmad F, Kapoor R, Sharma PK, Makharia G, Saxena R. Source: Indian Journal of Medical Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17130663&query_hl=19&itool=pubmed_docsum

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Evidence from a Ghanaian population of known African descent to support the proposition that hemochromatosis is a Caucasian disorder. Author(s): Jeffery S, Crosby A, Plange-Rhule J, Amoah-Danquah J, Acheampong JW, Eastwood JB, Malik AK. Source: Genetic Testing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10627947&query_hl=19&itool=pubmed_docsum

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Evolution of untreated hereditary hemochromatosis in the Busselton population: a 17year study. Author(s): Olynyk JK, Hagan SE, Cullen DJ, Beilby J, Whittall DE. Source: Mayo Clinic Proceedings. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15008603&query_hl=19&itool=pubmed_docsum

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Exclusion of ferritins and iron-responsive element (IRE)-binding proteins as candidates for the hemochromatosis gene. Author(s): Zheng H, Bhavsar D, Volz A, Ziegler A, Drysdale J. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8045562&query_hl=19&itool=pubmed_docsum

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Exercise capacity of cardiac asymptomatic hereditary hemochromatosis subjects. Author(s): Shizukuda Y, Bolan CD, Tripodi DJ, Yau YY, Smith KP, Arena R, Waclawiw MA, Leitman SF, Rosing DR. Source: Medicine and Science in Sports and Exercise. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17218876&query_hl=19&itool=pubmed_docsum

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Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism. Author(s): Bahram S, Gilfillan S, Kuhn LC, Moret R, Schulze JB, Lebeau A, Schumann K. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10557317&query_hl=19&itool=pubmed_docsum

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Expression of ferroportin in hemochromatosis liver. Author(s): Adams PC, Barbin YP, Khan ZA, Chakrabarti S. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12972034&query_hl=19&itool=pubmed_docsum

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Expression of the hemochromatosis gene modulates the cytotoxicity of doxorubicin in breast cancer cells. Author(s): Chitambar CR, Kotamraju S, Wereley JP. Source: International Journal of Cancer. Journal International Du Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16823846&query_hl=19&itool=pubmed_docsum

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Expression of the hereditary hemochromatosis protein HFE increases ferritin levels by inhibiting iron export in HT29 cells. Author(s): Davies PS, Enns CA. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15044462&query_hl=19&itool=pubmed_docsum

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Expression of the HFE hemochromatosis gene in a community-based population of elderly women. Author(s): Rossi E, Kuek C, Beilby JP, Jeffrey GP, Devine A, Prince RL. Source: Journal of Gastroenterology and Hepatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15377292&query_hl=19&itool=pubmed_docsum

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Expression of transferrin receptors on monocytes in hemochromatosis. Author(s): Adams PC, Chau LA, White M, Lazarovits A. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1858781&query_hl=19&itool=pubmed_docsum

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External validation for fibrosis predicting index in hereditary hemochromatosis. Author(s): Castiella A, Emparanza JI. Source: The American Journal of Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16181396&query_hl=19&itool=pubmed_docsum

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Familial perinatal hemochromatosis: a disease that causes recurrent non-immune hydrops. Author(s): Kassem E, Dolfin T, Litmanowitz I, Regev R, Arnon S, Kidron D. Source: Journal of Perinatal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10379502&query_hl=19&itool=pubmed_docsum

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Ferroportin mutation in autosomal dominant hemochromatosis: loss of function, gain in understanding. Author(s): Fleming RE, Sly WS. Source: The Journal of Clinical Investigation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11518724&query_hl=19&itool=pubmed_docsum

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Ferumoxide-enhanced MRI of sideronecrosis superimposed on genetic hemochromatosis. Author(s): Aizenstein RI, Chen R, Sato K, Mihalov M, O'Neil HK. Source: Journal of Computer Assisted Tomography. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10050815&query_hl=19&itool=pubmed_docsum

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Fetal and infantile hemochromatosis. Author(s): Whitington PF. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16557536&query_hl=19&itool=pubmed_docsum

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Finding the iron in the melting pot--practical use of a new genetic assay for hereditary hemochromatosis. Author(s): Glenn JS, Cheung RC. Source: The Western Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9655998&query_hl=19&itool=pubmed_docsum

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Fluorescent multicolor multiplex homogeneous assay for the simultaneous analysis of the two most common hemochromatosis mutations. Author(s): Ugozzoli LA, Chinn D, Hamby K. Source: Analytical Biochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12137778&query_hl=19&itool=pubmed_docsum

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Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis. Author(s): Cotter PD, May A, Li L, Al-Sabah AI, Fitzsimons EJ, Cazzola M, Bishop DF. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10029606&query_hl=19&itool=pubmed_docsum

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Frequencies of the hereditary hemochromatosis allele in different populations. Comparison of previous phenotypic methods and novel genotypic methods. Author(s): Milman N, Pedersen P, Steig T, Melsen GV. Source: International Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12568299&query_hl=19&itool=pubmed_docsum

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Frequency analysis and allele map in favor of the celtic origin of the C282Y mutation of hemochromatosis. Author(s): Lucotte G. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11500066&query_hl=19&itool=pubmed_docsum

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Frequency and biochemical expression of C282Y/H63D hemochromatosis (HFE) gene mutations in the healthy adult population in Italy. Author(s): Cassanelli S, Pignatti E, Montosi G, Garuti C, Mariano M, Campioli D, Carbonieri A, Baldini E, Pietrangelo A. Source: Journal of Hepatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11394651&query_hl=19&itool=pubmed_docsum

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Frequency and spectrum of hemochromatosis mutations in Tunisia. Author(s): Zorai A, Harteveld CL, Rachdi R, Dellagi K, Abbes S, Delbini P, Giordano PC. 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=14671616&query_hl=19&itool=pubmed_docsum

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Frequency of hemochromatosis C282Y and H63D mutations in Sardinia. Author(s): Melis MA, Cau M, Congiu R, Ruvoletto L, Cao A, Galanello R. Source: Genetic Testing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12537659&query_hl=19&itool=pubmed_docsum

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Frequency of hemochromatosis gene (HFE) mutations in Russian healthy women and patients with estrogen-dependent cancers. Author(s): Kondrashova TV, Neriishi K, Ban S, Ivanova TI, Krikunova LI, Shentereva NI, Smirnova IA, Zharikova IA, Konova MV, Taira S, Tsyb AF. Source: Biochimica Et Biophysica Acta. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16216474&query_hl=19&itool=pubmed_docsum

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Frequency of HFE mutations among Turkish blood donors according to transferrin saturation: genotype screening for hereditary hemochromatosis among voluntary blood donors in Turkey. Author(s): Simsek H, Sumer H, Yilmaz E, Balaban YH, Ozcebe O, Hascelik G, Buyukask Y, Tatar G. Source: Journal of Clinical Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15319650&query_hl=19&itool=pubmed_docsum

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Frequency of the C282Y and H63D mutations of the hemochromatosis gene (HFE) in 2501 ethnic Danes. Author(s): Milman N, Pedersen P, Ovesen L, Melsen GV, Fenger K. Source: Annals of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15141324&query_hl=19&itool=pubmed_docsum

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Frequency of the C282Y and H63D mutations of the hemochromatosis gene (HFE) in a cohort of 1,000 neonates in Madrid (Spain). Author(s): Ropero P, Briceno O, Mateo M, Polo M, Mora A, Gonzalez FA, Villegas A. Source: Annals of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16520984&query_hl=19&itool=pubmed_docsum

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Frequency of the C282Y mutation of hemochromatosis in five French populations. Author(s): Mercier G, Bathelier C, Lucotte G. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9642097&query_hl=19&itool=pubmed_docsum

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Frequency of the hemochromatosis C282Y and H63D mutations in a Polish population of Slavic origin. Author(s): Moczulski DK, Grzeszczak W, Gawlik B. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11386022&query_hl=19&itool=pubmed_docsum

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Frequency of the hemochromatosis gene mutations in the population of Serbia and Montenegro. Author(s): Saric M, Zamurovic Lj, Keckarevic-Markovic M, Keckarevic D, Stevanovic M, Savic-Pavicevic D, Jovic J, Romac S. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16879202&query_hl=19&itool=pubmed_docsum

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Frequency of the hemochromatosis HFE mutations C282Y, H63D, and S65C in blood donors in the Faroe Islands. Author(s): Milman N, a Steig T, Koefoed P, Pedersen P, Fenger K, Nielsen FC. Source: Annals of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15042317&query_hl=19&itool=pubmed_docsum

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Gene symbol: HFE2a (HJV). Disease: juvenile hemochromatosis. Author(s): Klomp C, Abbes AP, Engel H. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16521298&query_hl=19&itool=pubmed_docsum

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Generation of monocyte-derived dendritic cells in patients with hereditary hemochromatosis. Author(s): Phothirath P, Duperrier K, Bernaud J, Durieu D, Picollet J, Bienvenu J, Rigal D. Source: Clinical Immunology (Orlando, Fla.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12483998&query_hl=19&itool=pubmed_docsum

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Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin. Author(s): Lee PL, Beutler E, Rao SV, Barton JC. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14982867&query_hl=19&itool=pubmed_docsum

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Genetic and phenotypic expression of hemochromatosis in Canadians. Author(s): Borwein ST, Ghent CN, Flanagan PR, Chamberlain MJ, Valberg LS. Source: Clinical and Investigative Medicine. Medecine Clinique Et Experimentale. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6652983&query_hl=19&itool=pubmed_docsum

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Genetic counseling in neonatal hemochromatosis. Author(s): Shneider BL. 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=11973777&query_hl=19&itool=pubmed_docsum

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Genetic hemochromatosis presenting as asymptomatic hepatomegaly. Author(s): Shankaran K, Gill HH, Desai HG. Source: Indian J Gastroenterol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8206540&query_hl=19&itool=pubmed_docsum

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Genetic hemochromatosis update. Author(s): Brissot P, Le Lan C, Lorho R, Gaboriau F, Lescoat G, Loreal O. Source: Acta Gastroenterol Belg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15832585&query_hl=19&itool=pubmed_docsum

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Genetic hemochromatosis with normal transferrin saturation in a man with cholangiocarcinoma and yellow nail syndrome. Author(s): Di Stefano F, Verna N, Balatsinou L, Schiavone C, Di Gioacchino M. Source: Journal of Gastroenterology and Hepatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12974919&query_hl=19&itool=pubmed_docsum

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Genetic heterogeneity underlies juvenile hemochromatosis phenotype: analysis of three families of northern Greek origin. Author(s): Papanikolaou G, Papaioannou M, Politou M, Vavatsi N, Kioumi A, Tsiatsiou P, Marinaki P, Loukopoulos D, Christakis JI. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12490283&query_hl=19&itool=pubmed_docsum

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Genetic knowledge among participants of a German pilot study on hemochromatosis screening. Author(s): Stuhrmann M, Nippert I, Hoy L, Schmidtke J. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16813609&query_hl=19&itool=pubmed_docsum

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Genetic predisposition to iron overload: prevalence and phenotypic expression of hemochromatosis-associated HFE-C282Y gene mutation. Author(s): Distante S. Source: Scandinavian Journal of Clinical and Laboratory Investigation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16537242&query_hl=19&itool=pubmed_docsum

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Genetic screening for common mutations: lessons from hereditary hemochromatosis. Author(s): Njajou OT, Alizadeh BZ, van Duijn CM. Source: European Journal of Epidemiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12705616&query_hl=19&itool=pubmed_docsum

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Genetic screening for hemochromatosis: a cautionary tale. Author(s): Starczynski J, Hooper L, Ali N, Hill M, Fegan C, Pratt G. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15738526&query_hl=19&itool=pubmed_docsum

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Genetic testing for hemochromatosis: attitudes and acceptability among young and older adults. Author(s): Hicken BL, Calhoun DC, Tucker DC. Source: Genetic Testing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14641999&query_hl=19&itool=pubmed_docsum

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Genetic testing for HFE hemochromatosis in Australia: the value of testing relatives of simple heterozygotes. Author(s): Cavanaugh JA, Wilson SR, Bassett ML. Source: Journal of Gastroenterology and Hepatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12121511&query_hl=19&itool=pubmed_docsum

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Genetics of iron storage and hemochromatosis. Author(s): Beutler E, Felitti V, Gelbart T, Ho N. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11259339&query_hl=19&itool=pubmed_docsum

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Genetics, diagnosis and treatment of hemochromatosis. Author(s): Gordeuk VR. Source: Clin Adv Hematol Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16224408&query_hl=19&itool=pubmed_docsum

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Genotype-based screening for hereditary hemochromatosis: II. Attitudes toward genetic testing and psychosocial impact--a report from a German pilot study. Author(s): Stuhrmann M, Hoy L, Nippert I, Schmidtke J. Source: Genetic Testing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16225404&query_hl=19&itool=pubmed_docsum

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Grand rounds: idiopathic hemochromatosis. Author(s): Nestler JE. Source: Va Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7164562&query_hl=19&itool=pubmed_docsum

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Guideline for diagnosis of primary hemochromatosis. Author(s): Quisel A, Gill JM, Butt WG, Bercaw DM. Source: Del Med J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12149818&query_hl=19&itool=pubmed_docsum

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Helicobacter pylori infection and HFE hemochromatosis. Author(s): Beutler E, Gelbart T. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16996754&query_hl=19&itool=pubmed_docsum

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Hemochromatosis (HFE) gene splice site mutation IVS5+1 G/A in North American Vietnamese with and without phenotypic evidence of iron overload. Author(s): Steiner M, Leiendecker-Foster C, McLaren GD, Snively BM, McLaren CE, Adams PC, Eckfeldt JH. Source: Transl Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17240320&query_hl=19&itool=pubmed_docsum

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Hemochromatosis and liver transplant survival. Author(s): Perkins JD. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16568561&query_hl=19&itool=pubmed_docsum

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Hemochromatosis case definition: out of focus? Author(s): Adams PC. Source: Nat Clin Pract Gastroenterol Hepatol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16582939&query_hl=19&itool=pubmed_docsum

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Hemochromatosis discovered through blood donor screening for alanine aminotransferase. Author(s): Shoaf EH Jr. Source: N C Med J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2234109&query_hl=19&itool=pubmed_docsum

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Hemochromatosis gene mutations in patients with alcoholic cirrhosis. Author(s): Starcevic Cizmarevic N, Stepec S, Ristic S, Milic S, Brajenovic-Milic B, Stimac D, Kapovic M, Peterlin B. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16922731&query_hl=19&itool=pubmed_docsum

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Hemochromatosis--treatment is easy, diagnosis hard. Author(s): Finch CA. Source: The Western Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2219902&query_hl=19&itool=pubmed_docsum

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Hepatic iron and iron absorption in hemochromatosis. Author(s): Adams PC, Frei JV, Bradley C, Lam D. Source: Clinical and Investigative Medicine. Medecine Clinique Et Experimentale. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2276219&query_hl=19&itool=pubmed_docsum

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Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. Author(s): Goswami T, Andrews NC. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16893896&query_hl=19&itool=pubmed_docsum

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Hereditary hemochromatosis results in decreased iron acquisition and growth by Mycobacterium tuberculosis within human macrophages. Author(s): Olakanmi O, Schlesinger LS, Britigan BE. Source: Journal of Leukocyte Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17038583&query_hl=19&itool=pubmed_docsum

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Hereditary hemochromatosis screening: effect of mutation penetrance and prevalence on cost-effectiveness of testing algorithms. Author(s): Gagne G, Reinharz D, Laflamme N, Adams PC, Rousseau F. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17204047&query_hl=19&itool=pubmed_docsum

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Hereditary hemochromatosis. Author(s): Pietrangelo A. Source: Biochimica Et Biophysica Acta. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16891003&query_hl=19&itool=pubmed_docsum

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Hereditary hemochromatosis. Author(s): Pietrangelo A. Source: Annual Review of Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16848707&query_hl=19&itool=pubmed_docsum

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Hereditary hemochromatosis: a rare disease in Iran. Author(s): Nobakht H, Merat S, Malekzadeh R. Source: Arch Iran Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16649386&query_hl=19&itool=pubmed_docsum

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Hereditary hemochromatosis: a review of the genetics, mechanism, diagnosis, and treatment of iron overload. Author(s): Wheeler CJ, Kowdley KV. Source: Compr Ther. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16785576&query_hl=19&itool=pubmed_docsum

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Hereditary hemochromatosis: an opportunity for gene therapy. Author(s): Ezquer F, Nunez MT, Rojas A, Asenjo J, Israel Y. Source: Biol Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16629172&query_hl=19&itool=pubmed_docsum

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Hereditary hemochromatosis: genetic complexity and new diagnostic approaches. Author(s): Swinkels DW, Janssen MC, Bergmans J, Marx JJ. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16627556&query_hl=19&itool=pubmed_docsum

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Homozygous p.M172K mutation of the TFR2 gene in an Italian family with type 3 hereditary hemochromatosis and early onset iron overload. Author(s): Majore S, Milano F, Binni F, Stuppia L, Cerrone A, Tafuri A, De Bernardo C, Palka G, Grammatico P. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16923517&query_hl=19&itool=pubmed_docsum

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Identification of homozygous hemochromatosis subjects by measurement of hepatic iron index. Author(s): Summers KM, Halliday JW, Powell LW. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2373481&query_hl=19&itool=pubmed_docsum

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Impact of hemochromatosis screening in patients with indeterminate results: the hemochromatosis and iron overload screening study. Author(s): Anderson RT, Wenzel L, Walker AP, Ruggiero A, Acton RT, Hall MA, Tucker DC, Thomson E, Harrison B, Howe E 3rd, Holup J, Leiendecker-Foster C, Power T, Adams P. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17108759&query_hl=19&itool=pubmed_docsum

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Impact of HFE genetic testing on clinical presentation of hereditary hemochromatosis: new epidemiological data. Author(s): Scotet V, Le Gac G, Merour MC, Mercier AY, Chanu B, Ka C, Mura C, Nousbaum JB, Ferec C. Source: Bmc Medical Genetics [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15929798&query_hl=19&itool=pubmed_docsum

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In vitro functional analysis of human ferroportin (FPN) and hemochromatosisassociated FPN mutations. Author(s): Schimanski LM, Drakesmith H, Merryweather-Clarke AT, Viprakasit V, Edwards JP, Sweetland E, Bastin JM, Cowley D, Chinthammitr Y, Robson KJ, Townsend AR. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15692071&query_hl=19&itool=pubmed_docsum

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Incorrect diagnosis of hereditary hemochromatosis. Author(s): Mirochnik O, Halim-Kertanegara N, Hertzberg M, McDonald D, Liddle C. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10629581&query_hl=19&itool=pubmed_docsum

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Increased expression of hepcidin in obese patients: impact on phenotypic expression of hemochromatosis and pathophysiology of dysmetabolic iron overload syndrome. Author(s): Laine F, Deugnier Y. Source: Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17188970&query_hl=19&itool=pubmed_docsum

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Increased urinary excretion of 8-iso-prostaglandin F2alpha in patients with HFErelated hemochromatosis: a case-control study. Author(s): Kom GD, Schwedhelm E, Nielsen P, Boger RH. Source: Free Radical Biology & Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16545687&query_hl=19&itool=pubmed_docsum

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Inherited hemochromatosis: from genetics to clinics. Author(s): Camaschella C, Merlini R. Source: Minerva Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16175162&query_hl=19&itool=pubmed_docsum

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Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in Native Americans and whites in the Hemochromatosis and Iron Overload Screening Study. Author(s): Barton JC, Acton RT, Lovato L, Speechley MR, McLaren CE, Harris EL, Reboussin DM, Adams PC, Dawkins FW, Gordeuk VR, Walker AP; Hemochromatosis and Iron Overload Screening Study Research Investigators. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16451136&query_hl=19&itool=pubmed_docsum

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Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in whites and blacks in the Hemochromatosis and Iron Overload Screening Study. Author(s): Barton JC, Acton RT, Dawkins FW, Adams PC, Lovato L, Leiendecker-Foster C, McLaren CE, Reboussin DM, Speechley MR, Gordeuk VR, McLaren GD, Sholinsky P, Harris EL. Source: Genetic Testing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16225403&query_hl=19&itool=pubmed_docsum

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Intramuscular deferoxamine in hereditary hemochromatosis. Author(s): Polo-Romero FJ. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16493613&query_hl=19&itool=pubmed_docsum

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Investigation of genetic variants of genes of the hemochromatosis pathway and their role in breast cancer. Author(s): Abraham BK, Justenhoven C, Pesch B, Harth V, Weirich G, Baisch C, Rabstein S, Ko YD, Bruning T, Fischer HP, Haas S, Brod S, Oberkanins C, Hamann U, Brauch H; GENICA Network. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15894659&query_hl=19&itool=pubmed_docsum

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Iron absorption by heterozygous carriers of the HFE C282Y mutation associated with hemochromatosis. Author(s): Hunt JR, Zeng H. 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=15447900&query_hl=19&itool=pubmed_docsum

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Iron absorption in carriers of the C282Y hemochromatosis mutation. Author(s): Beutler E. 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=15447883&query_hl=19&itool=pubmed_docsum

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Iron beware: a common HFE gene polymorphism may prevent the accurate molecular diagnosis of homozygous hemochromatosis in low-risk, but not high-risk groups. Author(s): Press RD. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10655286&query_hl=19&itool=pubmed_docsum

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Iron binding saturation and genotypic testing for hereditary hemochromatosis in patients with liver disease. Author(s): Nichols L, Dickson G, Phan PG, Kant JA. Source: American Journal of Clinical Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16393683&query_hl=19&itool=pubmed_docsum

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Iron regulatory protein 1 and 2 in human monocytes, macrophages and duodenum: expression and regulation in hereditary hemochromatosis and iron deficiency. Author(s): Worwood M. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16531245&query_hl=19&itool=pubmed_docsum

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Iron regulatory proteins 1 and 2 in human monocytes, macrophages and duodenum: expression and regulation in hereditary hemochromatosis and iron deficiency. Author(s): Recalcati S, Alberghini A, Campanella A, Gianelli U, De Camilli E, Conte D, Cairo G. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16503547&query_hl=19&itool=pubmed_docsum

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Iron removal with phlebotomy and recombinant human erythropoietin in secondary hemochromatosis after allogeneic bone marrow transplantation. Author(s): Cho SJ, Lee SJ, Yoo ES, Ryu KH, Seoh JY, Hong KS, Koo H. 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=16635180&query_hl=19&itool=pubmed_docsum

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Iron, hemochromatosis, and hepatocellular carcinoma. Author(s): Kowdley KV. Source: Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15508107&query_hl=19&itool=pubmed_docsum

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Jaundice and bleeding from peripheral intravenous sites in a neonate. Neonatal hemochromatosis (idiopathic neonatal iron-storage disease). Author(s): Leal-khouri S, Mallory SB, Downey JC. Source: Archives of Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8961885&query_hl=19&itool=pubmed_docsum

82

Hemochromatosis

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Juvenile and adult hemochromatosis are distinct genetic disorders. Author(s): Camaschella C, Roetto A, Cicilano M, Pasquero P, Bosio S, Gubetta L, Di Vito F, Girelli D, Totaro A, Carella M, Grifa A, Gasparini P. Source: European Journal of Human Genetics : Ejhg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9450181&query_hl=19&itool=pubmed_docsum

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Juvenile genetic hemochromatosis is clinically and genetically distinct from the classical HLA-related disorder. Author(s): Cazzola M, Cerani P, Rovati A, Iannone A, Claudiani G, Bergamaschi G. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9763590&query_hl=19&itool=pubmed_docsum

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Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes. Author(s): Pietrangelo A, Caleffi A, Henrion J, Ferrara F, Corradini E, Kulaksiz H, Stremmel W, Andreone P, Garuti C. Source: Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15685557&query_hl=19&itool=pubmed_docsum

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Juvenile hemochromatosis due to G320V/Q116X compound heterozygosity of hemojuvelin in an Irish patient. Author(s): Daraio F, Ryan E, Gleeson F, Roetto A, Crowe J, Camaschella C. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15967692&query_hl=19&itool=pubmed_docsum

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Juvenile hemochromatosis HJV-related revealed by cardiogenic shock. Author(s): Filali M, Le Jeunne C, Durand E, Grinda JM, Roetto A, Daraio F, Bruneval P, Jeunemaitre X, Gimenez-Roqueplo AP. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15315789&query_hl=19&itool=pubmed_docsum

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Juvenile hemochromatosis in a Spanish family. Author(s): Montes-Cano M, Gonzalez-Escribano MF, Aguilar J, Nunez-Roldan A. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12064925&query_hl=19&itool=pubmed_docsum

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Juvenile hemochromatosis in the southeastern United States: a report of seven cases in two kinships. Author(s): Barton JC, Rao SV, Pereira NM, Gelbart T, Beutler E, Rivers CA, Acton RT. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12482411&query_hl=19&itool=pubmed_docsum

Studies

83

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Juvenile hemochromatosis locus maps to chromosome 1q in a French Canadian population. Author(s): Rivard SR, Lanzara C, Grimard D, Carella M, Simard H, Ficarella R, Simard R, D'Adamo AP, Ferec C, Camaschella C, Mura C, Roetto A, De Braekeleer M, Bechner L, Gasparini P. Source: European Journal of Human Genetics : Ejhg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12891378&query_hl=19&itool=pubmed_docsum

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Juvenile hemochromatosis locus maps to chromosome 1q. Author(s): Roetto A, Totaro A, Cazzola M, Cicilano M, Bosio S, D'Ascola G, Carella M, Zelante L, Kelly AL, Cox TM, Gasparini P, Camaschella C. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10205270&query_hl=19&itool=pubmed_docsum

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Juvenile hemochromatosis. Author(s): Camaschella C, Roetto A, De Gobbi M. Source: Semin Hematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12382199&query_hl=19&itool=pubmed_docsum

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Kupffer cell iron overload induces intercellular adhesion molecule-1 expression on hepatocytes in genetic hemochromatosis. Author(s): Stal P, Broome U, Scheynius A, Befrits R, Hultcrantz R. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7737636&query_hl=19&itool=pubmed_docsum

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Lack of detection of novel nonsense mutations on exon 3 of hemochromatosis gene in patients with hepatic iron overload. Author(s): Rosa I, De Roux N, Pelletier G, Lazure T, Chousterman M, Buffet C. Source: Journal of Hepatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14672632&query_hl=19&itool=pubmed_docsum

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Left ventricular systolic function during stress echocardiography exercise in subjects with asymptomatic hereditary hemochromatosis. Author(s): Shizukuda Y, Bolan CD, Tripodi DJ, Yau YY, Smith KP, Sachdev V, Birdsall CW, Sidenko S, Waclawiw MA, Leitman SF, Rosing DR. Source: The American Journal of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16923464&query_hl=19&itool=pubmed_docsum

84

Hemochromatosis

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Letter regarding article by Ellervik et al, "hereditary hemochromatosis and risk of ischemic heart disease: a prospective study and a case-control study". Author(s): Goland S, Malnick SD. Source: Circulation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16391159&query_hl=19&itool=pubmed_docsum

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LightCycler PCR assay for simultaneous detection of the H63D and S65C mutations in the HFE hemochromatosis gene based on opposite melting temperature shifts. Author(s): Bollhalder M, Mura C, Landt O, Maly FE. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10585367&query_hl=19&itool=pubmed_docsum

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Liver and iron metabolism--a comprehensive hypothesis for the pathogenesis of genetic hemochromatosis. Author(s): Stremmel W, Karner M, Manzhalii E, Gilles W, Herrmann T, Merle U. Source: Zeitschrift Fur Gastroenterologie. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17236123&query_hl=19&itool=pubmed_docsum

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Liver cell damage and lysosomal iron storage in patients with idiopathic hemochromatosis. A light and electron microscopic study. Author(s): Stal P, Glaumann H, Hultcrantz R. Source: Journal of Hepatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2254628&query_hl=19&itool=pubmed_docsum

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Liver diseases in the hemochromatosis and iron overload screening study. Author(s): Adams PC, Passmore L, Chakrabarti S, Reboussin DM, Acton RT, Barton JC, McLaren GD, Eckfeldt JH, Dawkins FW, Gordeuk VR, Harris EL, Leiendecker-Foster C, Gossman E, Sholinsky P; Hemochromatosis and Iron Overload Screening Study Research Investigators. Source: Clin Gastroenterol Hepatol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16797244&query_hl=19&itool=pubmed_docsum

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Liver iron accumulation in patients with chronic active hepatitis C: prevalence and role of hemochromatosis gene mutations and relationship with hepatic histological lesions. Author(s): Hezode C, Cazeneuve C, Coue O, Roudot-Thoraval F, Lonjon I, Bastie A, Duvoux C, Pawlotsky JM, Zafrani ES, Amselem S, Dhumeaux D. Source: Journal of Hepatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10604569&query_hl=19&itool=pubmed_docsum

Studies

85

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Liver iron deposits in hepatitis B patients: association with severity of liver disease but not with hemochromatosis gene mutations. Author(s): Martinelli AL, Filho AB, Franco RF, Tavella MH, Ramalho LN, Zucoloto S, Rodrigues SS, Zago MA. Source: Journal of Gastroenterology and Hepatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15304122&query_hl=19&itool=pubmed_docsum

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Liver transplantation in idiopathic hemochromatosis. Author(s): Dietze O, Vogel W, Braunsperger B, Margreiter R. Source: Transplantation Proceedings. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2389384&query_hl=19&itool=pubmed_docsum

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Liver transplantation: an "in vivo" model for the pathophysiology of hemochromatosis? Author(s): Kowdley KV. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15185289&query_hl=19&itool=pubmed_docsum

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Magnetic resonance imaging in neonatal hemochromatosis--are we there yet? Author(s): Williams H, McKiernan P, Kelly D, Baumann U. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17058258&query_hl=19&itool=pubmed_docsum

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Magnetic resonance imaging of hemochromatosis arthropathy. Author(s): Eustace S, Buff B, McCarthy C, MacMathuana P, Gilligan P, Ennis JT. Source: Skeletal Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7824984&query_hl=19&itool=pubmed_docsum

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Mechanisms of disease: The role of hepcidin in iron homeostasis--implications for hemochromatosis and other disorders. Author(s): Pietrangelo A, Trautwein C. Source: Nat Clin Pract Gastroenterol Hepatol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16265043&query_hl=19&itool=pubmed_docsum

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Mixture models of serum iron measures in population screening for hemochromatosis and iron overload. Author(s): McLaren CE, Li KT, McLaren GD, Gordeuk VR, Snively BM, Reboussin DM, Barton JC, Acton RT, Dawkins FW, Harris EL, Eckfeldt JH, Moses GC, Adams PC. Source: Transl Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17002922&query_hl=19&itool=pubmed_docsum

86

Hemochromatosis

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Molecular and clinical aspects of iron homeostasis: From anemia to hemochromatosis. Author(s): Nairz M, Weiss G. Source: Wiener Klinische Wochenschrift. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16957974&query_hl=19&itool=pubmed_docsum

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MR findings of secondary hemochromatosis: transfusional vs erythropoietic. Author(s): Yoon DY, Choi BI, Han JK, Han MC, Park MO, Suh SJ. Source: Journal of Computer Assisted Tomography. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8188909&query_hl=19&itool=pubmed_docsum

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MR imaging of hepatocellular carcinoma arising in genetic hemochromatosis. Author(s): Lwakatare F, Hayashida Y, Yamashita Y. Source: Magn Reson Med Sci. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16210821&query_hl=19&itool=pubmed_docsum

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MR imaging of hepatosplenic candidiasis superimposed on hemochromatosis. Author(s): Cho JS, Kim EE, Varma DG, Wallace S. Source: Journal of Computer Assisted Tomography. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2398158&query_hl=19&itool=pubmed_docsum

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Multiple liver abscesses due to Yersinia enterocolitica discloses primary hemochromatosis: three cases reports and review. Author(s): Vadillo M, Corbella X, Pac V, Fernandez-Viladrich P, Pujol R. 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=8086556&query_hl=19&itool=pubmed_docsum

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Mutations in the hereditary hemochromatosis gene are not associated with the increased body iron stores observed in overweight and obese women with polycystic ovary syndrome. Author(s): Botella-Carretero JI, Luque-Ramirez M, Alvarez-Blasco F, San Millan JL, Escobar-Morreale HF. Source: Diabetes Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17065702&query_hl=19&itool=pubmed_docsum

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Neonatal hemochromatosis: fetal liver disease leading to liver failure in the fetus and newborn. Author(s): Whitington PF, Kelly S, Ekong UD. Source: Pediatric Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16176424&query_hl=19&itool=pubmed_docsum

Studies

87

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Neonatal hemochromatosis: is it an alloimmune disease? Author(s): Whitington PF, Malladi P. 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=15861012&query_hl=19&itool=pubmed_docsum

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Neonatal hemochromatosis: it's OK to say "NO" to antioxidant-chelator therapy. Author(s): Leonis MA, Balistreri WF. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16237698&query_hl=19&itool=pubmed_docsum

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Neonatal hemochromatosis: long-term experience with favorable outcome. Author(s): Grabhorn E, Richter A, Burdelski M, Rogiers X, Ganschow R. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17079579&query_hl=19&itool=pubmed_docsum

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Neonatal hemochromatosis: radiographical and histological signs. Author(s): Udell IW, Barshes NR, Voloyiannis T, Lee TC, Karpen SJ, Carter BA, Finegold M, Goss JA. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16035090&query_hl=19&itool=pubmed_docsum

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Neonatal hemochromatosis--medical treatment vs. transplantation: the king's experience. Author(s): Rodrigues F, Kallas M, Nash R, Cheeseman P, D'Antiga L, Rela M, Heaton ND, Mieli-Vergani G. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16237701&query_hl=19&itool=pubmed_docsum

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Neonatal hyperphenylalaninemia, perinatal hemochromatosis, and renal tubulopathy: a unique patient or a novel metabolic disorder? Author(s): Waters PJ, Khashu M, Lillquist Y, Senger C, Mattman A, Demos M, Setchell K, Rupar A, Scott P, Blau N, Vallance HD. Source: Molecular Genetics and Metabolism. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16182582&query_hl=19&itool=pubmed_docsum

88

Hemochromatosis

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No hepatic iron overload 12 years after liver transplantation for hereditary hemochromatosis. Author(s): Bralet MP, Duclos-Vallee JC, Castaing D, Samuel D, Guettier C. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15349921&query_hl=19&itool=pubmed_docsum

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Non-HFE hemochromatosis. Author(s): Pietrangelo A. Source: Seminars in Liver Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16315138&query_hl=19&itool=pubmed_docsum

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Non-HFE hemochromatosis. Author(s): Solis-Herruzo JA, Solis Munoz P. Source: Rev Esp Enferm Dig. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15982182&query_hl=19&itool=pubmed_docsum

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Occult celiac disease prevents penetrance of hemochromatosis. Author(s): Geier A, Gartung C, Theurl I, Weiss G, Lammert F, Dietrich CG, Weiskirchen R, Zoller H, Hermanns B, Matern S. Source: World Journal of Gastroenterology : Wjg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15929194&query_hl=19&itool=pubmed_docsum

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Old age and hemochromatosis. Author(s): Crosby WH. 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=1640590&query_hl=19&itool=pubmed_docsum

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Orthotopic liver transplantation for hemochromatosis. Author(s): Pillay P, Tzoracoleftherakis E, Tzakis AG, Kakizoe S, Van Thiel DH, Starzl TE. Source: Transplantation Proceedings. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2053185&query_hl=19&itool=pubmed_docsum

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Osteoporosis in hemochromatosis: iron excess, gonadal deficiency, or other factors? Author(s): Diamond T, Stiel D, Posen S. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2919850&query_hl=19&itool=pubmed_docsum

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Osteoporosis in HFE2 juvenile hemochromatosis. A case report and review of the literature. Author(s): Angelopoulos NG, Goula AK, Papanikolaou G, Tolis G. Source: Osteoporosis International : a Journal Established As Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the Usa. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15997423&query_hl=19&itool=pubmed_docsum

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Outcome of liver transplantation in patients with hemochromatosis. Author(s): Farrell FJ, Nguyen M, Woodley S, Imperial JC, Garcia-Kennedy R, Man K, Esquivel CO, Keeffe EB. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8045502&query_hl=19&itool=pubmed_docsum

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Overestimation of HFE C282Y homozygous hemochromatosis prevalence as the result of a common primer-binding site polymorphism. Author(s): Press RD. Source: Molecular Diagnosis : a Journal Devoted to the Understanding of Human Disease Through the Clinical Application of Molecular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10671650&query_hl=19&itool=pubmed_docsum

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Overexpression of hemochromatosis protein, HFE, alters transferrin recycling process in human hepatoma cells. Author(s): Ikuta K, Fujimoto Y, Suzuki Y, Tanaka K, Saito H, Ohhira M, Sasaki K, Kohgo Y. Source: Biochimica Et Biophysica Acta. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10771090&query_hl=19&itool=pubmed_docsum

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Overexpression of the hereditary hemochromatosis protein, HFE, in HeLa cells induces and iron-deficient phenotype. Author(s): Corsi B, Levi S, Cozzi A, Corti A, Altimare D, Albertini A, Arosio P. Source: Febs Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10571078&query_hl=19&itool=pubmed_docsum

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Overview of hemochromatosis. Author(s): Smith LH Jr. Source: The Western Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2219895&query_hl=19&itool=pubmed_docsum

90

Hemochromatosis

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Peripheral blood erythrocyte parameters in hemochromatosis: evidence for increased erythrocyte hemoglobin content. Author(s): Barton JC, Bertoli LF, Rothenberg BE. 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=10638700&query_hl=19&itool=pubmed_docsum

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Population-based study of the relationship between mutations in the hemochromatosis (HFE) gene and arthritis. Author(s): Sherrington CA, Knuiman MW, Divitini ML, Bartholomew HC, Cullen DJ, Olynyk JK. Source: Journal of Gastroenterology and Hepatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16638105&query_hl=19&itool=pubmed_docsum

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Possible roles of the hereditary hemochromatosis protein, HFE, in regulating cellular iron homeostasis. Author(s): Enns CA. Source: Biol Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16629171&query_hl=19&itool=pubmed_docsum

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Posterior subcapsular cataracts in a patient with hemochromatosis. Author(s): Minotty PV, Gordon JK. Source: Ann Ophthalmol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6847051&query_hl=19&itool=pubmed_docsum

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Precipitation of iron overload and hereditary hemochromatosis after successful treatment of celiac disease. Author(s): Heneghan MA, Feeley KM, Stevens FM, Little MP, McCarthy CF. Source: The American Journal of Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10638603&query_hl=19&itool=pubmed_docsum

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Predictors of belief that genetic test information about hemochromatosis should be shared with family members. Author(s): Tucker DC, Acton RT, Press N, Ruggiero A, Reiss JA, Walker AP, Wenzel L, Harrison B, Fadojutimi-Akinsiku M, Harrison H, Adams P, Crabb JA, Anderson R, Thomson E. Source: Genetic Testing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16545004&query_hl=19&itool=pubmed_docsum

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Prevalence of C282Y, H63D and S65C mutations of the hemochromatosis (HFE) gene in a population from southeastern Spain (Murcia Region). Author(s): Muro M, Moya-Quiles MR, Botella C, Alvarez-Lopez MR. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17204056&query_hl=19&itool=pubmed_docsum

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Prevalence of HFE (hemochromatosis gene) mutations in unselected male patients with type 2 diabetes. Author(s): Sampson MJ, Williams T, Heyburn PJ, Greenwood RH, Temple RC, Wimperis JZ, Jennings BA, Willis GA. 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=10695662&query_hl=19&itool=pubmed_docsum

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Primary osteoarthritis in the ankle joint is associated with finger metacarpophalangeal osteoarthritis and the H63D mutation in the HFE gene: evidence for a hemochromatosis-like polyarticular osteoarthritis phenotype. Author(s): Carroll GJ. Source: J Clin Rheumatol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16755236&query_hl=19&itool=pubmed_docsum

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Prognostic factors and survival in patients with hereditary hemochromatosis and cirrhosis. Author(s): Beaton MD, Adams PC. Source: Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16609753&query_hl=19&itool=pubmed_docsum

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Quantitative determination of 8-hydroxy-2'-deoxyguanosine in human urine by isotope dilution mass spectrometry: normal levels in hemochromatosis. Author(s): Holmberg I, Stal P, Hamberg M. Source: Free Radical Biology & Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9890648&query_hl=19&itool=pubmed_docsum

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Quantitative image analysis as an alternative to chemical analysis for follow-up of liver biopsies from a toucan with hemochromatosis. A technique with potential value for the follow-up of hemochromatosis in humans. Author(s): Roels S, Ducatelle R, Cornelissen H. Source: Anal Quant Cytol Histol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8790836&query_hl=19&itool=pubmed_docsum

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Recurrence of iron deposition in the cardiac allograft in a patient with non-HFE hemochromatosis. Author(s): Kuppahally SS, Hunt SA, Valantine HA, Berry GJ. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16399547&query_hl=19&itool=pubmed_docsum

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Relationships of serum ferritin, transferrin saturation, and HFE mutations and selfreported diabetes in the Hemochromatosis and Iron Overload Screening (HEIRS) study. Author(s): Acton RT, Barton JC, Passmore LV, Adams PC, Speechley MR, Dawkins FW, Sholinsky P, Reboussin DM, McLaren GD, Harris EL, Bent TC, Vogt TM, Castro O. Source: Diabetes Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16936157&query_hl=19&itool=pubmed_docsum

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Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Author(s): Drakesmith H, Schimanski LM, Ormerod E, Merryweather-Clarke AT, Viprakasit V, Edwards JP, Sweetland E, Bastin JM, Cowley D, Chinthammitr Y, Robson KJ, Townsend AR. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15831700&query_hl=19&itool=pubmed_docsum

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Restless legs syndrome in patients with hereditary hemochromatosis. Author(s): Shaughnessy P, Lee J, O'Keeffe ST. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15985601&query_hl=19&itool=pubmed_docsum

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Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Author(s): Falize L, Guillygomarc'h A, Perrin M, Laine F, Guyader D, Brissot P, Turlin B, Deugnier Y. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16871557&query_hl=19&itool=pubmed_docsum

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Reversible cardiomyopathy in a patient with juvenile hemochromatosis. Author(s): Blank R, Wolber T, Maeder M, Rickli H. Source: International Journal of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15992946&query_hl=19&itool=pubmed_docsum

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Revisiting hereditary hemochromatosis: current concepts and progress. Author(s): Yen AW, Fancher TL, Bowlus CL. Source: The American Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16651049&query_hl=19&itool=pubmed_docsum

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Role of hemochromatosis genes in chronic hepatitis C. Author(s): Gattoni A, Parlato A, Vangieri B, Bresciani M, Derna R, Baldassarre R. Source: Clin Ter. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16669553&query_hl=19&itool=pubmed_docsum

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Screening for hemochromatosis: recommendation statement. Author(s): U.S. Preventive Services Task Force. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16880462&query_hl=19&itool=pubmed_docsum

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Screening for hereditary hemochromatosis in siblings and children of affected patients. A cost-effectiveness analysis. Author(s): El-Serag HB, Inadomi JM, Kowdley KV. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10681280&query_hl=19&itool=pubmed_docsum

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Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Author(s): Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16880463&query_hl=19&itool=pubmed_docsum

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Searching for hereditary hemochromatosis. Author(s): Laudicina RJ. Source: Clin Lab Sci. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16910235&query_hl=19&itool=pubmed_docsum

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Secondary hypogonadism in hemochromatosis. Author(s): Meyer WR, Hutchinson-Williams KA, Jones EE, DeCherney AH. Source: Fertility and Sterility. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2209900&query_hl=19&itool=pubmed_docsum

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Serum iron and copper and their relations to hepatocellular carcinoma in porphyria cutanea tarda and hemochromatosis patients--case report. Author(s): Dabrowska E, Jablonska-Kaszewska I, Lukasiak J, Dorosz A, Falkiewicz B. Source: Biofactors (Oxford, England). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10705984&query_hl=19&itool=pubmed_docsum

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Serum non-transferrin-bound iron and low-density lipoprotein oxidation in heterozygous hemochromatosis. Author(s): van Tits LJ, Jacobs EM, Swinkels DW, Lemmers HL, van der Vleuten GM, de Graaf J, Stalenhoef AF. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16682004&query_hl=19&itool=pubmed_docsum

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Significance of left atrial contractile function in asymptomatic subjects with hereditary hemochromatosis. Author(s): Shizukuda Y, Bolan CD, Tripodi DJ, Yau YY, Nguyen TT, Botello G, Sachdev V, Sidenko S, Ernst I, Waclawiw MA, Leitman SF, Rosing DR. Source: The American Journal of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16996882&query_hl=19&itool=pubmed_docsum

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Southern blood club symposium: an update on selected aspects of hemochromatosis. Author(s): Edwards CQ, Griffen LM, Kushner JP. 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=2248278&query_hl=19&itool=pubmed_docsum

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Surgery for hepatocellular carcinoma arising in hereditary hemochromatosis. Author(s): Sotiropoulos GC, Molmenti EP, Lang H, Beckebaum S, Kaiser GM, Brokalaki EI, Frilling A, Malago M, Neuhauser M, Broelsch CE. Source: European Surgical Research. Europaische Chirurgische Forschung. Recherches Chirurgicales Europeennes. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16837807&query_hl=19&itool=pubmed_docsum

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The CD8+ T-lymphocyte profile as a modifier of iron overload in HFE hemochromatosis: an update of clinical and immunological data from 70 C282Y homozygous subjects. Author(s): Cruz E, Melo G, Lacerda R, Almeida S, Porto G. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16762569&query_hl=19&itool=pubmed_docsum

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The clinical relevance of compound heterozygosity for the C282Y and H63D substitutions in hemochromatosis. Author(s): Walsh A, Dixon JL, Ramm GA, Hewett DG, Lincoln DJ, Anderson GJ, Subramaniam VN, Dodemaide J, Cavanaugh JA, Bassett ML, Powell LW. Source: Clin Gastroenterol Hepatol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16979952&query_hl=19&itool=pubmed_docsum

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The effect of the metabolic syndrome, hepatic steatosis and steatohepatitis on liver fibrosis in hereditary hemochromatosis. Author(s): Adams LA, Angulo P, Abraham SC, Torgerson H, Brandhagen D. Source: Liver International : Official Journal of the International Association for the Study of the Liver. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16584391&query_hl=19&itool=pubmed_docsum

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The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor. Author(s): Lebron JA, West AP Jr, Bjorkman PJ. Source: Journal of Molecular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10556042&query_hl=19&itool=pubmed_docsum

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The hereditary hemochromatosis gene (HFE): a MHC class I-like gene that functions in the regulation of iron homeostasis. Author(s): Feder JN. Source: Immunologic Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10580641&query_hl=19&itool=pubmed_docsum

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The significance of the hemochromatosis genetic variants in multiple myeloma in comparison to that of myelodysplastic syndrome. Author(s): Varkonyi J, Demeter J, Tordai A, Andrikovics H. Source: Annals of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17001480&query_hl=19&itool=pubmed_docsum

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Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis. Author(s): Fleming RE, Migas MC, Holden CC, Waheed A, Britton RS, Tomatsu S, Bacon BR, Sly WS. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10681454&query_hl=19&itool=pubmed_docsum

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Tumor necrosis factor-alpha -308G>A allelic variant modulates iron accumulation in patients with hereditary hemochromatosis. Author(s): Krayenbuehl PA, Maly FE, Hersberger M, Wiesli P, Himmelmann A, Eid K, Greminger P, Vetter W, Schulthess G. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16793930&query_hl=19&itool=pubmed_docsum

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Tumour necrosis factor alpha and its promoter polymorphisms' role in the phenotypic expression of hemochromatosis. Author(s): Distante S, Elmberg M, Foss Haug KB, Ovstebo R, Berg JP, Kierulf P, Hultcrantz R, Bell H. Source: Scandinavian Journal of Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12940442&query_hl=19&itool=pubmed_docsum

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Two novel missense mutations of the HFE gene (I105T and G93R) and identification of the S65C mutation in Alabama hemochromatosis probands. Author(s): Barton JC, Sawada-Hirai R, Rothenberg BE, Acton RT. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10575540&query_hl=19&itool=pubmed_docsum

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UbcH5A, a member of human E2 ubiquitin-conjugating enzymes, is closely related to SFT, a stimulator of iron transport, and is up-regulated in hereditary hemochromatosis. Author(s): Gehrke SG, Riedel HD, Herrmann T, Hadaschik B, Bents K, Veltkamp C, Stremmel W. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12480712&query_hl=19&itool=pubmed_docsum

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Uncommon mutations and polymorphisms in the hemochromatosis gene. Author(s): Pointon JJ, Wallace D, Merryweather-Clarke AT, Robson KJ. Source: Genetic Testing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10953955&query_hl=19&itool=pubmed_docsum

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Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Author(s): Camaschella C. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16030190&query_hl=19&itool=pubmed_docsum

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Unique genetic profile of hereditary hemochromatosis in Russians: high frequency of C282Y mutation in population, but not in patients. Author(s): Potekhina ES, Lavrov AV, Samokhodskaya LM, Efimenko AY, Balatskiy AV, Baev AA, Litvinova MM, Nikitina LA, Shipulin GA, Bochkov NP, Tkachuk VA, Bochkov VN. Source: Blood Cells, Molecules & Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16055358&query_hl=19&itool=pubmed_docsum

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Unsaturated iron binding capacity and transferrin saturation are equally reliable in detection of HFE hemochromatosis. Author(s): Murtagh LJ, Whiley M, Wilson S, Tran H, Bassett ML. Source: The American Journal of Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12190182&query_hl=19&itool=pubmed_docsum

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Unsaturated iron-binding capacity: a screening test for C282Y hemochromatosis? Author(s): Adams PC, Bhayana V. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11067840&query_hl=19&itool=pubmed_docsum

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Update on hereditary hemochromatosis and the HFE gene. Author(s): Brandhagen DJ, Fairbanks VF, Batts KP, Thibodeau SN. Source: Mayo Clinic Proceedings. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10488796&query_hl=19&itool=pubmed_docsum

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Use of blood therapeutically drawn from hemochromatosis patients. Council on Scientific Affairs, American Medical Association. Author(s): Tan L, Khan MK, Hawk JC 3rd. Source: Transfusion. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10533830&query_hl=19&itool=pubmed_docsum

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Use of denaturing HPLC and a heteroduplex generator to detect the HFE C282Y mutation associated with genetic hemochromatosis. Author(s): Fruchon S, Bensaid M, Borot N, Roth MP, Coppin H. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12709380&query_hl=19&itool=pubmed_docsum

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Use of HFE mutation analysis for hereditary hemochromatosis: the need for physician education in the translation of basic science to clinical practice. Author(s): Kohli M, Schichman SA, Fink L, Zent CS. Source: Southern Medical Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10832943&query_hl=19&itool=pubmed_docsum

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Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Author(s): Bassett ML, Halliday JW, Powell LW. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3943787&query_hl=19&itool=pubmed_docsum

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Variation in the phenotypic expression of C282Y hemochromatosis in an Italian family. Author(s): Bosio S, Zecchina G, Cicilano M, Roetto A, Salto AM, Camaschella C. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10091421&query_hl=19&itool=pubmed_docsum

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Variations in serum erythropoietin and transferrin receptor during phlebotomy therapy of hereditary hemochromatosis: a case report. Author(s): Thorstensen K, Egeberg K, Romslo I, Dalhoj J, Wiggers P. Source: European Journal of Haematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1915805&query_hl=19&itool=pubmed_docsum

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Vibrio vulnificus septicemia in a patient with the hemochromatosis HFE C282Y mutation. Author(s): Gerhard GS, Levin KA, Price Goldstein J, Wojnar MM, Chorney MJ, Belchis DA. Source: Archives of Pathology & Laboratory Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11473471&query_hl=19&itool=pubmed_docsum

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Was Beethoven's cirrhosis due to hemochromatosis? Author(s): Davies PJ. Source: Renal Failure. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7770648&query_hl=19&itool=pubmed_docsum

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What's new in hemochromatosis. Author(s): Gochee PA, Powell LW. Source: Current Opinion in Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11224684&query_hl=19&itool=pubmed_docsum

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What's wrong with this patient? Hemochromatosis. Author(s): Mackenzie DL. Source: Rn. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9783003&query_hl=19&itool=pubmed_docsum

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When and how should we screen for hereditary hemochromatosis? Author(s): Chales G, Guggenbuhl P. Source: Joint, Bone, Spine : Revue Du Rhumatisme. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12951308&query_hl=19&itool=pubmed_docsum

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Where does the gene for hemochromatosis lie in relation to HLA-A? Author(s): Jazwinska EC, Halliday JW, Powell LW. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8138245&query_hl=19&itool=pubmed_docsum

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Why there is discordance in reported decision thresholds for transferrin saturation when screening for hereditary hemochromatosis. Author(s): McCullen MA, Crawford DH, Dimeski G, Tate J, Hickman PE. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11186869&query_hl=19&itool=pubmed_docsum

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Wild-type HFE protein normalizes transferrin iron accumulation in macrophages from subjects with hereditary hemochromatosis. Author(s): Montosi G, Paglia P, Garuti C, Guzman CA, Bastin JM, Colombo MP, Pietrangelo A. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10910932&query_hl=19&itool=pubmed_docsum

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Will the real hemochromatosis please stand up? Author(s): Franks AL, Burke W. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10383352&query_hl=19&itool=pubmed_docsum

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Yersinia enterocolitica infection with multiple liver abscesses uncovering a primary hemochromatosis. Author(s): Hopfner M, Nitsche R, Rohr A, Harms D, Schubert S, Folsch UR. Source: Scandinavian Journal of Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11252417&query_hl=19&itool=pubmed_docsum

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Yersinia enterocolitica liver abscesses unmasking idiopathic hemochromatosis. Author(s): Santoro MJ, Chen YK, Seid NS, Abdulian JD, Collen MJ. Source: Journal of Clinical Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8034933&query_hl=19&itool=pubmed_docsum

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Young female with hemochromatosis. Author(s): Sajeev CG, Jayakumar TG, Fassaludeen AS, Krishnan MN, Venugopal K. Source: International Journal of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14729443&query_hl=19&itool=pubmed_docsum

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CHAPTER 2. ALTERNATIVE MEDICINE AND HEMOCHROMATOSIS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to hemochromatosis. 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 hemochromatosis 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 hemochromatosis (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 hemochromatosis: •

A comparison of the effect of Fe-3-Specific, versenol, and calcium disodium versenate on urinary iron excretion in a patient with hemochromatosis. Author(s): MCMAHON FG. 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=13367597&query_hl=1&itool=pubmed_docsum

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Abnormal bile acid metabolism and neonatal hemochromatosis: a subset with poor prognosis. Author(s): Siafakas CG, Jonas MM, Perez-Atayde AR. 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=9285385&query_hl=1&itool=pubmed_docsum

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Cardiac involvement in secondary haemochromatosis: a catheter biopsy study and analysis of myocardium. Author(s): Fitchett DH, Coltart DJ, Littler WA, Leyland MJ, Trueman T, Gozzard DI, Peters TJ. Source: Cardiovascular Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7260965&query_hl=1&itool=pubmed_docsum

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Cloning, sequencing and characterization of the rat hereditary hemochromatosis promoter: comparison of the human, mouse and rat HFE promoter regions. Author(s): Sanchez M, Queralt R, Bruguera M, Rodes J, Oliva R. Source: Gene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9931446&query_hl=1&itool=pubmed_docsum

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Compound heterozygosity for haemochromatosis gene mutations and hepatic iron overload in allogeneic bone marrow transplant recipients. Author(s): Grigg AP, Bhathal PS. Source: Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11280607&query_hl=1&itool=pubmed_docsum

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Congenital dyserythropoietic anaemia type II (HEMPAS) and haemochromatosis: a report of two cases. Author(s): Hovinga JA, Solenthaler M, Dufour JF. Source: European Journal of Gastroenterology & Hepatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14501626&query_hl=1&itool=pubmed_docsum

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Current approaches to the management of hemochromatosis. Author(s): Brissot P, de Bels F. Source: Hematology Am Soc Hematol Educ Program. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17124037&query_hl=1&itool=pubmed_docsum

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Current concepts in rational therapy for haemochromatosis. Author(s): Crawford DH, Halliday JW. Source: Drugs. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1715264&query_hl=1&itool=pubmed_docsum

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Diabetic ketoacidosis and hypogonadotropic hypogonadism in association with transfusional hemochromatosis in a man with beta-thalassemia major. Author(s): Lu JY, Chang CC, Tsai HC, Lin KS, Tsang YM, Huang KM. Source: J Formos Med Assoc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11579617&query_hl=1&itool=pubmed_docsum

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Ethylenediaminetetraacetic acid in the mobilization and removal of iron in a case of hemochromatosis. Author(s): WISHINSKY H, WEINBERG T, PREVOST EM, BURGIN B, MILLER MJ. 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=13096894&query_hl=1&itool=pubmed_docsum

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Evidence and mechanism for pectin-reduced intestinal inorganic iron absorption in idiopathic hemochromatosis. Author(s): Monnier L, Colette C, Aguirre L, Mirouze J. 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=6247906&query_hl=1&itool=pubmed_docsum

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Genetic hemochromatosis: pathogenesis, diagnosis, and therapy. Author(s): Barisani D, Green RM, Gollan JL. Source: Digestive Diseases (Basel, Switzerland). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8902416&query_hl=1&itool=pubmed_docsum

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Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy. Author(s): Kallianpur AR, Hulgan T, Canter JA, Ritchie MD, Haines JL, Robbins GK, Shafer RW, Clifford DB, Haas DW. Source: Aids (London, England). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16847405&query_hl=1&itool=pubmed_docsum

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Hemochromatosis and alcoholic liver disease. Author(s): Fletcher LM, Powell LW. Source: Alcohol (Fayetteville, N.Y.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12957297&query_hl=1&itool=pubmed_docsum

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Hemochromatosis and dietary iron supplementation: implications from US mortality, morbidity, and health survey data. Author(s): Gable CB. 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=1737903&query_hl=1&itool=pubmed_docsum

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Hemochromatosis and vitamin C. Author(s): Herbert V. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10498572&query_hl=1&itool=pubmed_docsum

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Hemochromatosis presenting as acute liver failure after iron supplementation. Author(s): Perez Roldan F, Amigo Echenagusia A, Gonzalez Carro P. 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=9687253&query_hl=1&itool=pubmed_docsum

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Hemochromatosis. Early intervention can arrest iron overload. Author(s): Beare J. Source: Adv Nurse Pract. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12400365&query_hl=1&itool=pubmed_docsum

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Hereditary hemochromatosis: recent advances in molecular genetics and clinical management. Author(s): Camaschella C, Piperno A. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9107091&query_hl=1&itool=pubmed_docsum

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Hereditary hemochromatosis: screening and management. Author(s): Waalen J, Beutler E. Source: Curr Hematol Rep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16537044&query_hl=1&itool=pubmed_docsum

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Hyperpigmentation and secondary hemochromatosis: a novel treatment with extracorporeal chelation. Author(s): Held JL, Yankiver B, Kohn SR. Source: Journal of the American Academy of Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8432923&query_hl=1&itool=pubmed_docsum

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Idiopathic haemochromatosis and eye symptoms. A case report. Author(s): Hoisen H, Kopstad G, Elsas T, Ringvold A, Tvedt KE, Odegaard A. Source: Acta Ophthalmol (Copenh). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3923775&query_hl=1&itool=pubmed_docsum

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Juvenile hemochromatosis associated with B-thalassemia treated by phlebotomy and recombinant human erythropoietin. Author(s): De Gobbi M, Pasquero P, Brunello F, Paccotti P, Mazza U, Camaschella C. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10942934&query_hl=1&itool=pubmed_docsum

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Lack of clinical manifestation of hereditary haemochromatosis in South African patients with multiple sclerosis.

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Author(s): Kotze MJ, de Villiers JN, Warnich L, Schmidt S, Carr J, Mansvelt E, Fourie E, van Rensburg SJ. Source: Metabolic Brain Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16850257&query_hl=1&itool=pubmed_docsum •

Liver transplantation for hereditary hemochromatosis. Author(s): Poulos JE, Bacon BR. Source: Digestive Diseases (Basel, Switzerland). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8902417&query_hl=1&itool=pubmed_docsum

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Reversal of cardiac complications by deferiprone and deferoxamine combination therapy in a patient affected by a severe type of juvenile hemochromatosis (JH). Author(s): Fabio G, Minonzio F, Delbini P, Bianchi A, Cappellini MD. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16960153&query_hl=1&itool=pubmed_docsum

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Reversibility of hypogonadotropic hypogonadism in a patient with the juvenile form of hemochromatosis. Author(s): Angelopoulos NG, Goula A, Dimitriou E, Tolis G. Source: Fertility and Sterility. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16359978&query_hl=1&itool=pubmed_docsum

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The haemochromatosis mutations do not modify the clinical picture of thalassaemia major in patients regularly transfused and chelated. Author(s): Borgna-Pignatti C, Solinas A, Bombieri C, Micciolo R, Gamberini MR, De Stefano P, De Menis E, Pignatti PF. Source: British Journal of Haematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9858237&query_hl=1&itool=pubmed_docsum

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The influence of hemochromatosis mutations on iron overload of thalassemia major. Author(s): Longo F, Zecchina G, Sbaiz L, Fischer R, Piga A, Camaschella C. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10477452&query_hl=1&itool=pubmed_docsum

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The irony of herbal hepatitis: Ma-Huang-induced hepatotoxicity associated with compound heterozygosity for hereditary hemochromatosis. Author(s): Bajaj J, Knox JF, Komorowski R, Saeian K. Source: Digestive Diseases and Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14627335&query_hl=1&itool=pubmed_docsum

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The new chelating agent ca-dtpa in the treatment of primary haemochromatosis. Author(s): KEMBLE JV. Source: Guys Hosp Rep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14114732&query_hl=1&itool=pubmed_docsum

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Turner's syndrome and hypogonadotrophic hypogonadism: thalassemia major and hemochromatosis. Author(s): Afonso Lopes L, Benador D, Wacker P, Wyss M, Sizonenko PC. Source: J Pediatr Endocrinol Metab. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7584702&query_hl=1&itool=pubmed_docsum

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Type 3 hemochromatosis and beta-thalassemia trait. Author(s): Riva A, Mariani R, Bovo G, Pelucchi S, Arosio C, Salvioni A, Vergani A, Piperno A. Source: European Journal of Haematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15059075&query_hl=1&itool=pubmed_docsum

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Wilson's disease and hemochromatosis. Author(s): Neimark E, Schilsky ML, Shneider BL. Source: Adolesc Med Clin. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15272264&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 hemochromatosis; 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 Iron-Deficiency Anemia Source: Healthnotes, Inc.; www.healthnotes.com Liver Cirrhosis Source: Healthnotes, Inc.; www.healthnotes.com Osteoarthritis Source: Integrative Medicine Communications; www.drkoop.com

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Herbs and Supplements Green Tea Alternative names: Camellia sinensis Source: Healthnotes, Inc.; www.healthnotes.com Liver Extracts 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 HEMOCHROMATOSIS 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.11 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 “hemochromatosis“ (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on hemochromatosis, we have not necessarily excluded non-medical patents in this bibliography.

Patent Applications on Hemochromatosis As of December 2000, U.S. patent applications are open to public viewing.12 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 hemochromatosis:

11Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm. 12 This has been a common practice outside the United States prior to December 2000.

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Diagnostics and therapeutics for autosomal dominant hemochromatosis Inventor(s): Duijn, Cock M. van; (Rotterdam, NL), Heutink, Peter; (Rotterdam, NL), Oostra, Ben A.; (Rotterdam, NL) Correspondence: Nath & Associates; 1030 15th Street; 6th Floor; Washington; DC; 20005; US Patent Application Number: 20030082553 Date filed: October 10, 2001 Abstract: This invention relates generally to the gene, and mutations, that are responsible for the disease hemochromatosis (HH). In particular, the present invention provides for the presence of one or more mutations on the ferroportin 1 (SLC11A3) gene which results in aberrant SLC11A3 mediated iron transport. The invention also relates to methods for diagnostic tools, drugs and therapies developed for the treatment of patients with HH or anemia. Excerpt(s): The present invention relates generally to the gene, and mutations, that are responsible for the disease hemochromatosis (MIM604653). In particular, the present invention provides for the presence of one or more mutations on the SLC11A3 gene which results in aberrant SLC11A3 mediated iron transport. The invention also relates to methods for screening for HH and to HH diagnosis, prenatal screening and diagnosis, and therapies of HH disease, including gene therapeutics, protein and antibody based therapeutics, and small molecule therapeutics. The invention further relates to drugs and therapies developed for the treatment of patients with HH or anemia. Over the years, several known genes involved in iron metabolism have been implicated in the pathology of HH. However, not all instances of HH patients can be explained by mutations in these genes. In particular, it is known that approximately 60-85% of all instances of HH in adult patients are indicated by homozygosity for the C282Y mutation in the HLA-H/HFE gene on Chromosome 6p. Compound heterozygosity accounts for an additional 10% of cases. It is also known that a form of juvenile hemochromatosis maps to chromosome 1q and that a single family was found with a mutation in a transferrin receptor gene (TFR2) on chromosome 7q. However, the remaining 5-15% of patients indicated with HH do not possess any mutations on the known genes. For example, Kato et al., describe a heterzygous A49T mutation in the 5_UTR of the Hsubunit of ferritin without specifically delineating the contributions of this gene to the HH disease state (Am. J. Human Genetics 69: 191-7 (2001)). Clearly, neither the precise physiological mechanism of iron overaccumulation nor every gene which is defective in this disease has been described. Hemochromatosis is an inherited disorder of iron metabolism wherein the body accumulates excess iron. In symptomatic individuals, excess iron is deposited in a variety of organs which leads to organ failure. Disease states such as cirrhosis, diabetes, sterility, and other serious illnesses occur as a result. It has also been discovered that HH can be inherited by a dominant or pseudo-dominant mode of inheritance. Heretofore, HH was believed to be inherited solely as a recessive trait. In particular, the prior art limits HH to patients having homozygotes carrying two defective copies of the gene. 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 hemochromatosis, 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 hemochromatosis (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 hemochromatosis. You can also use this procedure to view pending patent applications concerning hemochromatosis. 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 HEMOCHROMATOSIS Overview This chapter provides bibliographic book references relating to hemochromatosis. 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 hemochromatosis. 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 hemochromatosis at online booksellers’ Web sites, you may discover non-medical books that use the generic term “hemochromatosis” (or a synonym) in their titles. The following is indicative of the results you might find when searching for hemochromatosis (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

21st Century Complete Medical Guide to Hemochromatosis, Authoritative Government Documents, Clinical References, and Practical Information for Patients and Physicians PM Medical Health News (2004); ISBN: 1592487890; http://www.amazon.com/exec/obidos/ASIN/1592487890/icongroupinterna

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Discarded blood could be put to good use, say experts. (blood from patients with hemochromatosis could have therapeutic use): An article from: Medical Update Edwin W. Brown (2005); ISBN: B00097SG32; http://www.amazon.com/exec/obidos/ASIN/B00097SG32/icongroupinterna

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Gale Encyclopedia of Medicine: Hemochromatosis CGC Michelle Q. Bosworth MS (2004); ISBN: B00075UYP4; http://www.amazon.com/exec/obidos/ASIN/B00075UYP4/icongroupinterna

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Hemochromatosis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References ICON Health Publications (2004); ISBN: 059784450X; http://www.amazon.com/exec/obidos/ASIN/059784450X/icongroupinterna

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Hemochromatosis (SuDoc HE 20.3302:H 37/6) U.S. Dept of Health and Human Services (2000); ISBN: B00011308C; http://www.amazon.com/exec/obidos/ASIN/B00011308C/icongroupinterna

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Hemochromatosis and chronic poisoning with copper, (Mellon lecture) Frank Burr Mallory (1926); ISBN: B00085IWK2; http://www.amazon.com/exec/obidos/ASIN/B00085IWK2/icongroupinterna

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Hemochromatosis and hemosiderosis Richard Annis MacDonald (1964); ISBN: B0007F3UO6; http://www.amazon.com/exec/obidos/ASIN/B0007F3UO6/icongroupinterna

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Hemochromatosis Gene Variants in Three Different Ethnic Populations: Effects of Admixture for Screening Programs.: An article from: Human Biology Alexandre C. Pereira, Gloria F. A. Mota, and Jose E. Krieger (2005); ISBN: B0008HX048; http://www.amazon.com/exec/obidos/ASIN/B0008HX048/icongroupinterna

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Hemochromatosis perfect for genetic screening. (Common Condition, Easy Intervention).: An article from: Pediatric News Nancy Walsh (2005); ISBN: B0008ILIJG; http://www.amazon.com/exec/obidos/ASIN/B0008ILIJG/icongroupinterna

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Hereditary hemochromatosis.(Cover Story) : An article from: Medical Laboratory Observer Julie A. Meeker and Sharon M. Miller (2005); ISBN: B000CCVVIQ; http://www.amazon.com/exec/obidos/ASIN/B000CCVVIQ/icongroupinterna

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Living with Hemochromatosis Gregory T Md, Facp Everson and Marilyn Olsen (2003); ISBN: 157826104X; http://www.amazon.com/exec/obidos/ASIN/157826104X/icongroupinterna

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Routine Hemochromatosis Screening Is Premature.(Brief Article): An article from: Family Practice News Timothy F. Kirn (2005); ISBN: B0008H8P66; http://www.amazon.com/exec/obidos/ASIN/B0008H8P66/icongroupinterna

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Test all PCT patients for hereditary hemochromatosis. (Porphyria Cutanea Tarda).: An article from: Skin & Allergy News (2005); ISBN: B0008FRN8O; http://www.amazon.com/exec/obidos/ASIN/B0008FRN8O/icongroupinterna

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The Bronze Killer: The Story of a Family's Fight Against a Very Common Enemy Hemochromatosis Marie Warder (1989); ISBN: 0889258856; http://www.amazon.com/exec/obidos/ASIN/0889258856/icongroupinterna

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The Iron Disorders Institute Guide to Hemochromatosis P.D., M.D. Phatak, E.D., Ph.D. Weinberg, Wylie, Ph.D., M.D. Burke, and Iron Disorders Institute (2001); ISBN: 1581821603; http://www.amazon.com/exec/obidos/ASIN/1581821603/icongroupinterna

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The Official Patient's Sourcebook on Hemochromatosis James N. Parker and Philip M. Parker (2002); ISBN: 0597832196; http://www.amazon.com/exec/obidos/ASIN/0597832196/icongroupinterna

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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 hemochromatosis (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 by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine13: •

Cost-effective hemochromatosis screening in primary care: abstract, executive summary and final report Author: Phatak, Pradyumna D.; Year: 1998; Rockville, Md.: Agency for Health Care Policy and Research], 1998

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Hemochromatosis: genetics, pathophysiology, diagnosis and treatment Author: Barton, James C.; Year: 2000; Cambridge: Cambridge University Press, 2000; ISBN: 9780521593 http://www.amazon.com/exec/obidos/ASIN/9780521593/icongroupinterna

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Hemochromatosis: proceedings of the first international conference Author: Weintraub, Lewis R.; Year: 1988; New York, N.Y.: New York Academy of Sciences, 1988; ISBN: 9780897664 http://www.amazon.com/exec/obidos/ASIN/9780897664/icongroupinterna

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Hemochromatosis and hemosiderosis. Author: MacDonald, Richard Annis,; Year: 1964; Springfield, Ill., Thomas [c1964]

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Hereditary haemochromatosis Author: Campbell, Ken,; Year: 1999; London: NT Books, c1999; ISBN: 9781902499 http://www.amazon.com/exec/obidos/ASIN/9781902499/icongroupinterna

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Hypochromic iron loading anemia with secondary hemochromatosis. Author: Byrd, Richard Bourne,; Year: 1960; Minneapolis] 1960

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Prevention and control of hemochromatosis: improved diagnosis: report of a joint WHO; Year: 1998; Geneva?]: World Health Organization, Human Genetics Programme, Division of Noncommunicable Diseases, c1998

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The area postrema; a contribution to its normal and pathological anatomy, especially in haemochromatosis. Author: Cammermeyer, Jan,; Year: 1945; Oslo, Dybwad, 1945

13

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. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

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CHAPTER 5. MULTIMEDIA ON HEMOCHROMATOSIS Overview In this chapter, we show you how to find bibliographic information related to multimedia sources of information on hemochromatosis.

Bibliography: Multimedia on Hemochromatosis 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 hemochromatosis (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 hemochromatosis: •

Demystifying medicine, iron and disease, hemochromatosis [electronic resource] Source: Susan Leitman. Metabolism regulation / Tracey Rouault; Year: 2004; Format: Electronic resource; Bethesda, Md.: National Institutes of Health, 2004]

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Pathogenesis and management of hemochromatosis [motion picture] Source: a National Medical Audiovisual Center production; Year: 1969; Format: Motion picture; Washington, D.C.]: U.S. Dept. of Health, Education, and Welfare, Public Health Service, 1969

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APPENDICES

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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.14

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.

14 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.

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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.15 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 15

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.

•

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.

•

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.

•

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.

•

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.

•

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.

•

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

•

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.

•

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

•

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.

•

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.

•

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/.

•

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.

•

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.

•

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.

•

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.

•

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.

•

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.

•

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.

•

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 Institute16: •

National Institutes of Health (NIH); guidelines consolidated across agencies available at http://health.nih.gov/

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

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

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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancertopics/pdq

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

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

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

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

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

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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/

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

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

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

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

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

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

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

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

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

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National Institute of Biomedical Imaging and Bioengineering; general information at http://www.nibib.nih.gov/HealthEdu

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

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

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

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

NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.17 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

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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 Medicine18: •

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

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

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

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

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

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

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

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

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

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

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

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

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

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See http://www.nlm.nih.gov/databases/index.html.

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The NLM Gateway19 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.20 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type hemochromatosis (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 7134 58 51 5 0 7248

HSTAT21 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.22 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.23 Simply search by hemochromatosis (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists24 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. 19

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

20

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). 21 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 22 23

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. 24 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.25 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.26 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/.

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Medical Matrix: Lists over 6000 medical Web sites and links to over 1.5 million documents with clinical content, see http://www.medmatrix.org/.

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Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

25

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. 26 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 hemochromatosis 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 hemochromatosis. 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 hemochromatosis. 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 hemochromatosis:

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Anemia http://www.nlm.nih.gov/medlineplus/anemia.html Bile Duct Diseases http://www.nlm.nih.gov/medlineplus/bileductdiseases.html Bleeding Disorders http://www.nlm.nih.gov/medlineplus/bleedingdisorders.html Cirrhosis http://www.nlm.nih.gov/medlineplus/cirrhosis.html Genetic Testing http://www.nlm.nih.gov/medlineplus/genetictesting.html Heart Diseases http://www.nlm.nih.gov/medlineplus/heartdiseases.html Hemochromatosis http://www.nlm.nih.gov/medlineplus/hemochromatosis.html Hormones http://www.nlm.nih.gov/medlineplus/hormones.html Laboratory Tests http://www.nlm.nih.gov/medlineplus/laboratorytests.html Metabolic Disorders http://www.nlm.nih.gov/medlineplus/metabolicdisorders.html Pituitary Disorders http://www.nlm.nih.gov/medlineplus/pituitarydisorders.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.

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The National Guideline Clearinghouse™ The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword hemochromatosis (or synonyms). The following was recently posted: •

Screening for hemochromatosis: recommendation statement Source: United States Preventive Services Task Force - Independent Expert Panel; 2006; 5 pages http://www.guideline.gov/summary/summary.aspx?doc_id=9230&nbr=004959& amp;string=Haemochromatosis

•

Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians Source: American College of Physicians - Medical Specialty Society; 2005; 5 pages http://www.guideline.gov/summary/summary.aspx?doc_id=8147&nbr=004540& amp;string=Hemochromatoses 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: •

Amyloidosis Support Network Source: www.amyloidosis.org http://www.amyloidosis.org/faqs.asp

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Digestive Diseases AZ List of Topics and Titles Source: digestive.niddk.nih.gov http://digestive.niddk.nih.gov/ddiseases/a-z.asp

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FAQ's ABOUT HEMOCHROMATOSIS/IRON OVERLOAD Source: www.americanhs.org http://www.americanhs.org/faq.htm

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FCIC: Preventing Food-Borne Illness Source: www.pueblo.gsa.gov http://www.pueblo.gsa.gov/cic_text/food/unwelcome-dinner/dinguest.html

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Hemochromatosis (he-mo-kro-ma-toe-sis): What Is It? Source: www.americanhs.org http://www.americanhs.org/whatisit.htm

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Hemochromatosis and Anemia - Diet for Anemia and Iron Overload. Source: www.ironoverload.org http://www.ironoverload.org/Diet.html

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Hemochromatosis Fact Sheet: Health Information on Excess Iron and. Source: www.ironoverload.org http://www.ironoverload.org/facts.html

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Iron Disorders Institute - About Iron Source: www.irondisorders.org http://www.irondisorders.org/Disorders/about.asp

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Iron Disorders Institute - Hemochromatosis Source: www.irondisorders.org http://www.irondisorders.org/Disorders/Hemochromatosis.asp

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Iron Disorders Institute - Juvenile Hemochromatosis Source: www.irondisorders.org http://www.irondisorders.org/Disorders/JHemochromatosis.asp

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MedlinePlus: Hemochromatosis Source: www.nlm.nih.gov http://www.nlm.nih.gov/medlineplus/hemochromatosis.html

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NORD - National Organization for Rare Disorders, Inc. Source: www.rarediseases.org http://www.rarediseases.org/search/rdblist.html?query_start=501

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Objections and Dangers of Genetics Testing for Hemochromatosis Source: www.ironoverload.org http://www.ironoverload.org/objgen.html

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Publications: Recent Manuscripts, October 2002 – September 2003. Source: www.cdc.gov http://www.cdc.gov/nccdphp/dnpa/publications/manuscripts/research_2003.htm

•

Publications: Recent Manuscripts, October 2003 – September 2004. Source: www.cdc.gov http://www.cdc.gov/nccdphp/dnpa/publications/manuscripts/research_2004.htm

•

What is Hemochromatosis? - American Diabetes Association Source: www.diabetes.org http://www.diabetes.org/type-1-diabetes/hemochromatosis.jsp 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 hemochromatosis. 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 hemochromatosis (or synonyms) into the search box, and click Search. 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

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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 hemochromatosis. By consulting all of associations

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listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with hemochromatosis. 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 hemochromatosis. 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 hemochromatosis (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. 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 hemochromatosis (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 families27: •

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/

27

Adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/ghr/resource/patients.

Patient Resources

•

March of Dimes: http://www.marchofdimes.com

•

National Organization for Rare Disorders (NORD): http://www.rarediseases.org/

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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

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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

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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 hemochromatosis: •

Basic Guidelines for Hemochromatosis Alcoholism Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000944.htm Hemochromatosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000327.htm

•

Signs & Symptoms for Hemochromatosis Abdominal pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003120.htm Amenorrhea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003149.htm Edema Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003103.htm

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Enlarged liver Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003275.htm Enlarged spleen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003276.htm Fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Gynecomastia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003165.htm Hepatomegaly Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003275.htm Joint pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003261.htm Liver enlargement Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003275.htm Peripheral edema Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003104.htm Splenomegaly Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003276.htm Weakness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003174.htm Weight loss Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003107.htm •

Diagnostics and Tests for Hemochromatosis ALP Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003470.htm ALT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003473.htm AST Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003472.htm Biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003416.htm CAT scan Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm

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ECG Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003868.htm Echocardiogram Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm Ferritin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003490.htm FSH Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003710.htm Glucose tolerance test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003466.htm Liver biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003895.htm Liver function tests Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003436.htm MRI Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm Oral glucose tolerance test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003466.htm Serum ferritin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003490.htm Serum iron Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003488.htm SGOT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003472.htm Testosterone Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003707.htm TIBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003489.htm Ultrasound Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003336.htm •

Background Topics for Hemochromatosis Autosomal recessive Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002052.htm Endocrine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002351.htm

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Incidence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002387.htm Metabolism Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002257.htm Physical examination Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002274.htm Skin pigment Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002256.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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HEMOCHROMATOSIS 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] Aberrant: Wandering or deviating from the usual or normal course. [EU] 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] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Acquired Immunodeficiency Syndrome: An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive Tlymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993. [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] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Triphosphate: Adenosine 5'-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [NIH] Adolescence: The period of life beginning with the appearance of secondary sex

Dictionary 171

characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Aflatoxins: A group of closely related toxic metabolites that are designated mycotoxins. They are produced by Aspergillus flavus and A. parasiticus. Members of the group include aflatoxin B1, aflatoxin B2, aflatoxin G1, aflatoxin G2, aflatoxin M1, and aflatoxin M2. [NIH] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [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] 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] Allogeneic bone marrow transplantation: A procedure in which a person receives stem cells, the cells from which all blood cells develop, from a compatible, though not genetically identical, donor. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [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,

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magnet therapy, spiritual healing, and meditation. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] 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] Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anaemia: A reduction below normal in the number of erythrocytes per cu. mm., in the quantity of haemoglobin, or in the volume of packed red cells per 100 ml. of blood which occurs when the equilibrium between blood loss (through bleeding or destruction) and blood production is disturbed. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] 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] 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] Anginal: Pertaining to or characteristic of angina. [EU] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or

Dictionary 173

positive pole during electrolysis. [NIH] Ankle: That part of the lower limb directly above the foot. [NIH] Ankle Joint: The joint that is formed by the inferior articular and malleolar articular surfaces of the tibia, the malleolar articular surface of the fibula, and the medial malleolar, lateral malleolar, and superior surfaces of the talus. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anovulation: Suspension or cessation of ovulation in animals and humans. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] 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-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] 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] Antiserum: The blood serum obtained from an animal after it has been immunized with a particular antigen. It will contain antibodies which are specific for that antigen as well as antibodies specific for any other antigen with which the animal has previously been immunized. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH]

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Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] 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] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Arthropathy: Any joint disease. [EU] Articular: Of or pertaining to a joint. [EU] Aseptic: Free from infection or septic material; sterile. [EU] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atrial: Pertaining to an atrium. [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] Attenuated: Strain with weakened or reduced virulence. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous

Dictionary 175

systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Backcross: A cross between a hybrid and either one of its parents. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] Beta-Thalassemia: A disorder characterized by reduced synthesis of the beta chains of hemoglobin. There is retardation of hemoglobin A synthesis in the heterozygous form (thalassemia minor), which is asymptomatic, while in the homozygous form (thalassemia major, Cooley's anemia, Mediterranean anemia, erythroblastic anemia), which can result in severe complications and even death, hemoglobin A synthesis is absent. [NIH] Bewilderment: Impairment or loss of will power. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving

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chemical reactions in living organisms. [EU] Biochemical reactions: In living cells, chemical reactions that help sustain life and allow cells to grow. [NIH] Bioengineering: The application of engineering principles to the solution of biological problems, for example, remote-handling devices, life-support systems, controls, and displays. [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] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] 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 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 pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood Volume: Volume of circulating blood. It is the sum of the plasma volume and erythrocyte volume. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blotting and transferred to strips of nitrocellulose paper. The blots are then detected by radiolabeled antibody probes. [NIH] Body Fluids: Liquid components of living organisms. [NIH]

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Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [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 Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bone metastases: Cancer that has spread from the original (primary) tumor to the bone. [NIH]

Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] 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] Candidiasis: Infection with a fungus of the genus Candida. It is usually a superficial infection of the moist cutaneous areas of the body, and is generally caused by C. albicans; it most commonly involves the skin (dermatocandidiasis), oral mucous membranes (thrush, def. 1), respiratory tract (bronchocandidiasis), and vagina (vaginitis). Rarely there is a systemic infection or endocarditis. Called also moniliasis, candidosis, oidiomycosis, and formerly blastodendriosis. [EU] Candidosis: An infection caused by an opportunistic yeasts that tends to proliferate and become pathologic when the environment is favorable and the host resistance is weakened. [NIH]

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

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genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiogenic: Originating in the heart; caused by abnormal function of the heart. [EU] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] 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] Case-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Cataracts: In medicine, an opacity of the crystalline lens of the eye obstructing partially or totally its transmission of light. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH] Cathode: An electrode, usually an incandescent filament of tungsten, which emits electrons in an X-ray tube. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Caveolae: Endocytic/exocytic cell membrane structures rich in glycosphingolipids, cholesterol, and lipid-anchored membrane proteins that function in endocytosis (potocytosis), transcytosis, and signal transduction. Caveolae assume various shapes from open pits to closed vesicles. Caveolar coats are composed of caveolins. [NIH] Caveolins: The main structural proteins of caveolae. Several distinct genes for caveolins have been identified. [NIH] Celiac Disease: A disease characterized by intestinal malabsorption and precipitated by gluten-containing foods. The intestinal mucosa shows loss of villous structure. [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]

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Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Membrane Structures: Structures which are part of the cell membrane or have cell membrane as a major part of their structure. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell 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] Cellular metabolism: The sum of all chemical changes that take place in a cell through which energy and basic components are provided for essential processes, including the synthesis of new molecules and the breakdown and removal of others. [NIH] Cellulitis: An acute, diffuse, and suppurative inflammation of loose connective tissue, particularly the deep subcutaneous tissues, and sometimes muscle, which is most commonly seen as a result of infection of a wound, ulcer, or other skin lesions. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centromere: The clear constricted portion of the chromosome at which the chromatids are joined and by which the chromosome is attached to the spindle during cell division. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellar Diseases: Diseases that affect the structure or function of the cerebellum. Cardinal manifestations of cerebellar dysfunction include dysmetria, gait ataxia, and muscle hypotonia. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH]

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Chelating Agents: Organic chemicals that form two or more coordination bonds with a central metal ion. Heterocyclic rings are formed with the central metal atom as part of the ring. Some biological systems form metal chelates, e.g., the iron-binding porphyrin group of hemoglobin and the magnesium-binding chlorophyll of plants. (From Hawley's Condensed Chemical Dictionary, 12th ed) They are used chemically to remove ions from solutions, medicinally against microorganisms, to treat metal poisoning, and in chemotherapy protocols. [NIH] Chelation: Combination with a metal in complexes in which the metal is part of a ring. [EU] Chemotherapy: Treatment with anticancer drugs. [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] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [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] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] 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] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clathrin: The main structural coat protein of coated vesicles which play a key role in the intracellular transport between membranous organelles. Clathrin also interacts with cytoskeletal proteins. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] 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]

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Coated Vesicles: Vesicles formed when cell-membrane coated pits invaginate and pinch off. The outer surface of these vesicles are covered with a lattice-like network of coat proteins, such as clathrin, coat protein complex proteins, or caveolins. [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] 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] Colitis: Inflammation of the colon. [NIH] 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] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU]

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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] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] 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] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [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] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH]

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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 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] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Crystallization: The formation of crystals; conversion to a crystalline form. [EU] Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] 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] 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, . 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] Cytochrome b: Cytochromes (electron-transporting proteins) with protoheme or a related heme as the prosthetic group. The prosthetic group is not covalently bound to the protein moiety. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]

Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH]

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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] Daunorubicin: Very toxic anthracycline aminoglycoside antibiotic isolated from Streptomyces peucetius and others, used in treatment of leukemias and other neoplasms. [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] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] 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] 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] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]

Deoxyguanosine: A nucleoside consisting of the base guanine and the sugar deoxyribose. [NIH]

Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary 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] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Desquamation: The shedding of epithelial elements, chiefly of the skin, in scales or small sheets; exfoliation. [EU]

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Developmental Biology: The field of biology which deals with the process of the growth and differentiation of an organism. [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] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Digitalis: A genus of toxic herbaceous Eurasian plants of the Scrophulaceae which yield cardiotonic glycosides. The most useful are Digitalis lanata and D. purpurea. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] 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, or identity. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] 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] Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetics. It is a hydroxy derivative of daunorubicin and is used in treatment of both leukemia and solid tumors. [NIH]

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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 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] Echocardiography: Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Electrolysis: Destruction by passage of a galvanic electric current, as in disintegration of a chemical compound in solution. [NIH] Electrolytes: Substances that break up into ions (electrically charged particles) when they are dissolved in body fluids or water. Some examples are sodium, potassium, chloride, and calcium. Electrolytes are primarily responsible for the movement of nutrients into cells, and the movement of wastes out of cells. [NIH] 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]

Emaciation: Clinical manifestation of excessive leanness usually caused by disease or a lack of nutrition. [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] Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary disorder or as a complication of or in association with another disease. [EU] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endoderm: The inner of the three germ layers of the embryo. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endosomes: Cytoplasmic vesicles formed when coated vesicles shed their clathrin coat. Endosomes internalize macromolecules bound by receptors on the cell surface. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with

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the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enterocytes: Terminally differentiated cells comprising the majority of the external surface of the intestinal epithelium (see intestinal mucosa). Unlike goblet cells, they do not produce or secrete mucins, nor do they secrete cryptdins as do the paneth cells. [NIH] 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] 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] Epidemiology, Molecular: The application of molecular biology to the answering of epidemiological questions. The examination of patterns of changes in DNA to implicate particular carcinogens and the use of molecular markers to predict which individuals are at highest risk for a disease are common examples. [NIH] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] 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] 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] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythropoiesis: The production of erythrocytes. [EU] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the

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liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophagitis: Inflammation, acute or chronic, of the esophagus caused by bacteria, chemicals, or trauma. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Estrogen: One of the two female sex hormones. [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] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Excrete: To get rid of waste from the body. [NIH] Exfoliation: A falling off in scales or layers. [EU] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Extracellular: Outside a cell or cells. [EU] Extracorporeal: Situated or occurring outside the body. [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] 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] 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] Fatty Liver: The buildup of fat in liver cells. The most common cause is alcoholism. Other causes include obesity, diabetes, and pregnancy. Also called steatosis. [NIH] Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fibula: The bone of the lower leg lateral to and smaller than the tibia. In proportion to its length, it is the most slender of the long bones. [NIH]

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Fine-needle aspiration: The removal of tissue or fluid with a needle for examination under a microscope. Also called needle biopsy. [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] Fold: A plication or doubling of various parts of the body. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallium: A rare, metallic element designated by the symbol, Ga, atomic number 31, and atomic weight 69.72. [NIH] Gallium nitrate: A drug that lowers blood calcium. Used as treatment for hypercalcemia (too much calcium in the blood) and for cancer that has spread to the bone (bone metastases). [NIH] Gamma-interferon: Interferon produced by T-lymphocytes in response to various mitogens and antigens. Gamma interferon appears to have potent antineoplastic, immunoregulatory and antiviral activity. [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] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

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Gastroenterologist: A doctor who specializes in diagnosing and treating disorders of the digestive system. [NIH] Gastroenterology: A subspecialty of internal medicine concerned with the study of the physiology and diseases of the digestive system and related structures (esophagus, liver, gallbladder, and pancreas). [NIH] Gastroesophageal Reflux: Reflux of gastric juice and/or duodenal contents (bile acids, pancreatic juice) into the distal esophagus, commonly due to incompetence of the lower esophageal sphincter. Gastric regurgitation is an extension of this process with entry of fluid into the pharynx or mouth. [NIH] Gastroesophageal Reflux Disease: Flow of the stomach's contents back up into the esophagus. Happens when the muscle between the esophagus and the stomach (the lower esophageal sphincter) is weak or relaxes when it shouldn't. May cause esophagitis. Also called esophageal reflux or reflux esophagitis. [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 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 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] Generator: Any system incorporating a fixed parent radionuclide from which is produced a daughter radionuclide which is to be removed by elution or by any other method and used in a radiopharmaceutical. [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 Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Screening: Searching a population or individuals for persons possessing certain genotypes or karyotypes that: (1) are already associated with disease or predispose to

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disease; (2) may lead to disease in their descendants; or (3) produce other variations not known to be associated with disease. Genetic screening may be directed toward identifying phenotypic expression of genetic traits. It includes prenatal genetic screening. [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] Genetic transcription: The process by which the genetic information encoded in the gene, represented as a linear sequence of deoxyribonucleotides, is copied into an exactly complementary sequence of ribonucleotides known as messenger RNA. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] 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] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [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]

Gluten: The protein of wheat and other grains which gives to the dough its tough elastic character. [EU] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH]

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Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Goblet Cells: Cells of the epithelial lining that produce and secrete mucins. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Grading: A system for classifying cancer cells in terms of how abnormal they appear when examined under a microscope. The objective of a grading system is to provide information about the probable growth rate of the tumor and its tendency to spread. The systems used to grade tumors vary with each type of cancer. Grading plays a role in treatment decisions. [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] 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] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Hematocrit: Measurement of the volume of packed red cells in a blood specimen by centrifugation. The procedure is performed using a tube with graduated markings or with automated blood cell counters. It is used as an indicator of erythrocyte status in disease. For example, anemia shows a low hematocrit, polycythemia, high values. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have

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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] 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] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] 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] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemorrhaging: A copious discharge of blood from the blood vessels. [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] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatobiliary: Pertaining to the liver and the bile or the biliary ducts. [EU] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hepatology: The field of medicine concerned with the functions and disorders of the liver. [NIH]

Hepatoma: A liver tumor. [NIH] Hepatotoxicity: How much damage a medicine or other substance does to the liver. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH]

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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] Heterodimers: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

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] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]

Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Horny layer: The superficial layer of the epidermis containing keratinized cells. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hydrogel: A network of cross-linked hydrophilic macromolecules used in biomedical applications. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that

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readily interact with water. [EU] Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. [NIH] Hypercalcemia: Abnormally high level of calcium in the blood. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypogonadism: Condition resulting from or characterized by abnormally decreased functional activity of the gonads, with retardation of growth and sexual development. [NIH] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Idiopathic: Describes a disease of unknown cause. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunoblotting: Immunologic methods for isolating and quantitatively measuring immunoreactive substances. When used with immune reagents such as monoclonal antibodies, the process is known generically as western blot analysis (blotting, western). [NIH]

Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] 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 vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incompetence: Physical or mental inadequacy or insufficiency. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators

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or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant Mortality: Perinatal, neonatal, and infant deaths in a given population. [NIH] Infantile: Pertaining to an infant or to infancy. [EU] 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] 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] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] 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] Intercellular Adhesion Molecule-1: A cell-surface ligand with a role in leukocyte adhesion and inflammation. Its production is induced by gamma-interferon and it is required for neutrophil migration into inflamed tissue. [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] Intestinal: Having to do with the intestines. [NIH]

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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] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] 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] Iron Chelating Agents: Organic chemicals that form two or more coordination links with an iron ion. Once coordination has occurred, the complex formed is called a chelate. The ironbinding porphyrin group of hemoglobin is an example of a metal chelate found in biological systems. [NIH] Irreversible toxicity: Side effects that are caused by toxic substances or something harmful to the body and do not go away. [NIH] Ischemic stroke: A condition in which the blood supply to part of the brain is cut off. Also called "plug-type" strokes. Blocked arteries starve areas of the brain controlling sight, speech, sensation, and movement so that these functions are partially or completely lost. Ischemic stroke is the most common type of stroke, accounting for 80 percent of all strokes. Most ischemic strokes are caused by a blood clot called a thrombus, which blocks blood flow in the arteries feeding the brain, usually the carotid artery in the neck, the major vessel bringing blood to the brain. When it becomes blocked, the risk of stroke is very high. [NIH] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Ketoacidosis: Acidosis accompanied by the accumulation of ketone bodies (ketosis) in the body tissues and fluids, as in diabetic acidosis. [EU] Ketone Bodies: Chemicals that the body makes when there is not enough insulin in the blood and it must break down fat for its energy. Ketone bodies can poison and even kill body cells. When the body does not have the help of insulin, the ketones build up in the

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blood and then "spill" over into the urine so that the body can get rid of them. The body can also rid itself of one type of ketone, called acetone, through the lungs. This gives the breath a fruity odor. Ketones that build up in the body for a long time lead to serious illness and coma. [NIH] Ketosis: A condition of having ketone bodies build up in body tissues and fluids. The signs of ketosis are nausea, vomiting, and stomach pain. Ketosis can lead to ketoacidosis. [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] Language Disorders: Conditions characterized by deficiencies of comprehension or expression of written and spoken forms of language. These include acquired and developmental disorders. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lesion: An area of abnormal tissue change. [NIH] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytosis: A transient increase in the number of leukocytes in a body fluid. [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 A: Lipid A is the biologically active component of lipopolysaccharides. It shows

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strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharides: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH]

Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lower Esophageal Sphincter: The muscle between the esophagus and stomach. When a person swallows, this muscle relaxes to let food pass from the esophagus to the stomach. It stays closed at other times to keep stomach contents from flowing back into the esophagus. [NIH]

Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells

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that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphoblastic: One of the most aggressive types of non-Hodgkin lymphoma. [NIH] Lymphocyte Count: A count of the number of lymphocytes in the blood. [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 which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Mammography: Radiographic examination of the breast. [NIH] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH]

Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [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]

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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] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] 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] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Minority Groups: A subgroup having special characteristics within a larger group, often bound together by special ties which distinguish it from the larger group. [NIH] 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]

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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] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH] 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] Morphological: Relating to the configuration or the structure of live organs. [NIH] Mosaicism: The occurrence in an individual of two or more cell populations of different 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] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder

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control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] 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] Mycotoxins: Toxins derived from bacteria or fungi. [NIH] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelodysplasia: Abnormal bone marrow cells that may lead to myelogenous leukemia. [NIH]

Myelofibrosis: A disorder in which the bone marrow is replaced by fibrous tissue. [NIH] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [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] Needle biopsy: The removal of tissue or fluid with a needle for examination under a microscope. Also called fine-needle aspiration. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]

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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] Nickel: A trace element with the atomic symbol Ni, atomic number 28, and atomic weight 58.69. It is a cofactor of the enzyme urease. [NIH] Nifedipine: A potent vasodilator agent with calcium antagonistic action. It is a useful antianginal agent that also lowers blood pressure. The use of nifedipine as a tocolytic is being investigated. [NIH] Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear 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] Occult: Obscure; concealed from observation, difficult to understand. [EU] Oligomenorrhea: Abnormally infrequent menstruation. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Opacity: Degree of density (area most dense taken for reading). [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] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH]

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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] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Ouabain: A cardioactive glycoside consisting of rhamnose and ouabagenin, obtained from the seeds of Strophanthus gratus and other plants of the Apocynaceae; used like digitalis. It is commonly used in cell biological studies as an inhibitor of the NA(+)-K(+)-exchanging atpase. [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] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [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]

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] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Paneth Cells: Epithelial cells found in the basal part of the intestinal glands (crypts of Lieberkuhn). Paneth cells synthesize and secrete lysozyme and cryptdins. [NIH] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH]

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Particle: A tiny mass of material. [EU] Paternity: Establishing the father relationship of a man and a child. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] 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] Peer Review: An organized procedure carried out by a select committee of professionals in evaluating the performance of other professionals in meeting the standards of their specialty. Review by peers is used by editors in the evaluation of articles and other papers submitted for publication. Peer review is used also in the evaluation of grant applications. It is applied also in evaluating the quality of health care provided to patients. [NIH] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] 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] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Neuropathy: Nerve damage, usually affecting the feet and legs; causing pain, numbness, or a tingling feeling. Also called "somatic neuropathy" or "distal sensory polyneuropathy." [NIH]

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Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Phantom: Used to absorb and/or scatter radiation equivalently to a patient, and hence to estimate radiation doses and test imaging systems without actually exposing a patient. It may be an anthropomorphic or a physical test object. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] 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] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] 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] Photosensitivity: An abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280400 mm. There are two main types : photoallergy and photoxicity. [EU] 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

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cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polycystic Ovary Syndrome: Clinical symptom complex characterized by oligomenorrhea or amenorrhea, anovulation, and regularly associated with bilateral polycystic ovaries. [NIH] Polycythemia Vera: A myeloproliferative disorder of unknown etiology, characterized by abnormal proliferation of all hematopoietic bone marrow elements and an absolute increase in red cell mass and total blood volume, associated frequently with splenomegaly, leukocytosis, and thrombocythemia. Hematopoiesis is also reactive in extramedullary sites (liver and spleen). In time myelofibrosis occurs. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH]

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Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] 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] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] 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 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] Porphyria, Hepatic: Porphyria in which the liver is the site where excess formation of porphyrin or its precursors is found. Acute intermittent porphyria and porphyria cutanea tarda are types of hepatic porphyria. [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] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, 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

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designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Primary Sclerosing Cholangitis: Irritation, scarring, and narrowing of the bile ducts inside and outside the liver. Bile builds up in the liver and may damage its cells. Many people with this condition also have ulcerative colitis. [NIH] Prion: Small proteinaceous infectious particles that resist inactivation by procedures modifying nucleic acids and contain an abnormal isoform of a cellular protein which is a major and necessary component. [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] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promotor: In an operon, a nucleotide sequence located at the operator end which contains all the signals for the correct initiation of genetic transcription by the RNA polymerase holoenzyme and determines the maximal rate of RNA synthesis. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] 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

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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 Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] 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] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychotherapy: A generic term for the treatment of mental illness or emotional disturbances primarily by verbal or nonverbal communication. [NIH] Puberty: The period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] 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]

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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] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quality of Health Care: The levels of excellence which characterize the health service or health care provided based on accepted standards of quality. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiopharmaceutical: Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose. [NIH] 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] Reassurance: A procedure in psychotherapy that seeks to give the client confidence in a favorable outcome. It makes use of suggestion, of the prestige of the therapist. [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] Recessive gene: A gene that is phenotypically expressed only when homozygous. [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

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crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflux: The term used when liquid backs up into the esophagus from the stomach. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Regurgitation: A backward flowing, as the casting up of undigested food, or the backward flowing of blood into the heart, or between the chambers of the heart when a valve is incompetent. [EU] 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] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Research Design: A plan for collecting and utilizing data so that desired information can be obtained with sufficient precision or so that an hypothesis can be tested properly. [NIH] Research Support: Financial support of research activities. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Rhamnose: A methylpentose whose L- isomer is found naturally in many plant glycosides and some gram-negative bacterial lipopolysaccharides. [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

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attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] 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] 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] Sediment: A precipitate, especially one that is formed spontaneously. [EU] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Septicemia: Systemic disease associated with the presence and persistence of pathogenic microorganisms or their toxins in the blood. Called also blood poisoning. [EU] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] 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.

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[NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] 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] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [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] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solitary Nucleus: Gray matter located in the dorsomedial part of the medulla oblongata associated with the solitary tract. The solitary nucleus receives inputs from most organ systems including the terminations of the facial, glossopharyngeal, and vagus nerves. It is a major coordinator of autonomic nervous system regulation of cardiovascular, respiratory, gustatory, gastrointestinal, and chemoreceptive aspects of homeostasis. The solitary nucleus is also notable for the large number of neurotransmitters which are found therein. [NIH] 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

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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] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinous: Like a spine or thorn in shape; having spines. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Splenomegaly: Enlargement of the spleen. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Steatosis: Fatty degeneration. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] 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] 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]

Dictionary 217

Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [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] 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] Subacute: Somewhat acute; between acute and chronic. [EU] Subcapsular: Situated below a capsule. [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 conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Supplementation: Adding nutrients to the diet. [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] Suppurative: Consisting of, containing, associated with, or identified by the formation of pus. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH]

218

Hemochromatosis

Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Talus: The second largest of the tarsal bones and occupies the middle and upper part of the tarsus. [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] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Thalassemia: A group of hereditary hemolytic anemias in which there is decreased synthesis of one or more hemoglobin polypeptide chains. There are several genetic types with clinical pictures ranging from barely detectable hematologic abnormality to severe and fatal anemia. [NIH] 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] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] 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] Thrush: A disease due to infection with species of fungi of the genus Candida. [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]

Dictionary 219

Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Tibia: The second longest bone of the skeleton. It is located on the medial side of the lower leg, articulating with the fibula laterally, the talus distally, and the femur proximally. [NIH] Tic: An involuntary compulsive, repetitive, stereotyped movement, resembling a purposeful movement because it is coordinated and involves muscles in their normal synergistic relationships; tics usually involve the face and shoulders. [EU] 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 Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [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] Topical: On the surface of the body. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] 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] Traction: The act of pulling. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] 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

220

Hemochromatosis

analogous to bacterial transformation. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Translating: Conversion from one language to another language. [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] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] 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]

Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [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] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]

Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] 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

Dictionary 221

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] Urease: An enzyme that catalyzes the conversion of urea and water to carbon dioxide and ammonia. EC 3.5.1.5. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [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] Uroporphyrinogen Decarboxylase: One of the enzymes active in heme biosynthesis. It catalyzes the decarboxylation of uroporphyrinogen III to coproporphyrinogen III by the conversion of four acetic acid groups to four methyl groups. EC 4.1.1.37. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginitis: Inflammation of the vagina characterized by pain and a purulent discharge. [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]

Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] 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] 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] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU]

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Hemochromatosis

Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Villous: Of a surface, covered with villi. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Hepatitis: Hepatitis caused by a virus. Five different viruses (A, B, C, D, and E) most commonly cause this form of hepatitis. Other rare viruses may also cause hepatitis. [NIH] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] 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] Virulent: A virus or bacteriophage capable only of lytic growth, as opposed to temperate phages establishing the lysogenic response. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral Afferents: The sensory fibers innervating the viscera. [NIH] Vitelline Membrane: The plasma membrane of the egg. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] 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 Infection: Invasion of the site of trauma by pathogenic microorganisms. [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] Yolk Sac: An embryonic membrane formed from endoderm and mesoderm. In reptiles and birds it incorporates the yolk into the digestive tract for nourishing the embryo. In placental mammals its nutritional function is vestigial; however, it is the source of most of the intestinal mucosa and the site of formation of the germ cells. It is sometimes called the vitelline sac, which should not be confused with the vitelline membrane of the egg. [NIH]

Dictionary 223

Zebrafish: A species of North American fishes of the family Cyprinidae. They are used in embryological studies and to study the effects of certain chemicals on development. [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]

224

INDEX 3 3-dimensional, 11, 12, 122, 153, 170 5 5,8,11,14,17-Eicosapentaenoic Acid, 210 8 8,11,14-Eicosatrienoic Acid, 210 A Abdomen, 170, 177, 187, 197, 199, 206, 207, 216, 222 Abdominal, 3, 37, 170, 205, 207, 220 Abdominal Pain, 3, 220 Aberrant, 48, 108 Acceptor, 199, 205 Acetone, 198 Acetylcholine, 204 Acid, 172, 174, 191 Acidosis, 197 Acquired Immunodeficiency Syndrome, 40 Acute renal, 193 Adaptability, 179 Adaptation, 208 Adenine, 116, 170, 212 Adenocarcinoma, 27, 193 Adenosine, 117, 170, 207 Adenosine Triphosphate, 117, 170, 207 Adenovirus, 149 Adipose Tissue, 52 Administration, iv, 20, 42, 52, 149, 150, 157 Adolescence, 14, 171 Adrenal Glands, 172 Adrenal Medulla, 187 Adrenergic, 187 Adverse Effect, 41, 215 Aerobic, 48, 201 Afferent, 53 Affinity, 35, 36, 171, 199 Aflatoxins, 28 Age of Onset, 4, 220 Alanine, 76 Albumin, 208 Algorithms, 77, 176 Alkaline, 170, 177 Alleles, 31, 135, 194 Allogeneic, 81, 101 Allogeneic bone marrow transplantation, 81 Allograft, 91 Alpha Particles, 212

Alpha-1, 131, 135 Alpha-helix, 197 Alternative medicine, 182 Amenorrhea, 208 Amine, 194 Amino Acid Sequence, 173, 188, 190 Amino acids, 11, 12, 14, 19, 50, 118, 122, 128, 172, 174, 181, 190, 206, 209, 211, 214, 217, 220 Amino Acids, 11, 12, 14, 19, 50, 118, 122, 128, 172, 174, 181, 190, 206, 209, 211, 214, 217, 220 Ammonia, 221 Amnion, 172 Amniotic Fluid, 144, 146, 172 Amygdala, 175, 218 Amyloidosis, 161, 172 Anaemia, 101 Anaesthesia, 196 Analogous, 25, 220 Anaphylatoxins, 181 Anaplasia, 203 Anatomical, 174, 180, 195, 214 Anemia, 10, 21, 22, 23, 25, 28, 29, 30, 31, 32, 35, 37, 39, 45, 51, 53, 54, 57, 63, 66, 71, 86, 108, 112, 130, 131, 134, 135, 140, 160, 175, 192, 202, 218 Anemic, 38 Anesthetics, 187 Aneuploidy, 128, 129 Angina, 172 Anginal, 204 Animal model, 22, 27, 41, 51, 54 Anions, 197 Ankle, 91 Ankle Joint, 91 Annealing, 209 Anode, 172 Anovulation, 208 Anterior chamber, 197 Anthracycline, 184 Antibacterial, 216 Antibiotic, 184, 185, 206, 216, 218 Antibiotics, 50 Antibodies, 53, 173, 192, 202, 208 Antibody, 27, 108, 171, 173, 176, 181, 192, 194, 195, 196, 202, 212, 216 Anticoagulant, 211 Antigen, 171, 173, 181, 184, 194, 196

Index 225

Antigen-Antibody Complex, 181 Antigen-presenting cell, 184 Antigens, 173, 189, 195, 200, 216, 222 Antimetabolite, 201 Antimicrobial, 9, 10, 11, 39 Antineoplastic, 24, 189, 195, 201 Antioxidant, 87, 205 Antioxidants, 24 Antiserum, 20 Antiviral, 189, 206 Anuria, 198 Anus, 181 Anxiety, 46, 63 Aorta, 221 Apolipoproteins, 199 Apoptosis, 24, 117, 126, 178 Aqueous, 175, 183, 198 Arachidonic Acid, 210 Archaea, 201 Arginine, 194 Arterial, 195, 211, 218 Arteries, 174, 176, 183, 197, 199 Arterioles, 176 Arteriosus, 211 Artery, 174, 197, 211, 221 Arthropathy, 57, 85 Articular, 173, 205 Aseptic, 205, 216 Aspartic Acid, 11, 12 Aspiration, 189 Assay, 22, 24, 25, 36, 38, 46, 70, 84 Astigmatism, 213 Asymptomatic, 69, 74, 83, 94, 175 Ataxia, 48, 174, 218 Atrial, 94 Atrium, 174, 221 Attenuated, 185 Atypical, 139 Autoimmune disease, 203 Autonomic Nervous System, 46, 175, 215, 217 B Backcross, 44 Bacteria, 50, 115, 123, 127, 173, 175, 187, 188, 201, 203, 212, 216, 219, 221 Bacterial Infections, 9 Bacterium, 40, 193 Barbiturates, 212 Basal Ganglia, 174, 175 Basal Ganglia Diseases, 174

Base, 9, 10, 12, 15, 16, 17, 19, 35, 39, 51, 116, 117, 120, 122, 126, 127, 128, 151, 170, 183, 184, 189, 190, 198, 218 Base Sequence, 127, 189, 190 Basophils, 192 Benign, 203 Beta Rays, 186 Beta-Thalassemia, 28, 54, 58, 101, 105 Bewilderment, 182 Bilateral, 208 Bile, 100, 175, 190, 193, 199, 210 Bile Acids, 175, 190 Bile Acids and Salts, 175 Bile duct, 175, 210 Bile Ducts, 175, 210 Biliary, 193 Bilirubin, 32, 66 Biochemical, 25, 36, 49, 52, 71, 131, 171, 173, 198, 205 Biochemical reactions, 25 Bioengineering, 36 Biological response modifier, 176 Biological therapy, 192 Biological Transport, 185 Biomarkers, 46 Biopsy, 36, 45, 46, 49, 54, 65, 101, 168, 203, 206 Biosynthesis, 49, 174, 221 Biotechnology, 38, 151 Bladder, 202, 210, 221 Blastocyst, 182, 208 Blood Cell Count, 192 Blood Coagulation, 176, 177, 218 Blood Coagulation Factors, 176 Blood Glucose, 193, 196 Blood pressure, 134, 178, 195, 202, 204 Blood transfusion, 48 Blood urea, 198 Blood vessel, 138, 176, 177, 178, 179, 180, 182, 193, 199, 200, 206, 215, 217, 218, 221 Blood Vessels, 138, 178, 179, 180, 193, 200, 215, 221 Blood Volume, 208 Blot, 42, 195 Blotting, Western, 195 Body Fluids, 176, 186, 220 Body Mass Index, 205 Bone Marrow, 16, 101, 150, 171, 177, 188, 190, 199, 200, 202, 203, 208, 215 Bone Marrow Cells, 203 Bone Marrow Transplantation, 171 Bone metastases, 189

226

Hemochromatosis

Bone scan, 214 Bowel, 177, 185, 197, 207, 216, 220 Bowel Movement, 185, 216 Brachytherapy, 212 Bradykinin, 208 Brain Hypoxia, 218 Brain Neoplasms, 218 Breeding, 26 Bronchi, 187, 219 Bronchial, 194 Buccal, 144, 146, 177 C Caffeine, 212 Calcium, 100, 177, 181, 186, 189, 195, 204, 211, 215 Candidiasis, 86 Candidosis, 177 Capillary, 221 Carbohydrate, 27, 191, 192 Carbohydrates, 177, 179 Carbon Dioxide, 184, 208, 213, 221 Carcinogenic, 196, 210 Carcinogens, 187 Carcinoma, 28, 51, 177, 193 Cardiac, 46, 47, 69, 91, 104, 186, 187, 203 Cardiogenic, 82 Cardiomyopathy, 30, 67, 92 Cardiotonic, 185 Cardiovascular, 22, 153, 215 Cardiovascular disease, 153 Carrier Proteins, 208 Case report, 89, 93, 98, 103, 178 Case series, 57, 178 Case-Control Studies, 27 Caspase, 24 Cataracts, 90 Catheter, 101 Cathode, 178, 186 Cations, 45, 197 Caudal, 195, 209 Caudate Nucleus, 175 Cause of Death, 184 Caveolae, 48, 178 Caveolins, 178, 181 Cecum, 198 Celiac Disease, 65, 88, 90 Cell Cycle, 125, 126 Cell Death, 126, 174, 203 Cell Differentiation, 215 Cell Division, 118, 125, 126, 138, 139, 175, 179, 192, 200, 202, 208, 214 Cell membrane, 35, 178, 179, 184, 207

Cell Membrane Structures, 178 Cell proliferation, 215 Cell Respiration, 201, 213 Cell Survival, 192 Cellular metabolism, 25 Cellulitis, 58 Central Nervous System, 171, 175, 189, 191, 202 Centrifugation, 192 Centromere, 118, 121 Cerebellar, 174, 179, 213 Cerebellar Diseases, 174 Cerebellum, 179, 213 Cerebral, 174, 175, 179, 187 Cerebral Cortex, 174 Cerebral hemispheres, 175, 179 Cerebrovascular, 32, 175, 178, 218 Cerebrovascular Disorders, 218 Cerebrum, 179 Character, 184, 191 Chelating Agents, 41, 54 Chelation, 54, 103 Chemotactic Factors, 181 Chemotherapy, 180 Chiasma, 183 Chin, 201 Chlorophyll, 180, 189 Cholesterol, 48, 117, 175, 178, 183, 199 Cholesterol Esters, 199 Chromatin, 174, 200 Chromosomal, 44, 126, 128, 139, 140, 141, 143, 172, 180, 194, 202 Chromosomal Proteins, Non-Histone, 180 Chromosome Fragility, 220 Chronic, 10, 23, 28, 30, 35, 39, 43, 44, 46, 50, 51, 52, 54, 62, 84, 92, 111, 180, 185, 187, 188, 196, 198, 199, 208, 217 Chronic Disease, 10, 23, 30, 35, 39, 43, 51 Chronic renal, 208 Chylomicrons, 199 Cirrhosis, 27, 30, 39, 45, 57, 60, 76, 91, 98, 108, 160 CIS, 180, 190 Clamp, 27 Clathrin, 48, 181, 186 Clinical Medicine, 152, 209 Clinical trial, 21, 23, 32, 41, 149, 150, 153, 156, 206, 211 Clinical Trials, 23, 32, 41, 149, 150, 153, 156, 206 Cloning, 31, 176 Coagulation, 208

Index 227

Coated Vesicles, 180, 186 Codon, 123, 181, 190 Codon, Terminator, 181 Codons, 181, 190 Cofactor, 204, 211, 218 Cognition, 43 Colitis, 220 Colloidal, 186 Colon, 52, 132, 181, 198, 220 Colonoscopy, 134 Colorectal, 51, 68, 181 Colorectal Cancer, 51, 68, 181 Combination Therapy, 104 Combinatorial, 25 Complement, 181, 182, 190, 197, 200, 208 Complementary medicine, 100 Complete remission, 213 Complete response, 182 Computational Biology, 156 Computed tomography, 182, 214 Computerized axial tomography, 182, 214 Computerized tomography, 182 Concentric, 204 Conception, 125, 188, 215, 216 Confusion, 132, 185, 221 Conjugated, 175, 183 Connective tissue, 177, 179, 182, 188, 189, 199 Connective Tissue Cells, 182 Consciousness, 184, 185 Constriction, 118, 121 Consultation, 140, 141, 144, 145 Continuous infusion, 38 Contraindications, ii Contralateral, 213 Conus, 211 Coordination, 50, 180, 197, 202 Corneum, 187 Coronary, 178, 183 Coronary heart disease, 178 Cortical, 218 Craniocerebral Trauma, 175, 218 Creatinine, 198 Cricoid Cartilage, 222 Crossing-over, 213 Crystallization, 35 Cues, 20 Cultured cells, 29, 38 Curative, 218 Cutaneous, 177, 207 Cyclic, 210 Cysteine, 11, 12, 183, 217

Cystine, 183 Cytochrome, 66, 205 Cytochrome b, 66 Cytoplasm, 115, 116, 117, 123, 174, 179, 183, 192, 200, 204, 213 Cytosine, 116, 212 Cytoskeletal Proteins, 180 Cytoskeleton, 183 Cytotoxic, 215 Cytotoxicity, 24, 69 D Data Collection, 43 Daunorubicin, 185 De novo, 126 Death Certificates, 134 Decarboxylation, 194, 221 Decidua, 184, 208 Deferoxamine, 38, 80, 104 Degenerative, 57, 193, 205 Deletion, 17, 55, 128, 174 Dementia, 129, 170 Denaturation, 209 Dendrites, 184, 203 Dendritic, 73 Dendritic cell, 73 Dendritic Cells, 73 Deoxyguanosine, 91 Deoxyribonucleic, 116, 213 Deoxyribonucleic acid, 116, 213 Deoxyribonucleotides, 184, 191, 213 Depolarization, 215 Deprivation, 26 Desquamation, 26 Deuterium, 194 Developmental Biology, 51 Diabetes Mellitus, 191, 193, 196 Diagnostic procedure, 107, 207 Dialyzer, 193 Diastole, 185 Diastolic, 59, 195 Diastolic pressure, 195 Diffusion, 185 Digestion, 4, 11, 29, 175, 177, 197, 199, 216, 221 Digestive system, 185, 190 Digestive tract, 215, 222 Digitalis, 205 Dihydrotestosterone, 213 Dilution, 91 Diphosphates, 213 Diploid, 172, 202, 208, 220

228

Hemochromatosis

Direct, iii, 31, 32, 36, 46, 144, 145, 146, 180, 213 Discrimination, 146, 147, 152 Disease Progression, 49, 52 Diseases, 56, 58, 62, 64, 66, 69, 71, 72, 74, 76, 82, 85, 86, 87, 94, 96, 102, 104, 112, 155, 160, 161, 163, 164, 166, 175, 179, 218 Disorientation, 182 Dissociation, 171 Dissociative Disorders, 185 Distal, 190, 206, 211 Dopamine, 204, 207 Dorsal, 209 Doxorubicin, 69 Drive, 3, 25, 34, 186 Drug Resistance, 186 Drug Tolerance, 219 Duct, 175, 188 Duodenum, 22, 38, 81, 175, 205, 216 E Echocardiography, 83 Edema, 167 Effector, 181 Elastic, 191 Electrode, 178 Electrolysis, 173, 178 Electrolyte, 198 Electrolytes, 175, 198 Electrons, 173, 175, 178, 186, 197, 205, 212 Electrophoresis, 64 Elementary Particles, 186 Emaciation, 170 Embryo, 29, 125, 126, 127, 135, 172, 176, 179, 186, 195, 201, 222 Enamel, 197 Endemic, 40, 44, 216 Endocarditis, 177 Endocardium, 186 Endocytosis, 48, 178, 186 Endoderm, 222 Endogenous, 28, 211 Endometrium, 184 Endorphins, 204 Endosomes, 36, 42 Endothelial cell, 218 Endothelial cells, 218 Endotoxic, 199 Endotoxin, 186 Endotoxins, 181 End-stage renal, 180, 208 Enhancer, 29 Enkephalins, 204

Enterocytes, 18, 20, 29, 31, 38, 39, 48 Environmental Health, 155, 156 Enzymatic, 25, 177, 181, 194, 209 Enzyme, 50, 117, 187, 190, 201, 204, 208, 211, 213, 215, 217, 218, 219, 221, 222, 223 Enzyme Inhibitors, 208 Enzymes, 24, 96, 117, 127, 171, 201, 203, 205, 207, 211, 221 Eosinophils, 192 Epidemic, 28, 216 Epidemiological, 79, 187 Epidemiology, Molecular, 46 Epidermal, 26, 197 Epidermis, 26, 182, 187, 194, 197 Epigastric, 205 Epinephrine, 204, 220 Epithelial, 25, 48, 170, 184, 187, 192, 193 Epithelial Cells, 48, 187, 193 Epithelium, 27, 44, 187, 197 Erythrocyte Indices, 63 Erythrocyte Volume, 176 Erythrocytes, 30, 51, 172, 177, 187, 193, 213 Erythropoiesis, 29, 61 Erythropoietin, 81, 98, 103 Esophageal, 27, 190 Esophagitis, 190 Esophagus, 27, 185, 188, 190, 199, 207, 213, 216 Estrogen, 72 Ethnic Groups, 140, 143 Eukaryotic Cells, 26, 183, 205, 220 Evoke, 216 Excitation, 204 Excitatory, 191 Excrete, 34, 173, 198 Exfoliation, 184 Exocrine, 205 Exogenous, 45, 186, 188, 211, 220 Exon, 83 Exons, 188 Expiration, 213 External-beam radiation, 212 Extracellular, 182, 186 Extracellular Matrix, 182 Extracorporeal, 103 Eye Color, 127 Eye Infections, 170 F Facial, 215 Family Planning, 156 Fat, 27, 170, 174, 175, 177, 183, 188, 197, 199, 203, 205, 215

Index 229

Fathers, 135 Fatigue, 3 Fats, 175, 180, 188 Fatty acids, 52, 210 Fatty Liver, 52 Feces, 216 Femur, 219 Ferritin, 24, 29, 31, 33, 36, 42, 45, 46, 49, 59, 69, 80, 92, 108, 168 Fetus, 86, 143, 144, 146, 150, 188, 208, 209, 216, 221 Fibrin, 176, 218 Fibrinogen, 208, 218 Fibrosis, 52, 56, 59, 62, 66, 70, 92, 94, 97, 127, 130, 134, 135, 214 Fibula, 173, 219 Filtration, 198 Fine-needle aspiration, 203 Flatus, 189 Fluorescence, 25, 64, 189 Fold, 21, 28 Foramen, 180 Forearm, 61, 176 Fractionation, 48 Frameshift, 128 Frameshift Mutation, 128 Free Radicals, 48, 173, 185 Fructose, 192 Fungus, 177 G Gait, 179 Gait Ataxia, 179 Gallbladder, 170, 175, 185, 189, 190 Gallium, 23 Gallium nitrate, 23 Gamma Rays, 212 Gamma-interferon, 196 Ganglia, 203, 217 Gas, 177, 185, 194, 204 Gastric, 51, 190, 194 Gastrin, 51, 62, 194 Gastrins, 51 Gastroenterologist, 28 Gastroenterology, 28 Gastroesophageal Reflux, 27 Gastroesophageal Reflux Disease, 27 Gastrointestinal, 187, 215, 217, 220 Gastrointestinal tract, 220 Gene Expression, 31, 123, 124, 190 Gene Products, rev, 190 Gene Therapy, 78, 148, 149, 150, 170, 190 Generator, 97

Genes, env, 134 Genetic Code, 204 Genetic Engineering, 176, 180 Genetic Screening, 14, 111, 191 Genetic testing, 54, 75, 79, 137, 141, 142, 143, 144, 145, 146, 147, 152, 209 Genetic transcription, 210, 219 Genetics, 7, 8, 17, 25, 39, 51, 78, 79, 103, 112, 115, 126, 127, 128, 130, 132, 133, 137, 140, 141, 142, 147, 150, 151, 152, 165, 206 Genomics, 153 Genotype, 41, 53, 63, 72, 207 Germ Cells, 126, 150, 200, 215, 222 Germ Layers, 186 Germline mutation, 126, 191, 194 Gestation, 206, 208 Gland, 199, 205, 210, 214, 216, 218 Globus Pallidus, 175 Glomerular, 198 Glomerular Filtration Rate, 198 Glucose, 24, 25, 27, 168, 185, 191, 192, 193, 196 Glucose Intolerance, 27, 185 Glucose tolerance, 27, 168, 191 Glucose Tolerance Test, 27, 168, 191 Glutamate, 191 Glutamic Acid, 193, 204 Gluten, 178 Glycerol, 207 Glycerophospholipids, 207 Glycine, 14, 175, 204 Glycoprotein, 32, 192, 218 Glycoside, 205 Goblet Cells, 187 Gonad, 192 Gonadal, 88 Gonads, 195 Governing Board, 209 Government Agencies, 209 Grade, 192 Grading, 49, 192 Grafting, 195 Gram-negative, 187, 213 Granule, 213 Granulocytes, 198, 215, 222 Growth factors, 51, 192 Guanine, 116, 184, 212 H Habitual, 179 Hair Color, 127 Half-Life, 54

230

Hemochromatosis

Haploid, 208 Haplotypes, 33, 56 Haptens, 171 Heart attack, 178 Hematocrit, 187, 192 Hematopoiesis, 29, 31 Hematopoietic tissue, 177 Hemodialysis, 198 Hemoglobin, 90, 117, 172, 175, 180, 187, 193, 197, 198, 218 Hemoglobinopathies, 190 Hemolytic, 57, 218 Hemophilia, 135 Hemorrhage, 217 Hemorrhaging, 49 Hemosiderosis, 111, 112 Hepatic, 10, 24, 27, 31, 36, 42, 49, 53, 61, 65, 66, 78, 83, 84, 88, 92, 94, 97, 101, 191, 209 Hepatitis, 13, 28, 42, 49, 52, 53, 62, 84, 85, 92, 104, 222 Hepatobiliary, 32 Hepatocellular, 13, 28, 67, 81, 86, 93, 94 Hepatocellular carcinoma, 13, 28, 67, 81, 86, 93, 94 Hepatocytes, 18, 23, 31, 34, 83, 193 Hepatology, 53 Hepatoma, 89 Hepatotoxicity, 52, 104 Hereditary mutation, 126, 191, 194 Heredity, 118, 190, 191 Heterodimers, 36 Heterogeneity, 32, 74, 171, 194 Heterozygote, 61 Heterozygotes, 65, 75 Histamine, 194 Histidine, 11, 12, 194 Histones, 118, 180 Homeostasis, 8, 13, 17, 20, 22, 23, 24, 26, 29, 31, 33, 34, 35, 36, 38, 39, 42, 49, 50, 51, 53, 85, 86, 90, 95, 96, 215 Homodimer, 35 Homogeneous, 70 Homologous, 171, 183, 190, 194, 214, 217 Homozygotes, 26, 32, 33, 63, 108 Hormonal, 21 Hormone, 4, 10, 25, 53, 123, 187, 189, 194, 196, 201, 215, 218 Hormones, 4, 123, 160, 188, 191, 194, 214 Horny layer, 187 Hybrid, 38, 45, 175 Hydrogel, 49

Hydrogen, 170, 175, 177, 184, 194, 199, 202, 205 Hydrogen Peroxide, 199 Hydrolysis, 207, 209, 211 Hydrophilic, 194 Hydrophobic, 199 Hydroxyurea, 32 Hypercalcemia, 189 Hyperopia, 213 Hypertension, 47, 178 Hypogonadism, 93, 101, 104, 105 Hypothalamus, 175 Hypotonic Solutions, 202 Hypoxia, 53 I Idiopathic, 59, 62, 75, 81, 84, 85, 99, 102 Imaging procedures, 219 Immune response, 173, 174, 192, 195, 200, 217, 222 Immune system, 11, 16, 39, 173, 176, 195, 200, 203, 221, 222 Immunity, 40, 170, 171, 195 Immunoblotting, 24 Immunocompromised, 39 Immunodeficiency, 40, 170 Immunodeficiency syndrome, 40 Immunofluorescence, 30 Immunogenic, 199 Immunoglobulins, 208 Immunology, 39, 47, 171 Immunosuppressant, 201 Immunosuppression, 204 Immunotherapy, 176 Impairment, 188, 195, 201 Implant radiation, 212 Implantation, 182 Impotence, 4 In vitro, 35, 40, 43, 51, 190, 195, 219 In vivo, 23, 29, 35, 36, 38, 40, 43, 49, 51, 53, 54, 85, 190, 195 Incision, 197 Incompetence, 190 Induction, 23, 24 Infancy, 153, 196 Infant Mortality, 47 Infantile, 8, 70 Infection, 27, 39, 40, 52, 76, 99, 170, 174, 176, 177, 179, 195, 196, 199, 200, 203, 204, 206, 217, 218, 222 Infections, 4, 40, 148, 173 Inflammation, 39, 40, 43, 53, 62, 149, 179, 188, 196, 220

Index 231

Informed Consent, 32, 144, 147, 152 Infusion, 182, 196, 220 Ingestion, 191, 208 Inhalation, 208 Initiation, 210, 219 Inorganic, 37, 102, 202 Insight, 28, 31, 35, 49 Insulator, 203 Insulin, 25, 26, 191, 196, 197, 220 Insulin-dependent diabetes mellitus, 196 Intercellular Adhesion Molecule-1, 83 Interferon, 189 Intermittent, 199, 209 Internal Medicine, 190 Internal radiation, 212 Intestinal, 10, 11, 13, 16, 29, 34, 35, 38, 44, 48, 53, 57, 102, 178, 187, 191, 200, 205, 222 Intestinal Mucosa, 38, 178, 187, 222 Intestine, 16, 23, 31, 34, 38, 51, 175, 177, 181, 198, 215 Intestines, 9, 170, 196, 197 Intracellular, 26, 31, 32, 34, 42, 52, 180, 196, 201, 210, 215 Intracellular Membranes, 201 Intracranial Hemorrhages, 218 Intravenous, 27, 54, 81, 196 Intrinsic, 171 Invasive, 36, 45, 46, 195, 200 Involuntary, 175, 203, 219 Ions, 50, 51, 175, 180, 185, 186, 194, 211 Ipsilateral, 213 Iris, 188, 197 Iron Chelating Agents, 41 Irreversible toxicity, 54 Ischemic stroke, 56, 61, 197 Isotonic, 202 K Karyotype, 120 Karyotypes, 190 Keratin, 197 Keratinocytes, 26, 197 Ketoacidosis, 101, 198 Ketone Bodies, 197, 198 Ketosis, 197, 198 Kidney Failure, 129, 187, 198 Kidney Failure, Acute, 198 Kidney Failure, Chronic, 198 Kidney Transplantation, 198 Kinetic, 54 Kinetics, 45

L Labile, 181 Language Disorders, 47 Large Intestine, 181, 185, 197, 198, 213, 215 Larynx, 219 Latent, 209 Lectin, 201 Lens, 178 Lenses, 213 Lesion, 27, 199, 220 Leucine, 35 Leucocyte, 171 Leukemia, 47, 185, 190, 203 Leukocytosis, 208 Leukotrienes, 174 Ligament, 211 Ligaments, 183 Ligands, 35, 43, 50, 53, 54 Linkage, 62 Linkages, 193, 194 Lipid, 48, 52, 178, 196, 199, 203, 205 Lipid A, 52 Lipid Peroxidation, 205 Lipophilic, 42 Lipopolysaccharides, 198, 213 Lipoprotein, 199 Liver scan, 214 Liver Transplantation, 54, 88, 89 Localization, 30, 38 Localized, 34, 37, 172, 196, 208, 220 Locomotion, 208 Long-Term Care, 30 Loop, 38, 199 Low-density lipoprotein, 93, 199 Lower Esophageal Sphincter, 190 Lymph, 37, 199, 200 Lymph node, 37, 199, 200 Lymph nodes, 37, 199, 200 Lymphatic, 196, 199, 215, 216 Lymphatic system, 199, 215, 216 Lymphoblastic, 24 Lymphocyte Count, 170 Lymphocytes, 170, 173, 184, 189, 198, 199, 200, 216, 222 Lymphoid, 173, 198, 200 Lymphoma, 23, 200 Lysine, 193, 194 Lytic, 222 M Macrophage, 30, 35, 42, 126 Magnetic Resonance Imaging, 45, 66, 67, 214

232

Hemochromatosis

Major Histocompatibility Complex, 35, 192 Malabsorption, 178 Malignancy, 27, 28 Malignant, 170, 173, 199, 202 Malignant tumor, 202 Mammography, 134 Mandible, 180 Mannans, 189 Maximum Tolerated Dose, 186 Meat, 48 Medial, 173, 219 Medical Records, 134, 147 MEDLINE, 156 Megakaryocytes, 177 Meiosis, 125, 217 Melanin, 197, 207, 220 Melanocytes, 201 Melanoma, 220 Membrane, 18, 29, 35, 38, 44, 48, 116, 172, 178, 179, 181, 184, 186, 188, 192, 201, 202, 204, 205, 207, 209, 215, 220, 222 Membrane Lipids, 207 Membrane Proteins, 178 Membranes, 177, 187, 201, 202, 204, 219 Memory, 184, 201 Meninges, 179 Menopause, 4 Menstruation, 4, 172, 184, 201, 204 Mental, 139, 141, 143, 179, 180, 181, 182, 184, 185, 188, 195, 201, 211, 214, 221 Mental Health, 211 Mental Processes, 185 Mental Retardation, 139, 141, 143 Mentors, 47 Mesencephalic, 213 Mesentery, 207 Mesoderm, 222 Metabolic disorder, 87 Metastasis, 203 Methotrexate, 56 Microbe, 219 Microbiology, 174 Microorganism, 181, 206, 222 Microscopy, 38, 45, 48 Migration, 38, 196 Minority Groups, 47 Miscarriage, 146 Mitochondria, 24, 116, 117, 129, 135, 202, 205 Mitochondrial Swelling, 203 Mitosis, 125, 174

Mobilization, 102 Modeling, 41 Modification, 190 Modulator, 43 Molecular, 8, 13, 17, 20, 23, 25, 29, 30, 31, 32, 42, 43, 46, 49, 52, 53, 77, 81, 103, 120, 122, 124, 156, 158, 176, 182, 187, 219 Molecule, 20, 23, 25, 35, 108, 116, 117, 118, 123, 173, 175, 181, 185, 192, 194, 202, 205, 212, 215, 219, 221 Monitor, 11, 204 Monoclonal, 20, 195, 202, 212 Monoclonal antibodies, 20, 195, 202 Monocyte, 73 Monocytes, 42, 61, 69, 81 Monosomy, 129, 172 Morphological, 186, 189 Morula, 176 Mosaicism, 126 Motor Cortex, 213 Movement Disorders, 218 Mucins, 187, 192 Mucosa, 51, 202 Mucus, 202, 220 Multiple Myeloma, 95 Multiple sclerosis, 103 Muscle Hypotonia, 179 Mutagen, 203 Mutagenesis, 29, 31, 35, 40 Mutagens, 189, 203 Mycotoxins, 171 Myelin, 203 Myelodysplasia, 45 Myelofibrosis, 208 Myelogenous, 203 Myocardium, 101 Myopia, 213 Myotonic Dystrophy, 138, 220 N Nausea, 198, 221 NCI, 180, 206 Necrosis, 95, 174 Needle biopsy, 45, 49, 189 Neonatal, 4, 5, 8, 55, 64, 65, 73, 81, 85, 100, 196 Neoplasms, 170, 173, 177, 184, 203 Nervous System, 138, 171, 175, 179, 203 Neural, 43, 171 Neurodegenerative Diseases, 175 Neurologic, 46 Neuronal, 40, 43 Neurons, 184, 189, 203, 217

Index 233

Neuropathy, 135, 206 Neurophysiology, 184 Neurotoxicity, 46 Neurotransmitter, 170, 174, 191, 194, 204, 215, 217 Neurotransmitters, 215 Neutrons, 212 Neutrophil, 196 Neutrophils, 192 Nickel, 50 Nifedipine, 26, 204 Nitrogen, 37, 198 Nonverbal Communication, 211 Norepinephrine, 204 Nuclear, 116, 175, 186, 188, 190, 203, 204 Nuclear Envelope, 116, 204 Nuclear Pore, 204 Nuclear Proteins, 190, 204 Nuclei, 186, 190, 194, 200, 202 Nucleic acid, 64, 175, 183, 190, 203, 204, 210, 212, 213 Nucleic Acids, 175, 183, 203, 204, 210, 212, 213 Nucleus, 116, 117, 118, 123, 129, 148, 151, 174, 180, 183, 188, 200, 204, 215, 217, 218 Nurse Practitioners, 144 O Occult, 49 Oligomenorrhea, 208 Oliguria, 198 Opacity, 178 Operon, 210 Opportunistic Infections, 170 Optic Chiasm, 195 Organ Culture, 219 Organelles, 115, 116, 180, 183, 208 Organizations, 164 Osmotic, 202 Osteoarthritis, 91 Ouabain, 25 Ovaries, 143, 205, 208, 214 Ovary, 192 Overweight, 86 Ovulation, 173 Ovum, 184, 191, 222, 223 Oxidation, 34, 93, 170, 173, 183, 199, 205 Oxidative Phosphorylation, 117 Oxidative Stress, 40, 205 Oxygen Consumption, 24, 205, 213 Oxygenase, 38, 48 P Palliative, 218

Pancreas, 3, 24, 28, 32, 41, 44, 170, 176, 185, 190, 196, 205, 220 Pancreatic, 190 Pancreatic Juice, 190 Paneth Cells, 187 Parietal, 207 Partial remission, 213 Partial response, 205 Particle, 219 Paternity, 143 Pathogen, 39 Pathologic, 170, 174, 176, 177, 183 Pathologic Processes, 174 Pathophysiology, 7, 17, 44, 79, 85, 112 PDQ, 154, 206 Peduncle, 213 Peer Review, 39 Pelvic, 210 Pelvis, 170, 205, 221 Penicillin, 221 Peptide, 9, 10, 11, 25, 39, 43, 53, 64, 197, 206, 209, 211 Peptide T, 10, 39 Perception, 63 Percutaneous, 49 Perfusion, 195, 206, 219 Perinatal, 70, 87 Peripheral blood, 42 Peripheral Nervous System, 204, 217 Peripheral Neuropathy, 40, 102 Peritoneal, 49 Peritoneum, 207 Phagocytosis, 30 Phantom, 45 Pharmacologic, 192, 219 Pharynx, 190 Phenotype, 33, 35, 42, 53, 62, 66, 74, 89, 91, 207 Phenotypes, 43, 44, 67 Phenylalanine, 220 Phlebotomy, 21, 27, 38, 71, 81, 98, 103 Phospholipases, 215 Phospholipids, 188, 199 Phosphorus, 177, 207 Phosphorylation, 117 Photoallergy, 207 Photosensitivity, 209 Physical Examination, 141 Physiologic, 34, 176, 192, 201, 207, 210, 212 Physiology, 22, 38, 39, 40, 49, 190 Pigment, 169, 175, 201 Pigments, 208

234

Hemochromatosis

Pilot study, 46, 74, 75 Placenta, 51 Plants, 29, 50, 174, 177, 180, 185, 191, 192, 205, 219 Plasma, 116, 171, 173, 176, 179, 191, 193, 198, 202, 208, 211, 219, 222 Plasma cells, 173, 202 Plasma protein, 211 Plasma Volume, 176 Plasticity, 193, 208 Plastids, 205 Platelet Activation, 215 Platelets, 208 Pleated, 197 Pneumonia, 182 Poisoning, 111, 180, 214 Polycystic, 86, 208 Polycystic Ovary Syndrome, 86 Polycythemia Vera, 57, 207 Polymerase, 64, 208, 209, 210 Polymerase Chain Reaction, 64 Polymorphism, 57, 58, 81, 89, 145 Polypeptide, 36, 172, 218, 223 Polyposis, 181 Polysaccharide, 173 Porphyria, 12, 13, 64, 93, 207, 209 Porphyria Cutanea Tarda, 12, 13, 64, 93, 207, 209 Porphyria, Hepatic, 209 Posterior, 174, 197, 205 Postnatal, 216 Postsynaptic, 215 Potassium, 186 Potentiation, 215 Practice Guidelines, 157, 161 Preclinical, 41 Precursor, 27, 174, 187, 207, 211, 220, 221 Predisposition, 74 Prenatal, 108, 143, 146, 186, 191 Presynaptic, 204 Prevalence, 27, 32, 74, 77, 84, 89, 131 Primary Sclerosing Cholangitis, 57 Prion, 25 Progression, 4, 52, 172 Progressive, 129, 180, 184, 198, 203, 205, 208 Projection, 213 Promoter, 95, 101 Promotor, 57 Prone, 129, 138 Prophase, 217 Prospective Studies, 28

Prospective study, 84 Prostaglandin, 79, 210 Prostaglandins, 174, 210 Prostaglandins A, 210 Prostaglandins D, 210 Prostate, 176, 220 Protease, 181 Protein Binding, 219 Protein Conformation, 172, 197 Proteinuria, 202 Proteolytic, 43, 171, 181 Prothrombin, 32, 211, 218 Protocol, 32, 54, 149 Protons, 194, 212 Protozoa, 201 Proximal, 29, 185 Psychic, 201 Psychology, 185 Psychotherapy, 212 Puberty, 4 Public Health, 22, 23, 33, 47 Public Policy, 156 Pulmonary, 22, 176, 198, 221 Pulmonary Artery, 176, 221 Pulmonary Edema, 198 Pulse, 45, 202 Purines, 175 Purulent, 221 Putamen, 175 Pyrimidines, 175 Q Quality of Health Care, 206 Quality of Life, 217 R Race, 197, 201 Radiation, 170, 189, 207, 212, 214, 220, 222 Radiation therapy, 170, 189, 212 Radioactive, 54, 177, 192, 194, 195, 199, 202, 204, 212, 214 Radioisotope, 219 Radiolabeled, 43, 176, 212 Radiological, 32, 206 Radiology, 212 Radiopharmaceutical, 190 Radiotherapy, 212 Reactive Oxygen Species, 24, 212 Reassurance, 49 Receptor, 11, 12, 13, 18, 19, 20, 23, 24, 26, 31, 35, 39, 42, 43, 49, 53, 66, 77, 95, 98, 108, 132, 173, 192, 206, 212, 215 Recessive gene, 25 Recombinant, 81, 103, 221

Index 235

Recombination, 40, 190 Rectum, 173, 181, 185, 189, 198, 211 Red blood cells, 30, 193, 205, 209 Red Nucleus, 174 Reductase, 24, 32, 201 Refer, 1, 121, 125, 132, 150, 177, 181, 199, 219 Reflux, 190 Refraction, 216 Regurgitation, 190 Remission, 42, 55, 182, 205 Repressor, 204 Reproductive cells, 128, 139, 140, 191, 194 Research Design, 51 Research Support, 28 Respiration, 177, 202, 213 Retina, 198, 214 Retinoblastoma, 131 Retroperitoneal, 171 Retroviral vector, 30, 190 Rhamnose, 205 Ribonucleic acid, 123 Ribonucleoside Diphosphate Reductase, 195 Ribose, 170 Ribosome, 123, 220 Rigidity, 208 Risk factor, 13, 27, 28, 32, 42, 62, 210 Risk factors, 13, 27, 28, 32, 42, 62 Rod, 175, 180 S Salivary, 185 Salivary glands, 185 Scans, 49, 214 Scatter, 207, 221 Schizophrenia, 136 Scleroproteins, 197 Sclerosis, 132, 202 Screening, 33, 46, 54, 58, 63, 64, 67, 72, 74, 75, 76, 77, 78, 80, 84, 85, 97, 99, 103, 108, 112, 134, 143, 144, 146, 180, 191, 206 Secretion, 4, 26, 194, 196, 202, 214, 221 Sediment, 214 Sedimentation, 38 Segregation, 62, 212 Semen, 210 Sensibility, 172 Sensor, 59 Sensory loss, 218 Septic, 174 Septicemia, 98 Sequence Homology, 206

Sequencing, 101, 151, 209 Serotonin, 204 Serum, 23, 27, 33, 35, 40, 45, 46, 62, 80, 85, 92, 98, 173, 181, 198, 199 Sex Characteristics, 171, 211, 214, 218 Shock, 82, 214, 220 Side effect, 150, 153, 171, 176, 217, 219 Side effects, 150, 153, 176, 217, 219 Signal Transduction, 53, 178, 215 Signs and Symptoms, 3, 12, 137, 138, 143, 213 Skeletal, 14, 180, 202 Skeleton, 210, 215, 219 Skull, 218 Small intestine, 9, 11, 12, 16, 29, 44, 186, 194, 197 Smooth muscle, 194, 217 Social Work, 140 Sodium, 186 Soft tissue, 177, 215 Solid tumor, 185 Solitary Nucleus, 175, 215 Soma, 215 Somatic, 126, 129, 140, 171, 200, 202, 206 Somatic cells, 126, 129, 140, 200, 202 Somatic mutations, 129 Specialist, 144, 164 Species, 153, 171, 187, 194, 197, 200, 201, 202, 212, 214, 216, 217, 218, 220, 222, 223 Specificity, 45, 50, 171, 219 Spectrum, 15, 71 Sperm, 125, 126, 128, 129, 138, 139, 140, 143, 150, 180, 191, 194, 213, 215 Spinal cord, 179, 180, 203, 217 Spinous, 187, 197 Spleen, 16, 29, 35, 37, 44, 45, 167, 172, 199, 200, 208, 216 Splenomegaly, 208 Sporadic, 58, 68, 209, 213 Staging, 49, 214 Steatosis, 49, 94, 188 Steel, 180 Stem Cells, 171, 188 Sterile, 174 Sterility, 108 Stillbirth, 141 Stimulant, 194, 221 Stimulus, 186, 218 Stomach, 170, 185, 188, 189, 190, 191, 194, 198, 199, 207, 213, 215, 216 Stool, 181, 198 Strand, 116, 208

236

Hemochromatosis

Stress, 83, 175, 209 Stroke, 134, 178, 197 Stroma, 197 Stromal, 177 Stromal Cells, 177 Subacute, 196 Subcapsular, 90 Subclinical, 42, 196 Subcutaneous, 38, 54, 179, 186 Subspecies, 216 Substrate, 37 Sulfur, 65 Supplementation, 28, 102, 103 Supportive care, 206 Suppression, 38 Suppurative, 179 Sympathetic Nervous System, 175, 217 Sympathomimetic, 187 Symphysis, 180, 211 Symptomatic, 108 Synapse, 217 Synapsis, 217 Synaptic, 204, 215 Synergistic, 219 System, 31, 34, 45, 50, 106, 157, 159, 160, 181, 190, 192, 200, 204, 205, 215 Systemic, 22, 23, 24, 26, 34, 38, 53, 172, 176, 177, 187, 196 Systolic, 83, 195 T Talus, 173, 219 Tarsal Bones, 218 Tarsus, 218 Taurine, 175 Telencephalon, 175, 179 Temporal, 25 Testicle, 192 Testosterone, 213 Tetracycline, 39 Thalamic, 174 Thalamic Diseases, 174 Thalamus, 218 Thalassemia, 32, 36, 41, 45, 58, 103, 104, 105, 160, 175 Theophylline, 212 Therapeutics, 47, 108 Thermal, 185, 209 Third Ventricle, 195 Thoracic, 222 Threonine, 206 Threshold, 46, 195, 218 Thrombin, 211, 218

Thromboembolism, 57 Thrombomodulin, 211 Thrombosis, 32, 211, 217 Thromboxanes, 174 Thrush, 177 Thymus, 199, 200 Thyroid, 143, 218, 219, 220 Thyroid Gland, 143, 219 Thyroid Hormones, 218, 220 Thyroxine, 207 Tibia, 173, 188 Tic, 25 Tissue Culture, 38 Tissue Distribution, 19 Tolerance, 168, 170, 191 Tomography, 182 Topical, 26 Toxic, 34, 38, 45, 46, 48, 54, 115, 171, 183, 184, 185, 195, 197, 203, 219 Toxicity, 22, 23, 26, 34, 38, 41, 43, 44, 48, 54, 149, 197 Toxicology, 156 Toxin, 26, 186, 219 Toxins, 26, 173, 196, 202, 214 Trace element, 204 Tracer, 54 Trachea, 207, 218 Traction, 180 Transcriptase, 40 Transcription Factors, 124 Transduction, 30, 215 Transfection, 176, 190 Transfusion, 47, 176 Translating, 21 Translation, 97, 123, 124, 190 Translational, 40 Transplantation, 85, 87, 104, 180, 200 Trauma, 188, 203, 222 Trinucleotide Repeat Expansion, 138 Trinucleotide Repeats, 220 Trisomy, 129, 172 Trypsin, 223 Tuberculosis, 77 Tumor marker, 176, 220 Tungsten, 178 Tunica, 202 Type 2 diabetes, 26, 91 Tyrosine, 11, 12 U Ubiquitin, 96 Ulcer, 179 Ulcerative colitis, 57, 210

Index 237

Ultraviolet radiation, 126 Uracil, 212 Urea, 221 Urease, 204 Uremia, 198 Urethra, 210, 221 Urinary, 79, 100, 204 Urine, 91, 173, 176, 198, 204, 211, 221 Uroporphyrinogen Decarboxylase, 13, 209 Uterus, 143, 184, 201, 205, 221 V Vaccine, 47, 211 Vaccines, 222 Vacuoles, 186, 205 Vagina, 177, 201, 221 Vaginitis, 177 Vagus Nerve, 215 Valine, 14 Vascular, 196, 208, 218 Vasoconstriction, 187 Vasodilator, 194, 204 Vector, 148, 149, 213, 219, 222 Vein, 197, 204, 207 Veins, 176, 221 Venous, 211 Ventricle, 211, 218, 221 Ventricles, 185 Ventricular, 83 Venules, 176 Vertebrae, 216 Vesicular, 48 Veterinary Medicine, 156 Villi, 222 Villous, 178 Viral, 28, 57, 148, 190, 219

Viral Hepatitis, 28 Viral Regulatory Proteins, 190 Viral Structural Proteins, 190 Viral vector, 57 Virion, 190 Virulence, 40, 174, 219 Virulent, 27 Virus, 148, 170, 187, 190, 192, 213, 219, 222 Viruses, 123, 148, 170, 173, 188, 201, 221, 222 Viscera, 215, 222 Visceral, 175, 207 Visceral Afferents, 175 Vitelline Membrane, 222 Vitreous, 198 Vitro, 40, 43, 52, 79, 143, 195, 209 Vivo, 35, 40, 42, 52, 53, 195 Volition, 197 W White blood cell, 9, 126, 173, 199, 200, 202, 204, 208 Windpipe, 207, 218 Womb, 221 Wound Infection, 39 X Xenograft, 172 X-ray, 182, 204, 212, 214 X-rays, 204, 212 Y Yeasts, 177, 189, 207, 222 Yolk Sac, 29, 51 Z Zebrafish, 29, 31, 50 Zygote, 182, 202 Zymogen, 211, 223

Hemochromatosis - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Spinal and Bulbar Muscular Atrophy - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Malonyl-Coenzyme A Decarboxylase Deficiency - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

3-Methylcrotonyl-Coenzyme A Carboxylase Deficiency - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Jervell and Lange-Nielsen Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Klinefelter Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Ehlers-Danlos Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Carnitine Palmitoyltransferase II Deficiency - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Oculocutaneous Albinism - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Androgenetic Alopecia - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Alstrom Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Pseudoxanthoma Elasticum - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Type 1 Gaucher Disease - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Hypohidrotic Ectodermal Dysplasia - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Waardenburg Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Peutz-Jeghers Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Isobutyryl-CoA Dehydrogenase Deficiency - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Recessive Multiple Epiphyseal Dysplasia - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Andersen-Tawil Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Osteogenesis Imperfecta - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Nonsyndromic Deafness - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Cowden Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Ellis-van Creveld Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Cerebral Cavernous Malformation - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Cystinuria - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Triple X Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Glucose-6-Phosphate Dehydrogenase Deficiency - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

X-Linked Adrenoleukodystrophy - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Bloom Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Duane-Radial Ray Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Muenke Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Hemochromatosis - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Spinal and Bulbar Muscular Atrophy - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Malonyl-Coenzyme A Decarboxylase Deficiency - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

3-Methylcrotonyl-Coenzyme A Carboxylase Deficiency - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Jervell and Lange-Nielsen Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Klinefelter Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Ehlers-Danlos Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Carnitine Palmitoyltransferase II Deficiency - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Oculocutaneous Albinism - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Androgenetic Alopecia - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Alstrom Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Pseudoxanthoma Elasticum - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Type 1 Gaucher Disease - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Hypohidrotic Ectodermal Dysplasia - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Waardenburg Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Peutz-Jeghers Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Isobutyryl-CoA Dehydrogenase Deficiency - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Recessive Multiple Epiphyseal Dysplasia - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Andersen-Tawil Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Osteogenesis Imperfecta - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Nonsyndromic Deafness - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Cowden Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Ellis-van Creveld Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Cerebral Cavernous Malformation - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Cystinuria - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Triple X Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Glucose-6-Phosphate Dehydrogenase Deficiency - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

X-Linked Adrenoleukodystrophy - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Bloom Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Duane-Radial Ray Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Muenke Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

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