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

FERRITIN A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Ferritin: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00463-1 1. Ferritin-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 ferritin. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON FERRITIN ................................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Ferritin........................................................................................ 12 E-Journals: PubMed Central ....................................................................................................... 62 The National Library of Medicine: PubMed ................................................................................ 68 CHAPTER 2. NUTRITION AND FERRITIN........................................................................................ 113 Overview.................................................................................................................................... 113 Finding Nutrition Studies on Ferritin....................................................................................... 113 Federal Resources on Nutrition ................................................................................................. 116 Additional Web Resources ......................................................................................................... 117 CHAPTER 3. ALTERNATIVE MEDICINE AND FERRITIN ................................................................. 119 Overview.................................................................................................................................... 119 National Center for Complementary and Alternative Medicine................................................ 119 Additional Web Resources ......................................................................................................... 126 General References ..................................................................................................................... 127 CHAPTER 4. DISSERTATIONS ON FERRITIN ................................................................................... 129 Overview.................................................................................................................................... 129 Dissertations on Ferritin............................................................................................................ 129 Keeping Current ........................................................................................................................ 129 CHAPTER 5. PATENTS ON FERRITIN .............................................................................................. 131 Overview.................................................................................................................................... 131 Patents on Ferritin..................................................................................................................... 131 Patent Applications on Ferritin ................................................................................................. 142 Keeping Current ........................................................................................................................ 144 CHAPTER 6. BOOKS ON FERRITIN .................................................................................................. 147 Overview.................................................................................................................................... 147 Book Summaries: Online Booksellers......................................................................................... 147 CHAPTER 7. PERIODICALS AND NEWS ON FERRITIN .................................................................... 149 Overview.................................................................................................................................... 149 News Services and Press Releases.............................................................................................. 149 Academic Periodicals covering Ferritin ..................................................................................... 151 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 155 Overview.................................................................................................................................... 155 NIH Guidelines.......................................................................................................................... 155 NIH Databases........................................................................................................................... 157 Other Commercial Databases..................................................................................................... 159 APPENDIX B. PATIENT RESOURCES ............................................................................................... 161 Overview.................................................................................................................................... 161 Patient Guideline Sources.......................................................................................................... 161 Finding Associations.................................................................................................................. 167 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 169 Overview.................................................................................................................................... 169 Preparation................................................................................................................................. 169 Finding a Local Medical Library................................................................................................ 169 Medical Libraries in the U.S. and Canada ................................................................................. 169 ONLINE GLOSSARIES................................................................................................................ 175 Online Dictionary Directories ................................................................................................... 176

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FERRITIN DICTIONARY............................................................................................................ 177 INDEX .............................................................................................................................................. 253

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with ferritin is indexed in search engines, such as www.google.com or others, a nonsystematic 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 ferritin, 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 ferritin, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on ferritin. 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 ferritin, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on ferritin. The Editors

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

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

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and ferritin, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “ferritin” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Hereditary Hemochromatosis: Early Detection of a Common Yet Elusive Disease Source: Consultant. 42(2): 237-249. February 2002. Contact: Available from Cliggott Publishing Company. 330 Boston Post Road, Darien, CT 06820-4027. (203) 661-0600. Summary: About 1 in 200 persons in certain populations of northern Europe descent has hereditary hemochromatosis. Persons with this disease are predisposed to absorb excess iron from the gastrointestinal tract; the excess iron deposits in the organs (including the liver) and produces clinical symptoms including diabetes, cirrhosis (liver scarring) and heart failure. This article discusses the early detection of this common, yet elusive, disease. The three most common symptoms are fatigue, arthralgia (pain in the joints), and libido (sex drive) loss. Radiographic (x ray) findings can mimic those of

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osteoarthritis (OA); however, OA in unusual sites, in large non-weightbearing joints, or in a patient younger than 50 years can be clues to hereditary hemochromatosis. Diabetes develops in about 50 percent of affect patients, but the well known finding of bronze diabetes (skin hyperpigmentation) occurs late in the disease. The first phenotypic expression of hereditary hemochromatosis is an elevated transferrin saturation (TS). When fasting TS is greater than 45 percent, patients should have tests for serum ferritin levels, liver function, and genetic testing for the mutations associated with hemochromatosis (C282Y and H63D). Liver biopsy can help differentiate between hereditary hemochromatosis and other causes of liver disease. However, genetic testing may obviate the need for liver biopsy in selected cases. Treatment consists of dietary restrictions and therapeutic phelobotomy (blood removal) to keep ferritin levels low. First degree adult relatives of patients with hereditary hemochromatosis should also undergo screening for the condition. The article includes a patient care algorithm. 3 figures. 1 table. 7 references. •

Just the FAQs: Frequently Asked Questions About Iron and Anemia in Patients with Chronic Kidney Disease Source: American Journal of Kidney Diseases. 39(2): 426-432. February 2002. Contact: Available from W.B. Saunders Company. Periodicals Department, 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452 or (407) 345-4000. Summary: Anemia in patients with chronic kidney disease is caused by insufficient production of erythropoietin (epoetin). Iron deficiency, chronic inflammation, hyperparathyroidism, and blood loss each may contribute to anemia in these patients. This article answers a series of frequently asked questions, many of which concern the patient who fails to respond to usual doses of epoetin. The authors provide the answers they have given at seminars held during meetings of the National Kidney Foundation (April 2000) and the American Society of Nephrology (October 2000). Questions and issues discussed include the best measure of iron status (hemoglobin tests), handling patients with low or normal transferrin saturation and high serum ferritin, diagnosing infection, patient selection for iron administration, administration and dosage of serum ferritin, the addition of vitamin C to drug regimens, maintenance iron protocols versus periodic iron therapy, maintenance iron therapy administered through dialysis facilities, total dose iron infusion, how to compare adverse reaction rates, and the use of iron and epoetin therapy in patients with chronic kidney disease who are not on dialysis. 3 figures. 33 references.

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Iron and Inflammatory Bowel Disease Source: Alimentary Pharmacology and Therapeutics. 15(4): 429-438. April 2001. Contact: Available from Alimentary Pharmacology and Therapeutics. Blackwell Science Ltd., Osney Mead, Oxford OX2 OEL, UK. +44(0)1865 206206. Fax +44(0)1865 721205. Email: [email protected]. Website: www.blackwell-science.com. Summary: Both anemia of iron deficiency and anemia of chronic disease are frequently encountered in patients with inflammatory bowel disease (IBD, consisting of Crohn's disease or ulcerative colitis). Anemia of iron deficiency is mostly due to inadequate intake or loss of iron. Anemia of chronic disease probably results from decreased erythropoiesis (creation of the hormone erythropoietin, which helps the body use oxygen), secondary to increased levels of proinflammatory cytokines, reactive oxygen metabolites, and nitric oxide. This article reviews the problem of iron in patients with IBD. The authors note that assessment of the iron status in a condition association with

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inflammation, such as IBD, is difficult. The combination of serum transferrin receptor with ferritin concentrations, however, allows a reliable assessment of the iron deficit. The best treatment for anemia of chronic disease is the cure of the underlying disease. Erythropoietin reportedly may increase hemoglobin levels in some of these patients. The anemia of iron deficiency is usually treated with oral iron supplements. Iron supplementation may lead to an increased inflammatory activity through the generation of reactive oxygen species. To date, data from studies in animal models of IBD support the theoretical disadvantage of iron supplementation in this respect. However, the results cannot be easily generalized to the human situation, because the amount of supplemented iron in these experiments was much higher than the does used in patients with iron deficiency. 2 figures. 97 references. •

Effect of Wheat Bran on Glycemic Control and Risk Factors for Cardiovascular Disease in Type 2 Diabetes Source: Diabetes Care. 25(9): 1522-1528. September 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Cohort studies indicate that cereal fiber reduces the risk of diabetes and coronary heart disease (CHD). This article reports on a study that assessed the effect of wheat bran on glycemic control and CHD risk factors in type 2 diabetes. A total of 23 subjects with type 2 diabetes (16 men and 7 postmenopausal women) completed two 3month phases of a randomized crossover study. In the test phase, bread and breakfast cereals were provided as products high in cereal fiber (19 grams per day additional cereal fiber). In the control phase, supplements were low in fiber (4 grams per day additional cereal fiber). Between the test and control treatments, no differences were seen in body weight, fasting blood glucose, HbA1c (glycosylated hemoglobin, a test of blood glucose over time), serum lipids (blood fats), apolipoproteins, blood pressure, serum uric acid, clotting factors, homocysteine, C-reactive protein, magnesium, calcium, iron, or ferritin. Of the subjects originally recruited, more dropped out of the study for health and food preference reasons from the control phase (16 subjects) than the test phase (11 subjects). The authors conclude that high-fiber cereal foods did not improve conventional markers of glycemic control or risk factors for CHD in type 2 diabetes over 3 months. Possible longer studies are required to demonstrate the benefits of cereal fiber. Alternatively, cereal fiber in the diet may be a marker for another component of whole grains that imparts health advantages or a healthy lifestyle. 1 figure. 2 tables. 38 references.

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Reclaim Your Energy Source: Health. p. 48, 50, 52. January/February 2001. Summary: Cornell University nutritionist Jere D. Haas tested 42 healthy women who had low blood iron stores (but were not anemic) to see what would happen to endurance levels once they received an iron supplement. Half of the women in the study took iron while the other half received a placebo. They rode a stationary bike five times a week for 30 minutes during a 4-week period. At the end of the study, the women in the iron supplement group raised their iron stores to normal, and their energy levels also improved. Haas concluded that women who are low in iron may receive some benefit from iron, and that their deficiency is holding them back. He recommends that if you are feeling unusually fatigued during and after workouts, you should first try eating more iron-rich foods. If this does not seem to work, ask a doctor for a blood test

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called a serum ferritin test, which measures total iron. If iron stores are low, taking a supplement of 18 milligrams (mgs) should help. •

Non-Transferrin-Bound Iron in Untreated and Ribavirin-treated Chronic Hepatitis C Patients Source: Alimentary Pharmacology and Therapeutics. 16(8): 1555-1562. August 2002. Contact: Available from Alimentary Pharmacology and Therapeutics. Blackwell Science Ltd., Osney Mead, Oxford OX2 OEL, UK. +44(0)1865 206206. Fax +44(0)1865 721205. Email: [email protected]. Website: www.blackwell-science.com. Summary: In patients with chronic hepatitis C, elevations in serum iron levels, hepatic iron content, and oxidative stress-related molecules have been reported. Treatment with ribavirin induces an increases in hepatic (liver) iron concentration. In situations of iron overload, non-transferrin-bound iron can appear. This article reports on a study that determined non-transferrin-bound iron levels in untreated chronic hepatitis C patients and in patients during interferon-ribavirin treatment. In 10 untreated and 19 interferonribavirin-treated chronic hepatitis C patients, the authors examined non-transferrinbound iron levels by a colorimetric method using nitrilotriacetic acid as a ligand and sodium triscarbondatecobalt (III) to block free iron binding sites on transferrin. Despite the presence of high serum iron saturation and ferritin levels, non-transferrin-bound iron was absent in the majority of hepatitis C virus patients (25 of 29 patients, 86 percent). There was no difference in non-transferrin-bound iron levels between untreated and treated patients. Four patients with high non-transferrin-bound iron levels were distinguished by higher serum iron levels. In two of these patients, hepatocytic iron was present on liver biopsy. 2 figures. 2 tables. 31 references.

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Evaluating Iron Status in Hemodialysis Patients Source: Nephrology Nursing Journal. 29(4): 366-369. August 2002. Contact: Available from American Nephrology Nurses' Association. East Holly Avenue, Box 56, Pitman, NJ 08071-0056. (856) 256-2320. Fax (856) 589-7463. Website: www.annanurse.org. Summary: Iron is essential for hemoglobin formation and productive erythropoiesis. In hemodialysis patients, accurately assessing iron status is a prerequisite for diagnosing iron deficiency (anemia), monitoring the response to iron supplementation, and maintaining effective erythropoiesis. This article focuses on strategies to evaluate iron status in hemodialysis patients. Ideal laboratory tests of iron status should accurately indicate whether a patient has an excess or deficiency in stored iron, as well as in iron readily available for erythropoiesis. Serum ferritin and transferrin saturation (TSAT) are iron indices recommended by the KDOQI guidelines for assessing iron deficiency and iron overload. However, since serum (blood) ferritin and TSAT are indirect measures of iron status, they can be unreliable in hemodialysis patients, particularly in those who are receiving recombinant erythropoietin. Relying on inaccurate indices of iron status can lead to false interpretations of iron overload or iron deficiency, which may lead to the unnecessary discontinuation or overdosing of iron supplementation. The author concludes that newer methods of measuring iron status, such as reticulocyte hemoglobin content (CHr), may be less variable and more sensitive and specific than the current iron parameters. 2 tables. 13 references.

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Update on Anemia and Iron Management in Dialysis Patients Source: Contemporary Dialysis and Nephrology. 19(5): 31, 32, 34. May 1998. Summary: Maintaining adequate iron levels is critically important for the management of anemia in dialysis patients. This article provides an update on anemia and iron management in patients on dialysis. In addition to cardiovascular problems, anemia also impacts such critical outcome areas as morbidity, hospitalizations, and quality of life. The author reviews related studies, particularly Canadian research. Some of the studies highlighted the beneficial effects of improving anemia on hospitalization rates. Improving anemia led to a decrease in the number of hospital admissions and the length of hospital stays, decreasing the morbidity factor. The author also reports on work establishing and reviewing the target hematocrit (Hct) levels for this population. They conclude that improving anemia from a Hct of 25 percent (the level achieved prior to the use of erythropoietin) to the current upper target level of 36 percent significantly improves brain function. A new test (the reticulocyte hemoglobin concentration) is available that may replace the transferrin saturation and serum ferritin tests currently used to determine and define iron deficiency. An additional problem is the poor absorption and the side effects of oral iron taken with food or medication in this patient population; patient noncompliance is common. The author reports work discussing the best methods of administering erythropoietin (including subcutaneously and intravenously) and stresses the importance of individualizing the iron management strategy for each patient. A given dose of erythropoietin will cause a different rate of production of red blood cells in different patients; the demand side is also different in each patient.

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Maintaining Iron Balance with Total-Dose Infusion of Intravenous Iron Dextran Source: ANNA (American Nephrology Nurses' Association) Journal. 25(1): 65-68. February 1998. Contact: Available from American Nephrology Nurses' Association. Box 56, East Holly Avenue, Pitman, NJ 08071. (609) 256-2320. Summary: Recombinant human erythropoietin (rHuEPO) is an important component of anemia management in patients with chronic renal (kidney) failure; however, use of rHuEPO can lead to functional iron deficiency (FID). Patients with FID are less likely to have an optimal response to rHuEPO. This article describes strategies to maintain iron balance in these patients with total dose infusion of intravenous (IV) iron dextran. IV iron dextran is often required to replace iron losses, maintain adequate iron stores, and correct iron deficiency. The author provides a rationale for the use of IV iron dextran and details one unit's protocols and experience with its use. Until the introduction of rHuEPO, blood transfusions were necessary to correct anemia associated with chronic kidney disease. However, rHuEPO helps to stimulate the patient's own bone marrow to make a sufficient amount of red blood cells. This can lead to increased iron utilization, which in turn results in iron deficiency. The author discusses the value of serum ferritin and TSAT as indicators of iron deficiency, strategies to correct iron deficiency, and the protocol for iron supplementation. The protocol includes initiation of oral iron therapy when the serum (blood) ferritin level is between 100 ng per milliliter and 300 ng per milliliter. The recommended dosage is about 200 milligrans of elemental iron per day. Some patients have problems taking oral preparations because of gastrointestinal (GI) intolerance. IV iron should be initiated when ferritin levels remain below 100 nanograms (ng) per milliliter, despite oral iron supplementation. Total dose infusion (TDI) protocol also offers an option for iron administration, without some of the side

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effects of IV administration. The authors conclude that TDI with IV iron dextran (when diluted and administered slowly as part of the dialysis treatment) is a safe and effective method for ensuring adequate iron stores to prevent FID in dialysis patients. 2 tables. 26 references. •

Erythropoietin Therapy in Pre-Dialysis Patients with Chronic Renal Failure: Lack of Need for Parenteral Iron Source: American Journal of Nephrology. 23(3): 78-85. 2003. Summary: Scant information exists regarding the optimal target percent saturation of transferrin (TSAT), ferritin, and the mode and amount of iron supplementation during erythropoietin therapy in pre-dialysis patients with anemia due to chronic kidney disease (CKD). Pre-dialysis CKD patients may have different needs for iron supplementation than end-stage renal disease (ESRD) subjects during erythropoietin therapy. This article reports on a retrospective analysis of pre-dialysis CKD subjects (n = 31) treated with erythropoietin at the authors' institution. In this population, target hematocrit (33 to 36 percent) was achievable with erythropoietin without parenteral iron therapy. This response extends even to subgroups with TSAT or ferritin levels deemed to indicate iron deficiency in CKD subjects, and may mean that no functional iron deficiency exists in this group of patients. 3 figures. 2 tables. 34 references.

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Clinical Features of Genetic Hemochromatosis in Women Compared with Men Source: Annals of Internal Medicine. 127(2): 105-110. July 15, 1997. Summary: The clinical expression of hemochromatosis is presumed to be less frequent and less severe in women than in men because of the iron loss associated with menses and pregnancy. This article reports on research undertaken to test this hypothesis by comparing the clinical features of women who have genetic hemochromatosis with those of men who have the disease. The cross-sectional study measured age at presentation, clinical symptoms, transferrin saturation, serum ferritin level, hepatic iron concentration, and hepatic iron index in 176 women and 176 men with hemochromatosis, matched for year of birth. Hepatic iron concentration and hepatic iron index were similar in men and women. Women had lower serum ferritin levels than men did, and less iron removed by venesections. Compared with women, men had a higher incidence of cirrhosis and diabetes. Compared with men, women had a higher incidence of fatigue and pigmentation. Hepatic iron concentration and hepatic iron index were greater in women in whom menstruation had stopped before 50 years of age. The authors conclude that homozygous hemochromatosis is slightly underexpressed in women, although severe disease can be present, including cirrhosis. The clinical features in women are different than those seen in men. Women with genetic hemochromatosis can and do develop progressive iron overload and clinical symptoms despite menstruation and pregnancy. Recognizing the nonspecific nature of presenting symptoms in women is essential for early diagnosis and treatment. 4 tables. 24 references. (AA-M).

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Effect of HFE Genotypes on Measurements of Iron Overload in Patients Attending a Health Appraisal Clinic Source: Annals of Internal Medicine. 133(5): 329-337. September 5, 2000. Contact: Available from American College of Physicians. American Society of Internal Medicine. 190 North Independence Mall West, Philadelphia, PA 19106-1572. Website: www.acponline.org.

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Summary: The gene that causes most cases of hereditary hemochromatosis (HH, an inherited propensity to absorb excess iron) is designated HFE. Three mutations exist at this locus at a relatively high gene frequency. This article reports on a study undertaken to determine the gene frequency of the three HFE mutations and to relate genotypes to various clinical and laboratory variables. The observational study included 10,198 adults who registered for health appraisal and consented to DNA examination for hemochromatosis. Consenting patients were slightly older and had attained a slightly higher educational level than nonconsenting patients. In white participants, the gene frequencies were 0.063 for the C282Y mutation, 0.152 for the H63D mutation, and 0.016 for the S65C mutation. Gene frequencies were lower in other ethnic groups. In participants with HFE mutations, blood tests showed that the average serum transferrin saturation and ferritin levels were slightly increased, as were mean hemoglobin levels and mean corpuscular volume. The prevalence of iron deficiency anemia was lower in women who carried HFE mutations. The authors conclude that screening for transferrin saturation and ferritin levels does not detect all homozygotes for the major hemochromatosis mutation. The authors briefly discuss the ongoing question of determining which screening practices are most practical and effective for identifying HH. 1 figure. 6 tables. 33 references. •

Utility of Radiological Imaging in Nonalcoholic Fatty Liver Disease Source: Gastroenterology. 123(3): 745-750. September 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Website: www.gastrojournal.org. Summary: This article reports on a prospective study that evaluated the role of radiological modalities in establishing the diagnosis of nonalcoholic steatohepatitis (NASH). Consecutive patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) were enrolled in the study. Each patient underwent liver biopsy, limited abdominal ultrasonography (US), computerized tomography (CT), and magnetic resonance imaging (MRI). Patients with NASH had greater aspartate aminotransferase levels, greater ferritin levels, more hepatocyte ballooning, and more fibrosis. None of the radiological features distinguished between NASH and other types of NAFLD. No radiological modality detected the presence of hepatocyte ballooning, Mallory's hyaline, or fibrosis, which are important features in the diagnosis of NASH. The presence of more than 33 percent fat on liver biopsy was optimal for detecting steatosis on radiological imaging. 3 tables. 35 references.

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Trends in Anemia Management Among US Hemodialysis Patients Source: JASN. Journal of the American Society of Nephrology. 13(5): 1288-1295. May 2002. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-6423. Summary: This article reports on a study undertaken to describe the relationship between hematocrit (Hct, a measure of oxygen-carrying red blood cells) and changes in the prescribed dose of erythropoietin (EPO) as well as selected patient and process care measures across annual national samples of hemodialysis patients from 1994 to 1998. The study used statistics for each of these years, and patient demographic and clinical information was collected from October to December for each year. Surrogates of iron stores and patterns of iron and EPO administration were profiled from 1996 to 1998. Mean Hct and EPO dose increased each year. Increasing Hct was positively associated

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with male gender, more years on dialysis, older age, higher urea reduction ratio (URR) and transferrin saturation, prescription of intravenous iron, and lower ferritin and EPO dose. Male gender, older age, diabetes, higher Hct, and increasing weight, URR, and transferrin saturation were associated with lower EPO doses. Conversely, intravenous EPO and iron were associated with higher prescribed EPO doses. Although increasing Hct is associated with decreasing EPO dose at the patient level, the increase in Hct seen across years among the cohorts of hemodialysis patients in the United States has been associated with increasing doses of EPO at the population level. The authors conclude that to achieve still higher hematocrit values, as has been advocated by some clinicians, disproportionately greater EPO dose is likely, unless alternative routes of administration are used, or different patterns of iron administration are demonstrated to be safe, effective, and can be implemented. 3 figures. 5 tables. 56 references. •

Management of Hemochromatosis Source: Annals of Internal Medicine. 129(11): 932-938. December 1, 1998. Contact: Available from American College of Physicians. American Society of Internal Medicine. 190 North Independence Mall West, Philadelphia, PA 19106-1572. Website: www.acponline.org. Summary: This article reviews how the complications of iron overload in hemochromatosis (an inherited propensity to absorb excess iron) can be avoided by early diagnosis and appropriate management. Therapeutic phlebotomy (blood removal) is used to remove excess iron and maintain low normal body iron stores, and it should be initiated in men with serum ferritin levels of 300 micrograms per liter or more, and in women with serum ferritin levels of 200 micrograms per liter or more, regardless of the presence or absence of symptoms. Typically, therapeutic phlebotomy consists of removal of 1 unit of blood weekly until the serum feritin level is 10 to 20 micrograms per liter; and maintenance of the serum ferritin level at 50 micrograms per liter or less thereafter by periodic removal of blood. Hyperferritinemia (too much iron in the blood) attributable to iron overload is resolved by therapeutic phlebotomy. When applied before iron overload becomes severe, this treatment also prevents complications of iron overload, including hepatic cirrhosis (liver scarring), primary liver cancer, diabetes mellitus, hypogonadotrophic hypogonadism, joint disease, and cardiomyopathy. In patients with established iron overload disease, weakness, fatigue, increased hepatic enzyme concentrations, right upper quadrant pain, and hyperpigmentation are often substantially alleviated by therapeutic phlebotomy. Patients with liver disease, joint disease, diabetes mellitus and other endocrine abnormalities, and cardiac abnormalities often require additional, specific management. Dietary management of hemochromatosis includes avoidance of medicinal iron, mineral supplements, excess vitamin C, and uncooked seafoods. This can reduce the rate of iron reaccumulation, reduce retention of nonferrous metals, and help reduce complications of liver disease, diabetes mellitus, and Vibrio infection. This comprehensive approach to the management of hemochromatosis can decrease the frequency and severity of iron overload, improve quality of life, and increase longevity. 4 tables. 86 references.

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When and How To Screen for Liver Disease Source: Patient Care. 32(15): 19-20, 23, 27-30, 33. September 30, 1998. Contact: Available from Medical Economics. 5 Paragon Drive, Montvale, NJ 07645. (800) 432-4570. Fax (201) 573-4956.

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Summary: This article reviews when and how to screen patients for liver disease. In its early stages, liver disease is often insidious, silently and progressively destroying the organ months or even years before symptoms appear. But much of the morbidity and mortality associated with hepatic dysfunction is preventable if the condition is recognized before irreversible damage has occurred. Diagnosing viral hepatitis is even more urgent because of the risk of transmission. However, today's health care environment demands that this be accomplished in the most efficient and least costly manner possible. The authors discuss risk factors for liver diseases, including prior blood transfusion, other risk factors for viral hepatitis, excessive alcohol intake, hepatotoxic drug use, occupation, family history, and systemic disease. The authors review the basic tests included in a liver biochemistry panel: aminotransferases, alkaline phosphatase, and bilirubin. In addition to these biochemistry tests, a routine ferritin level should be obtained at the initial screening to rule out iron overload. Guidelines for testing for hepatitis C antibody or hepatitis B core antibody are also provided. The article concludes with a brief discussion of four followup tests of liver function: gamma glutamyltransferase, albumin and prothrombin, lactate dehydrogenase, and 5 nucleotide. A patient care flowchart is included to help physicians with routine liver function testing. Sidebars list drugs mentioned in the article, selected hepatotoxic drugs and herbs, and ways to handle slight elevations in the results of liver function testing. 1 figure. 3 tables. 7 references. •

Hereditary Hemochromatosis Source: Physician Assistant. p. 31-40, 43-44. February 1999. Contact: Available from Springhouse Corporation. Physician Assistant, P.O. Box 908, Springhouse, PA 19477. (215) 646-8700. Fax (215) 646-4399. Summary: This continuing education article familiarizes physician assistants with hereditary hemochromatosis (HHC), one of the most common genetic disorders in the United States. HHC is an autosomal recessive condition associated with primary overabsorption of iron from the gastrointestinal tract. It may cause lifelong excessive iron absorption and accumulation and serious health effects including arthritis, cirrhosis, diabetes, impotence, myocardial infarction, and death. HHC is often considered primarily a disease of European men. However, iron overloading occurs in all ethnic groups. HHC eventually causes serious illness and death if untreated. Complications can be avoided by routine screening before clinical symptoms develop. HHC is effectively treated by the early use of therapeutic phlebotomy. The cornerstone of screening is measurement of serum transferrin saturation and the serum ferritin level. A DNA based test for the hemochromatosis gene is commercially available, but its place in the diagnosis of HHC is still being evaluated. Appended to the article is a study guide and a posttest for earning continuing medical education (CME) credits. 4 figures. 1 table. 22 references.

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Relation between Antioxidants and Memory Performance in the Old and Very Old Source: Journal of the American Geriatrics Society. 45(6): 718-724. June 1997. Summary: This journal article describes a study of the relationship between plasma antioxidant vitamin levels and cognitive performance in healthy older people. Participants were 312 men, 132 women, aged 65 to 94 years, from Basel, Switzerland. Plasma vitamin levels for ascorbic acid, beta-carotene, and alpha-tocopherol, measured previously in 1971, were measured in 1993 along with plasma cholesterol, ferritin, and systolic blood pressure. Participants also completed memory tests assessing priming,

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Ferritin

working memory, free recall, recognition, and vocabulary (semantic memory). The results suggest significant stability in plasma antioxidant levels between 1971 and 1993. Performances on free recall, recognition, and vocabulary, but not priming or working memory, were significantly correlated with levels of ascorbic acid and beta-carotene in both the cross-sectional 1993 data and the longitudinal 1971-1993 analysis. These two antioxidants remained significant predictors, especially of semantic memory, after controlling for age, education, and gender. The authors conclude that higher plasma levels of some antioxidants may be associated with better memory performance in older people. 2 figures, 3 tables, 36 references. •

Nutritional Implications of Recombinant Human Erythropoietin Therapy in Renal Disease Source: Journal of the American Dietetic Association. 94(9): 1023-1029. September 1994. Summary: This review article discusses the pathogenesis of the anemia related to renal failure and the biology of erythropoietin (rHuEPO). The authors outline the causes of poor response to rHuEPO therapy and highlight the importance of adequate available iron. They discuss the parameters used to measure iron adequacy, including serum iron levels, transferrin saturation, and ferritin levels. They also consider other nutritional deficiencies, such as folic acid and vitamin B-12, that can impair rHuEPO response. They stress that optimal nutrition management is critical for the success of erythropoietin therapy in renal disease. 2 figures. 94 references. (AA-M).

Federally Funded Research on Ferritin The U.S. Government supports a variety of research studies relating to ferritin. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to ferritin. 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 ferritin. The following is typical of the type of information found when searching the CRISP database for ferritin: •

Project Title: A TRAIL OF MICRONUTRIENTS AND ADVERSE PREGNACY OUTCOMES Principal Investigator & Institution: Fawzi, Wafaie W.; Associate Professor; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 11-SEP-2000; Project End 31-MAY-2004

2

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

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Summary: (Adapted from the Investigator's Abstract) Adverse pregnancy outcomes are major public health problems, particularly in developing countries. The investigators reported that multivitamin supplements resulted in about 40 percent reductions in fetal loss, low birth weight, and severe preterm birth, and significantly improved the immune status of HIV positive pregnant women in Tanzania. The investigators state that ascertaining whether these results are generalizable to the much larger population of HIV negative women is a research priority of health officials in many developing countries and of senior officials at international organizations, and is the next priority of the investigators. They propose to study the efficacy of the supplements on these outcomes among 6000 consenting women. Women who are no more than 27 weeks pregnant will receive standard prenatal care and daily doses of one of two regimens between baseline and delivery: multivitamins including all B, C, E, A, folate, and iron OR vitamin A, folate, and iron supplements only. They will undertake a comprehensive assessment of diet among these women, and relate dietary intake to pregnancy outcomes. HIV infected women will receive multivitamins and will not be randomized. Each woman will be followed monthly until the 36th week of pregnancy and then once every week until delivery. Compliance will be examined by pill count and measurement of urine riboflavin and plasma ferritin levels in a random subsample. They will administer a food frequency questionnaire (FFQ) at randomization and at 36 weeks of gestation, and a 24 hour dietary recall at each monthly visit until 36 weeks of gestation. Research assistants will attend to women throughout the study. They will also study the effect of prenatal multivitamin supplements on infant mortality and growth. At three month intervals during infancy, they will measure maternal and infant dietary intake and anthropomorphic status. The associations of maternal dietary intake with infant mortality and growth will be examined controlling for breastfeeding, infectious morbidity, and other postpartum influences on infant health. To examine potential mechanisms of action of the supplements or dietary patterns and intake of individual nutrients, they will assess the following secondary outcomes among women: hemoglobin levels, T cell counts, and placental weight. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALTERATION OF HOST IRON HOMEOSTASIS BY NEISSERIA Principal Investigator & Institution: Bonnah, Robert A.; Vaccine and Gene Therapy Institute; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2006 Summary: (provided by applicant): Neisseria gonorrhoeae (GC) infects a variety of mucosal epithelial surfaces, including the eye, causing hyperacute conjunctivitis. Untreated, these infections can cause visual impairment and blindness. GC infect only humans due to a tropism for human forms of host cell receptors and a requirement for human transferring (Tf). Tf is a host iron-binding glycoprotein that shuttles iron from sites of absorption to cells of the body. To acquire essential iron in vivo GC produce specific Tf-binding proteins (Tbps) in their outer membrane that allow the piracy of iron from host Tf. GC mutants devoid of Tbps are unable to initiate urethral infection in male volunteers. The goal of the proposed study is to improve current understanding of how pathogenic microbes alter the physiology of cells of the ocular surface, to attain sufficient iron for growth. GC likely play an active role in enhancing their supply of iron on the mucosal surface, by manipulating host conjunctival epithelial cells to downregulate transferrin receptors (TfR), and altering their TfR cycling and TfR distribution patterns. Since animal models for GC eye infections are lacking, conjunctival cell lines and where appropriate, donor tissues will be used to assess

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Ferritin

uninfected and infected conjunctival cells for downregulated Tf-receptor (TfR) by semiquantitative RT-PCR. Using a functional assay with radiolabeled Tf and live cells, the levels of host cell TfR will be measured and the TfR cycling rate will be determined in the presence and absence of infection. The other key host iron homeostasis proteins, ferritin, iron regulatory protein-1 (IRP1) and IRP2 levels and biological activity will also be monitored during the course of GC infection. Wild type and isogenic GC mutants lacking specific virulence determinants will be used for the assays. In addition, a specially designed DNA microarray, the 'iron chip', will be used for simultaneous comprehensive analysis of GC alteration of host gene regulation of some 200 genes known to play a role in cellular iron homeostasis. These studies will aid in delineating the specific bacterial products and host signaling factors that may significantly contribute to the processes of iron withholding by host epithelial cells. These studies may lead to novel treatment strategies, since withholding iron can arrest bacterial growth. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOCHEMICAL AND GENETIC MARKERS OF TYPE 2 DIABETES RISK Principal Investigator & Institution: Manson, Joann E.; Associate Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-MAR-2001; Project End 28-FEB-2005 Summary: This proposal seeks to extend our prospective evaluation of predictors of Type 2 diabetes mellitus (DM) in the Nurses' Health Study, a large prospective cohort with archived blood specimens. Diabetes mellitus is a major and increasing public health problem, affecting at least 16 million Americans (of whom 15 million have Type 2 DM). A novel hypothesis implicates inflammation and endothelial dysfunction in the pathogenesis of Type 2 DM. We propose to study the role of several novel and promising biomarkers of inflammation (including tumor necrosis factor alpha receptor 2, interleukin-6, C-reactive protein, and ferritin) and endothelial dysfunction (including E-selectin, intercellular adhesion molecule-1 [VCAM-1]) as predictors of risk of Type 2 DM. We also propose to study the pathogenic roles of specific genetic markers associated with inflammation and endothelial dysfunction, including the peroxisome proliferator-activated receptor gamma [PAR-g2} Pro12A1a, tumor necrosis factor alpha G308A, and E-selectin Ser128Arg polymorphisms. Elucidation of interrelationships between these biomarkers and development of Type 2 DM may suggest new treatment and/or prevention strategies. Previous work in this cohort has contributed to clarifying the major roles of obesity, body fat distribution, physical activity level, and several dietary factors as determinants of Type 2 DM. We seek to build on this body of work by utilizing an existing database which includes 121,700 U.S. female nurses currently aged 54-79, with follow-up and documentation of DM endpoints through the 1998-90, with 774 incident cases of type 2 DM by the year 2000. We will use a nested case control design for the biomarker analyses. Several unique features of this established cohort stud, including its prospective design, large size, long duration, high follow-up rates (exceeding 90 percent over 20 years), availability of stored blood specimens, and costefficiency, make this database an unparalleled resource in the etiologic study of Type 2 DM in women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CARDIAC THALASSEMIA

FUNCTION

AND

CARDIAC

Studies

15

(T2*)

IN

IRON

Principal Investigator & Institution: Wood, John C.; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 900276062 Timing: Fiscal Year 2004; Project Start 05-JUL-2004; Project End 31-MAY-2008 Summary: (provided by applicant): Thalassemia is the most common genetic disease worldwide, affecting over 600,000 individuals in Thailand alone. With increasing East Asian immigration to the Pacific States in the last two decades, thalassemia major is becoming an important domestic as well as international health challenge. Patients with thalassemia major depend on monthly transfusions for survival. Each transfusion contributes more than a year's dietary iron intake, producing toxic iron overload in many organ systems including the heart. While daily iron chelation therapy with subcutaneous deferoxamine ameliorates much of the iron toxicity, deadly iron cardiomyopathy still remains the norm, usually in the 3 rd or 4 th decade of life. Conventional cardiac monitoring fails to detect impending cardiac compromise early enough for effective reversal therapy. Serial monitoring of liver iron, while vital to titrating chelator therapy, has not successfully identified patients at risk for iron cardiomyopathy. Cardiac MRI measurements of the ironsensitive relaxation time, T2*, demonstrate great promise for preclinical diagnosis of cardiac iron overload. We have demonstrated that liver T2* measurements are accurate predictors of liver iron content by biopsy, hence cardiac T2* measurements should similarly reflect cardiac iron content. We have further demonstrated that patients with low cardiac T2* have significantly greater risk of resting systolic dysfunction and need for cardiac medications than patients with T2* in the normal range. While cardiac T2* represents a potentially invaluable tool to study chelation therapies and their effect on cardiac iron flux and function, the relationship of cardiac T2* to heart iron and heart function needs to be clarified. Therefore, the overall objective of this proposal is to determine the etiology of myocardial T2* changes and their relationship to cardiac rhythm and function in cardiac iron overload. Specifically, we hypothesize that cardiac 1/T2* is linearly related to cardiac iron concentration. Both the magnitude of myocardial iron loading, reflected by cardiac T2*, and duration of cardiac iron exposure determine cardiac toxicity in iron loaded thalassemia patients. The ability of MRI to quantitate cardiac and liver iron will be assessed in an established gerbil iron overload model. Other contributions to the T2* signal, such as changes in tissue oxygenation and coronary blood flow, will be evaluated as well. Validation of the T2*-iron relationship in the heart is vital for future analyses of cardiac iron fluxes. The relationship between cardiac T2*, liver iron content, and cardiac function, rhythm and exercise capacity will be evaluated in thalassemia patients. Eighty thalassemia major patients will be recruited from California and Nevada. Complete cardiology evaluation, including ECG, echo, Holter, exercise stress test and cardiac MR( will be performed at Childrens Hospital Los Angeles. The study goals are three-fold l) determine normative data for cardiac rhythm and performance for thalassemia patients, 2) determine prevalence of exercise and cardiac rhythm abnormalities in thalassemia patients with high cardiac iron and normal resting function, 3) determine the relationships between liver iron content, ferritin, cardiac T2* and cardiac function. These studies will provide the necessary groundwork for longitudinal studies of cardiac iron load on cardiac performance in thalassemia patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Ferritin

Project Title: CATARACTOGENESIS IN HYPERFERRITINEMIA CATARACT SYNDROME Principal Investigator & Institution: Brooks, David G.; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2004 Summary: Hyperferritinemia cataract syndrome (HCS) is a recently discovered genetic disease defined by elevated serum ferritin and cataracts. Dysregulation of L ferritin gene expression is the basis of this human disorder. Specifically, mutations in a discrete regulatory region of the L ferritin gene, the iron' response element, lead to over production of wild type L ferritin protein. Although ferritin is found at high levels in all tissues and extracellular fluids examined to date, cataracts are the only proven pathologic consequence of this constitutive over expression of ferritin. The mechanism of cataract formation in hyperferritinemia cataract syndrome (HCS) is unknown. Understanding the pathobiology of cataractogenesis in HCS is essential to design a rational approach to cataract prevention and treatment. The objective 9f this proposal is to determine the mechanism of HCS cataractogenesis with a long term goal of developing effective preventive and/or therapeutic strategies for these cataracts. The mechanism of cataract formation in HCS will likely have broader implications for cataract formation in general. The specific aims of this proposal all involve investigation of ferritin in eye. First, the normal expression of ferritin in lens and lens cell lines will be determined. Second, over expression of L ferritin in human cell lines and in mouse will be generated as models of HCS. Third, quantitative expression and distribution of L ferritin in HCS lens material will be determined. An animal model that reproduces cataract promises opportunity to 1investigate cataract formation as a function of the interaction of HCS genotype with environmental factors including iron, antioxidants and UV light. This proposal describes a 4 year training program in which the applicant will acquire the requisite experience to become an independent clinician scientist. The sponsor and collaborator's extensive experience in clinical ophthalmology, eye histopathology, genetic cataract and mouse genetics will complement the applicant's prior training in molecular biology, internal medicine and clinical genetics. A strong ophthalmology research program will provide the requisite environment in which to transition the applicant to being an independent physician/researcher in genetics and eye disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CELLULAR RESPONSES TO HYPOXIA Principal Investigator & Institution: Kourembanas, Stella; Associate Professor of Pediatrics; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2003; Project Start 06-SEP-1996; Project End 31-AUG-2007 Summary: (provided by applicant): Tissue hypoxia is central to pathologic conditions such as myocardial ischemia and chronic lung disease. In the pulmonary vasculature, hypoxia causes vasoconstriction and vessel wall remodeling with resultant right ventricular hypertrophy. These pathophysiologic responses are the hallmark of pulmonary hypertension (PHTN). We and others have shown that hypoxia induces the expression of key smooth muscle cell mitogens and vasoconstrictors that play an important role in vessel wall remodeling in vivo. We have previously reported that hypoxia also increases the expression of heme oxygenase-1 (HO-1), a cytoprotective enzyme. HO-1 degrades heme to generate carbon monoxide (CO, a vasodilating gas that has anti-inflammatory properties), biliverdin (which is rapidly converted to the

Studies

17

antioxidant bilirubin), and iron (sequestered by ferritin). Due to properties of HO-1 and its products, the consensus is that HO-1 may play an important role in protecting cells and tissues from hypoxia-induced injury. Studies by our group using HO-1 null (-/-) mice and transgenic mice with lung-specific HO-1 over expression support this hypothesis by showing that hypoxia produced right ventricular dilatation and infarction in all mice lacking HO-1 whereas mice with high lung HO-1 levels were protected from PHTN. Moreover, we noted that wild-type mice exposed to hypoxia developed marked lung inflammation with elevated expression of chemokines and cytokines as well as neutrophil infiltration prior to the manifestation of PHTN. Mice deficient in HO-1 had a more pronounced and sustained inflammatory response to hypoxia than wild-type controls whereas transgenic mice with high lung HO-1 levels manifested a complete absence of inflammation. The specific aims of this proposal are: A. To study the molecular mechanisms and signaling pathways by which hypoxia induces chemokine gene expression leading to lung inflammation. B. To investigate the mechanisms by which HO-1 inhibits inflammatory gene expression and vascular permeability induced by hypoxia. C. To determine whether inflammation plays a role in the development of hypoxic PHTN. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHOROID NEUROTOXICITY

PLEXUS

A

TARGET

IN

METAL-INDUCED

Principal Investigator & Institution: Zheng, Wei; Professor; Environmental Health Sciences; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-MAR-1998; Project End 30-NOV-2005 Summary: (provided by applicant): The recent addition of a manganese (Mn)-containing antiknock compound methylcyclo-pentadienyl Mn tricarbonyl (MMT) to the US gasoline supply has raised a great concern about the health risks associated with a potential increase in the environmental levels of Mn. Both environmental and occupational exposures to (Mn) result in neurodegenerative symptoms resembling Parkinson's disease. However, the mechanisms underlying Mn neurotoxicity remain unknown. Our recent results show that in vivo and in vitro exposures to Mn alter both systemic and subcellular Fe status. While the former facilitates influx of Fe from the blood circulation to the cerebral spinal fluid (CSF), the latter promotes cellular Fe overload. We also found that accumulation of Mn in the choroid plexus, a tissue where blood-CSF barrier resides, enhances the density of transferrin receptor (TfR) mRNA, which has 3' binding IRE (iron responsive element) loops receptive to [4Fe-4S] clustercontaining iron regulatory protein-1 (IRP-1, or cytosolic aconitase). These findings have led us to propose that the mechanism by which Mn causes abnormal Fe metabolism is likely via its interaction with IRP-1 and the subsequent overexpression of TfR. The events, in turn, expedite Fe transport at the brain barrier systems and aggravate Fe accumulation in neuronal cells. Thus, we hypothesize in this proposal that accumulation of Mn in the choroid plexus alters Fe regulatory mechanisms in the blood-CSF barrier and thereby disturbs Fe homeostasis in the CSF, which may contribute to Mn-induced neurodegenerative Parkinsonism. Our research goals are to better understand the mechanism of Mn-induced Parkinsonism and in so doing identify and prevent environmental causes of neurodegenerative diseases. Our specific aims are (1) to test the working hypothesis that Mn exposure alters the Fe regulatory mechanism in the choroid plexus, leading to a distorted Fe status in the CSF. We will define the dose and time response relationship of Mn exposure and Fe in CSF, blood, and choroid plexus, examine the activity of IRP-1, and determine the expression of TfR in blood-CSF barrier

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Ferritin

and selected brain areas; (2) to test the working hypothesis that Mn-facilitated transport of Fe at the blood-CSF barrier is directed toward the CSF and quantitatively is more significant than transport by the blood-brain barrier. We will use in vitro transport models to determine the direction and magnitude of Fe fluxes at two major brain barriers and to investigate if blocking of cellular trafficking of TfR antagonizes Mnaugmented unidirectional transport of Fe; and (3) to test the working hypothesis that alteration by Mn of cellular Fe regulation takes place at the level of mRNA expression, but not at the level of transcriptional modulation of genomic DNA. We will deterrnine the effect of Mn on RNA binding capability of IRP-1 and pertinent expression of TfR, examine if Mn inhibits degradation of TfR mRNA, and study cellular ferritin status in both barriers. In addition, we will study the effect of Mn on the RNA binding capability of a newly discovered IRP which regulates the synthesis of an [Fe-S] subunit of Complex-I. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLINICAL PET AND LABORATORY STUDIES OF ADRENERGIC TUMORS Principal Investigator & Institution: Shulkin, Barry L.; Professor; Radiology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-APR-1991; Project End 31-AUG-2004 Summary: (From the Applicant's Abstract): Neuroblastomas and pheochromocytomas are tumors derived from tissues of the sympathetic nervous system. Neuroblastomas are common and highly lethal malignancies of children. Pheochromocytomas are an uncommon but curable source of hypertension and its associated morbidity, direct results from the excessive production of catecholamines. These tumors concentrate catecholamines and catecholamine analogs, and thus can be assessed scintigraphically utilizing specifically designed radiotracers. Epinephrine is a naturally occurring catecholamine product of the adrenal medulla and of some pheochromocytomas. When epinephrine is labeled with carbon-11, its distribution in vivo can be mapped noninvasivel in a variety of physiologic and pathophysiologic conditions using positron emission tomography (PET). The aim of this proposal is to evaluate the biodistribution of C-11epinephrine in patients with the neuroendocrine tumors neuroblastoma and pheochromocytoma, and to characterize the uptake and retention within tumors themselves. The applicants expect to show, by virtue o the superior image resolution of PET technology and the information provided b the distribution of C-11 epinephrine, an advance in ability to characterize these tumors. Utilizin C-11- epinephrine as a tracer of catecholamine uptake and storage, the applicants will examine the degree of tumor uptake by neuroblastomas as an indicator of histopathology, of prognosis and of N-myc and Bcl-2 proto-oncogen expression, in an effort to better characterize these lesions noninvasively. This information is anticipated to be useful in selection of therapeutic regimens appropriate for the expected degree of chemotherapy resistance. In patients with neuroblastoma undergoing radiation or chemotherapy, it is anticipated that serial studies will show that changes in tumor uptake of C-11 epinephrine reflect the tissue response to treatment and serve as an early indicator of therapeutic efficacy or failure. Such knowledge obtained early during the course of therapy would allow for prompt changes from ultimately unsuccessful therapeutic regimens to more promising combinations, or continuation of regimens with evidence of early success. In neuroblastoma cell lines, we will explore the mechanism of uptake and storage of epinephrine, and compare the retention and already characterized genetic alterations for additional index of prognosis. The applicants expect to show that the retentio of C-11

Studies

19

epinephrine within pheochromacytoma reflects catecholamine storage capacity, and thus could identify those tumors with greatest tendency for bloo pressure lability and dangerous catecholamine surges. If such information abou neuroblastomas and pheochromocytomas can be made available noninvasively by PE scanning with C-11 epinephrine, the understanding of the pathophysiologic process and the management of patients with these neuroendocrine tumors could be substantially improved. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONTINUOUS CELL SORTING BY MAGNETOPHORESIS Principal Investigator & Institution: Zborowski, Maciej; Associate Staff; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2004; Project Start 18-FEB-1994; Project End 31-JAN-2008 Summary: (provided by applicant): In the previous support period, we developed tools for continuous magnetic flow cell sorting based on cell magnetophoresis. We also developed cell tracking velocimetry to measure cell magnetophoretic mobility. Cell sorting based on magnetophoresis of freely suspended cells has the potential for improved performance over current magnetic separation methods that rely on cell immobilization on magnetic wire and bead matrices. By optimizing both the flow sorter channel geometry and the applied magnetic field (annular flow in a quadrupole field), we achieved high sorting speed (10[7] cells/s) with high cell purity (90% purity of CD34+, at recovery of 30%). Furthermore, separated cell viability remained high due to relatively low shear stress experienced during sorting. The technology development was aided by collaboration with the Cleveland Clinic Taussig Cancer Center and the Ohio State University. Based on the strengths of the current effort, we propose to further evaluate the technology with the focus on the following: Aim 1: To compare the technology with a benchmark high-gradient magnetic separation (HGMS) method based on extrinsic cell magnetization with antibody-conjugated magnetic nanoparticles. First, we will test positive cell separation of long term colony-initiating cells from committed blood progenitor cells. The fractionated cells will be fully characterized in terms of their phenotypic and functional characteristics (in collaboration with Dr. Maciejewski at the Taussig Cancer Center). Second, we will test negative separation in application to isolation of rare cancer cells from circulating blood. Circulating white blood cells will be targeted by anti pan WBC antibody (such as anti CD45 Ab) and will be separated from the un-labeled, non-mobile non-WBCs, representing the likely candidates for the cancer cells in the circulating blood (in collaboration with Dr. Chalmers at the OSU). Aim 2: To investigate the intrinsic magnetophoresis of fresh, un-manipulated (unlabeled) cells. Magnetophoretic cell sorting may allow separation of cells differing in their intrinsic magnetization (without application of extrinsic magnetic nanoparticles). We will test the technology first on cell lines that can be induced to express high levels of ferritin, and second, on selected primary leukemia samples known for their elevated intracellular ferritin level. Aim 3: To further investigate the magnetophoretic process and refine the cell tracking velocimetry instrumentation for applications to cancer therapy. In particular, we will determine the applicability of MRI contrast agents to modification of the magnetic susceptibility of suspending medium to enhance magnetophoretic cell sorting and achieve high purity and recovery of the target cells (in collaboration with Dr. Hafeli). The proposed research will help to fully characterize the magnetophoretic cell sorting process, further improve the tools, and determine the applications relevant to the diagnosis and therapy of cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Ferritin

Project Title: CORE--TRACE METAL ANALYSIS FACILITY Principal Investigator & Institution: Graziano, Joseph H.; Professor Public Health And; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002 Summary: The trace metal laboratory has been established for twenty-five years. It has a long-standing interest and experience in the measurement of metals and of metalloproteins. It has served as a service facility for multiple funded projects and for several important pilot or development projects. It served as the core laboratory for the P20 Development Grant. Due to the increased demand for the procedures and measurements provided by the laboratory, the Columbia School of Public Health is providing space to the Center to establish a core laboratory specifically and solely dedicated to trace metals and matalloprotein analyses. This Center would provide, in a centralized laboratory, analyses not otherwise available at the Columbia Health Sciences Campus. The core laboratory will provide the ability to measure a wide range of metals in biologic samples and will measure in serum and plasma major proteins involved in mineral metabolism. The present laboratory from which this core will be developed has extensive capabilities in the analyses of metals and a long history of success in It has developed and is continuing to develop modern and appropriate methods to measure such proteins as lactoferrin, lactoferrin receptors and melanotransferrin. It is using standardized methods for measurement of ferritin, transferrin, and transferrin receptors. accomplishing excellent performance on quality control and standardization programs for lead and mercury. It is using modern and well-developed atomic absorption methods for these analyses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROTECTION

CORNEAL

EPITHELIAL

NUCLEAR

FERRITIN

AND

UV

Principal Investigator & Institution: Linsenmayer, Thomas F.; Professor; Anatomy and Cellular Biology; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: Ultraviolet (UV) light constitutes a major environmental insult to all exposed tissues of the body, including those comprising the cornea and other underlying ocular structures. UV light can damage a wide variety of macromolecular components ranging from DNA, to proteins, to lipids, with damage to DNA resulting, for example, in cancer. This damage can be direct, or it can be indirect through the generation of active oxygen species (AOS). Corneal epithelial (CE) cells, however, seems to be refractory to such damage. Cancers of these cells are extra-ordinarily rare, even though this tissue is transparent and constantly exposed to mutagenic UV light and other sources of AOS such as H2O2. Our results suggest that one mechanism that CE cells have evolved to prevent damage to their DNA involves ferritin in a nuclear localization, rather than the cytoplasmic location it has in all other cell types. This molecule seems to directly diminish the effects of UV-produced AOS to DNA and possibly other nuclear components-most likely be sequestering free iron which acts as a catalyst in generating hydroxyl radicals, the most damaging AOS. The areas that will be investigated further: 1) the mechanisms involved in the nuclear localization of ferritin in CE cells, 2) how this molecule protects DNA from UV-induced and other oxidative damage, and 3) how production of the molecule is developmentally regulated. For the nuclear localization in CE cells two possible mechanisms will be examined. One is the involvement of a CE tissue-specific chaperone that is capable of carrying ferritin "piggy-back" into the

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nucleus, and the other is that some specialization of the CE cell nucleus itself is responsible for the transport. Then the role of iron sequestration in decreasing UVinduced damage to the DNA of CE cells will be evaluated further. It will also be determined whether this protection extends to other sources of AOS, and whether similar protection can be afforded to other cell types in which UV-induced and other sources of AOS potentially have deleterious effects. Lastly, the regulation of production of nuclear ferritin will be investigated-chiefly at the early, pre-ferritin stage of development, which our preliminary data suggest may be under a unique type of translational regulation involving low levels of iron plus another component(s) such as thyroxine. This mechanism may produce a low-iron ferritin that is highly efficient at iron sequestration and therefore protection against damage by AOS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CRYSTALLOGRAPHIC STUDIES OF IRE BINDING PROTEIN Principal Investigator & Institution: Lawrence, Charles Martin.; Chemistry and Biochemistry; Montana State University (Bozeman) Bozeman, Mt 59717 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 30-APR-2004 Summary: (adapted from the application) The goal of this application is to study the interactions of iron response proteins with their RNA binding sites, using X-ray crystallography. These interactions play a central role in the regulation of iron transport and homeostasis. Diseases of iron transport and metabolism are among the most prevalent causes of human suffering and mortality. A greater understanding of the regulation of iron absorption and utilization will be important in developing treatments for iron deficiency and iron overload. Iron regulatory proteins (IRPs) exert translational control over the levels of other proteins involved in iron metabolism. Two IRPs are known, IRP-1 and IRP-2. When iron levels are low, these proteins recognize specific stem/loop structures known as iron response elements (IREs), which are present in the target mRNAs. For proteins whose levels are downregulated in low iron, the IRE is typically found in the 5' untranslated region of the message and binding of the IRP to the IRE inhibits translation of the message. For proteins that need to be expressed at higher levels under low iron conditions, the IRE is generally found in the 3' untranslated region, where IRP binding stabilizes the transcript, resulting in increased expression of the protein. Using X-ray crystallography, we will pursue the structure of IRP-2 alone and in complex with the two known classes of IRE mRNA binding sites. We will pursue crystal structures of IRP-2 in complex with a C bulge type IRE, and in complex with a ferritin loop/bulge type IRE. Upon the completion of IRP-2 structures, further structure function studies will be initiated. These studies will use site directed mutagenesis, biochemical characterization and structure determination to further explore IRP-2/IRE structure and function. The greater insight provided by these studies into the specific interactions of IRPs with IREs may lead us a step closer towards the development of treatments for disease of iron metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CURCUMIN, FERRITIN, AND OXIDATIVE STRESS Principal Investigator & Institution: Torti, Suzy V.; Biochemistry; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 15-SEP-2001; Project End 31-AUG-2003 Summary: (provided by applicant) Ferritin is a protein with a pivotal role in the protection against oxidative stress. Due to its ability to sequester iron, ferritin reduces

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the availability of iron to catalytically generate oxygen free radicals through Fenton chemistry. Consistent with this protective role, the investigators have recently observed that ferritin is transcriptionally-induced in response to oxidative stress, and that ferritin overexpression can substantially dampen free radicals generated in response to exogenous stress stimuli. The response of ferritin is mediated by a cis-acting element, the antioxidant response element (ARE, also called EpRE or OSRE). The ARE is also found in other cytoprotective proteins, such as the gluthatione-S-transferases, heme oxygenase, gamma glutamyl cysteine synthetase, NAD(P)H quinone oxidoreductase and others. These enzymes constitute the so-called Phase II response. The investigators' observations therefore link ferritin and hence iron biology to this antioxidant cytoprotective response, and suggest that ferritin might play a role in the cytoprotective action of chemopreventive agents. They further suggest that dietary nutrients that induce the phase II response will induce ferritin. The preliminary results show that this is in fact the case: curcumin, a natural chemopreventive agent found in turmeric, curry and mustard, induces ferritin in vitro. The overall hypothesis to be tested in this proposal is that ferritin plays a role in the protection against oxidative stress and oxidative stress-induced tumorigenesis mediated by the dietary nutrient curcumin. The Specific Aims are to: (1) Characterize the effect of curcumin on ferritin. Mice will be fed diets containing curcumin, and the response of ferritin compared to that of other Phase II proteins will be assessed. The relationship between ferritin induction, oxidative stress, and tumor formation in mice will be assessed. (2) Isolate and evaluate the contribution of ferritin induction to the overall cytoprotective response induced by curcumin. Cells will be treated with curcumin, and their response to oxidative challenge assessed. The role of ferritin induction in oxidative stress protection will be tested by selectively blocking ferritin induction. The investigators will also test whether protection afforded by curcumin can be recapitulated by overexpression of ferritin. Over the long term, the studies may suggest practical nutritional intervention strategies for the reduction of oxidative stress through nutritional modulation of ferritin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF INDUCIBLE ANTIOXIDANTS ON HEMOGLOBIN TOXICITY Principal Investigator & Institution: Regan, Raymond F.; Emergency Medicine; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2003; Project Start 01-DEC-2002; Project End 30-NOV-2006 Summary: (provided by applicant): Hemorrhage complicates many traumatic injuries to the CNS and about 20% of strokes. Over subsequent hours, erythrocytes lyse and release their contents into the extravascular space. The most abundant protein released is hemoglobin (Hb). A growing body of experimental evidence suggests that the oxidative toxicity of extracellular Hb contributes to the pathogenesis of hemorrhagic CNS injury. Moreover, because of its prolonged time course, Hb toxicity may be an ideal target for therapeutic intervention. Further insight into the cellular mechanisms and prevention of this toxicity therefore seems desirable. Cultured neurons are highly vulnerable to Hb, but astrocytes are resistant via a mechanism that requires protein synthesis. Preliminary experiments suggest that this discrepancy may be explained in part by the effects of two inducible antioxidants: heme oxygenase (HO)- and ferritin. The former is rapidly induced by Hb and may facilitate synthesis of L-rich ferritin in astrocytes. In contrast, Hb decreases the expression of L-rich ferritin in neurons; iron released as a product of heme breakdown may then be toxic. This project will address the role of HO and ferritin in cell culture and in vivo models. Overexpression of HO-1 will be accomplished in

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glial, neuronal, or mixed cultures via gene transfer; the relationship between activity, heme-mediated reactive oxygen species formation, and cell death will be established. Cellular vulnerability to Hb or hemin will then be compared in cultures prepared from wild-type, HO-1 knockout, and HO-2 knockout mice. Using antibodies that specifically recognize H- or L-ferritin, the subunit content of ferritin will be assessed at baseline and in response to Hb in these cultures. Expression of HasA, which binds to and may facilitate heme iron uptake, will also be determined. H and L-rich ferritin heteropolymers will be constructed from recombinant H or L-ferritin. Neuronal and glial uptake of these heteropolymers via receptor-mediated endocytosis will allow investigation of the effect of the H:L ratio on cellular vulnerability to heme-mediated injury. Finally, the putamen of wild type, HO-1 or HO-2 knockout, and transgenic mice that overexpress HO-1 will be injected with Hb, or with collagenase to induce an endogenous hemorrhage. Surrounding neuronal loss, DNA cleavage, and caspase-3 activation will then be quantified at defined time points 12-96 hours after injection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTIVE ORAL IRON SUPPLEMENT FOR PRE-DIALYSIS PATIENTS Principal Investigator & Institution: Janghorbani, Morteza; Biochemanalysis Corporation 2201 W Campbell Park Dr Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: (provided by applicant): Development of anemia is a major problem in chronic renal failure. Its prevention/early treatment with recombinant human erythropoietin (rHuEpo) during pre-dialysis phase is important. Available iron is required for efficient action of rHuEpo; iron supplements are often needed; oral iron therapy is the preferred mode. Availability of oral iron varies widely in these patients; its efficacy cannot be ensured. We propose to develop a noninvasive method for direct assessment of the two steps that determine iron absorption: initial mucosal uptake (IMU), mucosal-serosal transfer (MST). Our approach is based on oral administration of a GelCap with known amounts of stable-isotope-labeled 58FESO4, the non-absorbable marker DyC13, and the visual marker brilliant blue to fasted patients, followed by laboratory analysis of the ratio 58Fe- Excess/Dy in the visually-marked sample of stool. Normalizing this ratio to the known intake of Dy yields IMU. Laboratory analysis of a blood sample taken two weeks later for 58Fe-Excess provides data for whole-body retention and the ratio of this to IMU is MST. We hypothesize that the inverse correlation between iron absorption (IMU and MST) and iron stores (as indicated by serum ferritin) is the basis for the widely variable absorption of oral iron in these patients; and that iron absorption can be enhanced by chronic ingestion of safe doses of ascorbic acid, and/or appropriate rHuEpo treatment. During Phase-I we will establish the feasibility of the approach by testing the following HYPOTHESIS: absorption of nonheme iron (IMU and MST) is inversely related to serumferritin in pre-dialysis patients, in 20 pre-dialysis patients with serum ferritin in the range expected in clinical practice. During Phase-II we will focus on how to optimize iron absorption (IMU and MST) by judicious administration of ascorbic acid and rHuEpo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECTS OF HEAT AND/OR RADIATION ON PROTEASOME FUNCTION Principal Investigator & Institution: Mcbride, William H.; Professor of Radiation Oncology; Radiation Oncology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-MAR-2001; Project End 28-FEB-2005 Summary: (Provided by applicant): The ubiquitin/proteasome system is the major mechanism for dynamically regulating selective, time controlled destruction of key signaling molecules. Through the control it exerts on cell cycle progression, transcription, DNA repair, and apoptosis, it critically determines the cellular responses to stress. Importantly, the rate of degradation of substrates by the proteasome varies with physiological and pathological conditions. (We have made the novel observation that radiation or heat treatment directly affects proteasome activity. This has profound implications for radiation- and heat-induced molecular responses. For example, the rate of degradation of IkappaBalpha is slowed, with consequences for NF-kB activation and cell survival. Proteasome structures within cells come in several distinct forms that vary between cells and tissues. This study will use a number of genetic and biochemical approaches to determine the type of proteasome and the subunits that are most affected by heat and/or radiation. The hypothesis that hsp90, a known endogenous inhibitor of proteasome function, mediates heat- and radiation-induced proteasome blockade will be tested. Proteasome structure will be linked to biological function using genetically deficient cells and the biological consequences of proteasome diversity for the response to heat and/or radiation will be evaluated in vitro and in vivo.) Many studies have focused on transcriptional activation of genes following heat and radiation. Here, we will evaluate the importance of a major non-transcriptional control mechanism that can rapidly, selectively, and simultaneously co-ordinate multiple facets of the molecular response of cells to therapeutic agents. We believe that this cellular control mechanism is critical in determining cellular responses to heat and radiation and serves as a potential novel target for therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FACTORS REGULATING THE CELLULAR UPTAKE OF IRON Principal Investigator & Institution: Kaplan, Jerry; Professor; Pathology; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-JAN-1982; Project End 31-DEC-2004 Summary: (Adapted from investigator's abstract) The applicants note that iron is an essential element but that excessive iron accumulation leads to cell and organ dysfunction. Multiple tightly regulated mechanisms exist to meet the cellular need for iron and to remove iron from biological fluids. The applicants plan to continue their approach of using yeast genetics to identify genes involved in iron metabolism. They first plan to study multicopper oxidase-based iron-transport systems. Studies in humans and in yeast have identified the ferroxidase activity of multicopper-based iron-transport systems as responsible for selective high-affinity iron transport across the plasma membrane. The applicants propose to use a combined genetic and biochemical approach to determine the mechanisms of assembly of the active site of multicopper oxidases. Studies in yeast by the applicants have provided evidence that chloride provided by intracellular chloride channels is required to assemble copper on the yeast Fet3p. They now propose to determine how chloride is involved in copper assembly and whether chloride binds to the enzyme. In yeast, the ferroxidase is involved in iron uptake, while

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in humans ferroxidases are involved in iron export and import. The applicants plan to determine the physical relationship between multicopper oxidases and the direction of iron transport, testing their hypothesis that it is the iron carrier or transporter that determines the direction of iron transport. In addition, the applicants will determine if Hephaestrin, the gene responsible for the phenotype of defective iron transport in the sex-linked anemia (sla) mouse, is a multicopper oxidase. If so, they plan to examine its cellular location and assembly. Iron, as well as other transition metals, is transported across the membrane of the vesicular system (endoplasmic reticulum, Golgi and lysosomes). The function of vesicular metal transport is two-fold: i) to store metals within the vesicular system, thereby removing them from the cytosol; and ii) to assemble metallo-proteins that are either resident or secreted enzymes. Using yeast genetics, the applicants have identified iron and copper-regulated or dependent transport systems in the vesicular apparatus. They now plan to define the function of these transporters, determining whether these transporters are involved in metal storage or metallo-enzyme assembly. They propose genetic approaches to determine if zinc or iron is stored in the vacuole and to identify the responsible transporters. They plan to determine where the lysosomal iron enzyme tartrate-resistant acid phosphatase (TRAP) obtains its iron by expressing this molecule in yeast and, then using selection systems to define iron transporters. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FERRITIN, IRON HOMEOSTASIS AND CELLULAR STRESS Principal Investigator & Institution: Torti, Frank M.; Director/Chairperson; Internal Medicine; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-SEP-1989; Project End 31-JUL-2006 Summary: (provided by applicant): The metallochemistry and molecular biology of iron converge in the study of ferritin structure and function. Ferritin is an iron binding protein whose regulation, once thought to be responsive only to changes in cellular iron content, has more recently been shown to be targeted by stress-induced stimuli, including cytokines, oxidants, and a range of xenobiotics. We now know that agents such as tumor necrosis factor, reactive oxygen species, and other stimuli trigger ferritin induction; ferritin, in turn, alters cellular iron homeostasis by sequestering reactive, "low molecular weight" cellular iron. This in turn reduces susceptibility to subsequent stress. In this proposal we explore the hypothesis that ferritin regulation is instrumental in modulating the magnitude and character of the cellular response to injury and stress. We examine the unique contribution of ferritin to the phenotype of cells and tissues exposed to prooxidants and antioxidants. In our first Specific Aim, we explore the molecular mechanisms by which ferritin participates in the chemopreventive response to prooxidant xenobiotics. In our second Specific Aim, we explore potential pathways by which oxidative stress regulates ferritin in health and disease. In our third Specific Aim, we develop in vivo mouse models to test the relevance of our findings in the context of whole animals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FERRITIN, ISO-IRES AND IRON IN VITRO AND IN CELLS Principal Investigator & Institution: Theil, Elizabeth C.; Senior Scientist; Children's Hospital & Res Ctr at Oakland Research Center at Oakland Oakland, Ca 946091809 Timing: Fiscal Year 2002; Project Start 01-AUG-1977; Project End 31-JUL-2003

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Summary: Ferritin overcomes the 10(-13-)-fold mismatch between iron needs and solubility by concentrating iron as a solid mineral. High ferritin expression in erythrocytes of the embryonic cell line, plus easy access to embryonic red cells in tadpoles, led to the frog model. Frog iron metabolism accurately models humans; studying common features assures fundamental biological significance and health relatedness. Iron is mineralized in a commodious cavity of iso-ferritins created by mixtures of 24 (H, L, H+L, H+L+M) protein subunits. Iron ions are translocated through the protein, to and from the cavity. Ferritin expression is precisely is precisely regulated, using both DNA and mRNA targets. Red cell ferritin is coordinately regulated with erythroid aminolevulinate (eALAS), the transferrin receptor (TfR) [Nramp2?] via the mRNA iso-elements (IREs), and a family of IRE recognition proteins, (IRPs). The wide range of ferritin function and regulation possible emphasize the central role of iron in red cells and other cells. During the last grant period the major results obtained were: 1mRNA (IRE/IRP). a) NMR structure and model of the ferritin-IRE; b) identification of IRE isoform structure and differential IRP + binding; c) Targeting mRNA of the ferritinIRE; b) Identification of IRE isoform structure and differential IRP + binding; C) Targeting mRNA o with a TMC in vivo; 2- Ferritin protein: a) Identification of new intermediates in ferritin mineralization: diferric peroxo decay, and tri-iron clusters; b) Location of a ferritin protein site where iron exits, a new target for iron chelation. 3Ferritin genes and iron nutrition: a) Dietary ferritin, pure or in soybeans, cured iron deficiency anemia in rats. b) Characterizing soybean ferritin genes, to improve seed iron composition, showed the absence of the IRE. Both the newly identified ferritin DNA promoter in plants and mRNA "promoter" in animals responded to the same signals, emphasizing the fundamental chemistry of iron/oxygen in biology and the central significance of ferritin signals, emphasizing the fundamental chemistry of iron/oxygen in biology and the central significance of ferritin. Specific aims proposed are: 1-Iso-Ire structure/function. Effects of IRE subdomains of ferritin synthesis, mRNA stability, Tm (+/- metals) and nuclease cleavage related to IRP1/IRP2 binding in vitro and in vivo 2. Ferritin function-iron uptake and release related to cellular iron metabolism: Effects of engineered H and L type subunits on iron uptake and release in vitro (UV-vis, RFQ Mossbauer, RR, ENDOR and EXAFS and X-ray crystallography) and in vivo. 3. IsoIRE/protein "footprint" interactions in vivo. Long term goals are the targeting of ferritin mRNA and protein for therapies in iron overload and targeting mRNAs in viral and oncogenic diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FET3 (FERROXIDASE) AND FTRL (PERMEASE) IN IRON UPTAKE Principal Investigator & Institution: Kosman, Daniel J.; Professor; Biochemistry; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2004; Project Start 01-MAY-1999; Project End 30-NOV-2007 Summary: (provided by applicant): Eukaryotic iron metabolism involves two processes: redox cycling and trafficking. The transport of 'free' iron across eukaryotic plasma and some intracellular membranes is a paradigm of this metabolism. Thus, uptake of environmental Fe3+ involves first its reduction by a plasma membrane ferrireductase. The Fe2+ produced can be substrate for a multicopper oxidase - a ferroxidase - that couples the reduction of O2 to the production of 4Fe3+. This ferric iron is then ligand for an iron permease that transports the iron across the plasma membrane. High affinity iron uptake in the yeast, Saccharomyces cerevisiae, exhibits all of these features. The metalloreductase, Fre1p, produces the Fe2+ that is substrate for ferroxidation by Fet3p, a ceruloplasmin ortholog, with permeation facilitated by Ftr1p. In yeast, as in the

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intestinal epithelium, the ferroxidation and permeation steps are coupled in the strict metabolic sense: permeation requires ferroxidation. This coupling suggests a primary hypothesis of this research: in the Fet3p, Ftr1p system the ferric iron product of the Fet3p ferroxidase reaction is channeled to Ftr1p for subsequent transmembrane trafficking. A template for this model is the movement of iron into and out of the ferritin (Ft) core. This hypothesis requires that both Fet3p and Ftr1p possess amino acid residues that participate in this channeling process, in addition to those structural motifs required for ferroxidation and permeation per se. There also may be motifs associated with the coupling of these two processes. The objective of this research is a full and detailed structure-function analysis of the Fet3p, Ftr1 system using biochemical, biophysical, genetic and cell biology approaches. These include: kinetic, spectral and crystallographic studies of wild type and mutant Fet3 proteins; iron uptake kinetic analysis of Ftr1p iron trafficking mutants; biochemical, genetic and fluorescence analysis of the physical and functional interaction between Fet3p and Ftr1p; and kinetic and electrophysiologic analysis of the coupling of ferroxidation and uptake. This structurefunction characterization of the Fet3p, Ftr1p system will provide significant new understanding of eukaryotic iron trafficking. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FOLATE-GENOME INTERACTIONS IN COLORECTAL CANCER Principal Investigator & Institution: Stover, Patrick J.; Associate Professor; Div/Nutritional Sciences; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853 Timing: Fiscal Year 2004; Project Start 07-MAY-2004; Project End 30-APR-2008 Summary: (provided by applicant): This research aims to elucidate the molecular mechanisms that account for the associations between impaired folate status and risk for colon cancer using purpose-designed mouse models. Folate metabolism is necessary for the synthesis of nucleotides (purines and dTMP) and S-adenosylmethionine (SAM). Disruption of folate metabolism by vitamin deficiency or single nucleotide polymorphisms can affect SAM and dTMP syntheses and thereby influence DNA methylation density and uracil content. Both DNA uracil content and methylation density affect DNA stability, and DNA methylation also regulates the expression of many genes. It is not known if the associations between folate and colon cancer risk result from altered SAM synthesis and/or dTMP synthesis. Recently, we have demonstrated that the enzyme cytoplasmic serine hydroxymethyltransferase (cSHMT) is a metabolic switch that directs the flux of folate-activated one-carbon units between dTMP and SAM biosynthetic pathways, cSHMT expression and activity is regulated by several dietary components including retinoic acid, iron/ferritin and vitamin B6. Therefore, the eSHMTmediated metabolic switch is likely involved in the etiology of folate-related pathologies and may be a target for prevention. In this proposal, we will determine the metabolic role of eSHMT in regulating folate metabolism, DNA and histone methylation, DNA stability and gene expression in the colonic crypts and determine if disruption of either dTMP or SAM synthesis increases (or protects against) colon cancer incidence in established mouse cancer models. The principle hypotheses to be tested are that: (1). cSHMT regulates folate metabolism in the colonic crypt. (2). cSHMT expression is regulated in the crypts of the colon by ferritin and influences cancer risk. (3). changes in cSHMT influences genomic methylation, expression and stability in the colonic crypt. The long-term goal of this project is: (1). to determine the mechanism whereby alterations in folate metabolism influence cancer risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FREE RADICALS IN HYPERTHERMIA Principal Investigator & Institution: Buettner, Garry R.; Professor/ Senior Research Scientist; Radiology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: Therapeutic hyperthermia is the production of super-physiological temperatures for treatment of disease. Hyperthermia is currently being investigated as an adjuvant for many cancer therapies, (e.g. prostate cancer) including radiation and photodynamic therapy. The oxidative stress theory of heat shock has the following components: heat shock can produce free radicals and related oxidants; these species can cause part of the cellular injury produced by heat; and cellular injury can be tolerated if protective proteins are induced. The research proposed in this application is designed to test the oxidative stress theory of heat shock. We hypothesize that cells subjected to hyperthermia (e.g., 41-45 C) will produce an increased flux of free radicals. Thus, using cultured cells we will: detect and identify these free radicals using electron paramagnetic resonance; examine the overall flux or oxidants in cells; and examine the response of cells to these oxidants. We hypothesize that elevated levels of the antioxidant enzymes superoxide dismutase (SOD) and/or glutathione peroxidase (GPx) will lead to thermotolerance, whereas depressed levels of SOD and/or GPx will lead to heat sensitivity. We will test this hypothesis by using molecular biology techniques to alter the antioxidant enzyme level in cells and then test their thermotolerance. For those cells capable of generating nitric oxide, we hypothesize that heat will result in increased production of nitric oxide, which under certain circumstances, can be cytotoxic. We will examine the ability of cultured endothelial (and other appropriate) cells to generate nitric oxide in response to hyperthermia and determine if this nitric oxide is detrimental. If ROS are important, then we would predict that catalytic iron would increase in heatstressed cells, thereby amplifying the oxidations initiated by heat treatment. We will examine the role of this iron in producing cell toxicity during hyperthermia and determine if modulation of catalytic iron levels will alter the thermotolerance of cells. This proposed research program is designed to test the hypothesis that production of free radicals and related oxidants is an important aspect of the detrimental effects of hyperthermia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC MODIFIERS IN CHILDREN WITH SICKLE CELL ANEMIA Principal Investigator & Institution: Ware, Russell E.; Director; Pediatrics; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; 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)

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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. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC MODIFIERS OF HEMOCHROMATOSIS PHENOTYPE Principal Investigator & Institution: Gertig, Dorota M.; University of Melbourne Parkville 3052, Australia Parkville, Timing: Fiscal Year 2004; 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 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

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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. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GPX1 ENZYME REGULATION BY OXIDATIVE XENOBIOTICS Principal Investigator & Institution: Kelner, Michael J.; Professor; Pathology; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 01-DEC-1997; Project End 30-NOV-2004 Summary: (Adapted from the Investigator's Abstract) Oxygen metabolism release toxic products called free radicals which are implicated in many human diseases including autoimmune, ischemia/stroke, drug/toxin damage, atherosclerosis, arthritis, diabetes, ALS, aging, and cancer. Protection against free radical damage is provided by antioxidant enzymes including GSH-dependent enzymes. The cytosolic seleniumdependent glutathione peroxidase (GPXl) is one of the most important GSH-dependent protective enzymes. While detailed biochemical studies on GPXl regulation have been accomplished, little is known of regulatory control at a molecular level, notably in regard to induction of GPXl during stress. This proposal will investigate the regulation of GPXl by characterizing novel negative and positive regulatory elements in the flanking 5-nontranslated (5'NTR) or promoter region of the gene. Studies include DNA footprinting, nucleotide mutagenesis, and serial nucleotide deletion from 5'NTR GPXl/reporter chimeric constructs to identify nucleotides comprising the elements. The DNA-binding protein to the major oxidant-responsive element (ORE3) will be isolated. A novel element ORE4 is identified in the 5'UTR of GPX1 that may repress GPXl mRNA translation until oxidative stress occurs, similar to the iron-responsive element (IRE) in ferritin. Studies will determine the functional role of this element and its corresponding binding protein (ORE4-BP (previously isolated). The elements responsible for basal or core GPXl expression, as well as tissue-specific elements responsible for the unusual tissue expression of GPXl, will be identified. The mouse GPXl gene will be characterized to allow comparison to human GPXl in regards to basal, oxidative-responsive, and tissue-specific elements. These studies will provide critical information regarding cellular response to oxidative stress and aid in determining if a common regulatory mechanism exists for GSH-dependent enzymes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HCV & ALCHOOL-- EPIDEMIOLOGY & HOST-VIRUS CORRELATES Principal Investigator & Institution: Peters, Marion G.; Professor of Medicine; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2005 Summary: Alcohol and hepatitis C virus (HCV) infection are recognized as independent causes of chronic liver disease and cirrhosis. Further, significant alcohol ingestion, defined variably as >30 gnvday (women) or >50-60 grnlday (men) has been associated with more severe histological disease, including cirrhosis and hepatocellular carcinoma and an accelerated rate of disease progression in patients with chronic HCV infection.

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The effect of more limited alcohol intake or non-daily drinking patterns on the progression of HCV disease are not known. In this study, we will establish a prospective cohort of at least 550 HCV-infected patients who drink varying amounts of alcohol at study entry. Total lifetime alcohol intake, patterns of alcohol ingestion, and periods of abstinence will be ascertained using validated questionnaires (Skinner, 1979; Russell, 1991) at study entry and annually for four years. Additional data collected at study entry include demographic, epidemiological and dietary history (including duration of HCV infection, mode of acquisition, use of iron supplements). A comprehensive evaluation of HCV RNA including viral titer in serum, liver and peripheral blood mononuclear cells (PBMCs), and baseline quasispecies complexity, will be obtained. Subjects with an alcohol intake of >30 gm/day (females) or >60 gm/day (males) will be counseled to completely abstain. A subset of 150 subjects drinking E10) ciliary ganglion neurons were not killed. N-terminal sequencing revealed that this activity was ovotransferrin. Death inducing activity required that iron be bound to the transferrin. The EC50 of diferric recombinant transferrin in inducing apoptosis was 5nM, well within the levels found in embryonic extracellular fluid and blood (30-40 uM). This effect of FeTr was not limited to ciliary ganglion neurons: lumbar sympathetic ganglia contain two populations of neurons, one which survives in nerve growth factor and does not die when exposed to FeTf, and another which survives in clilary neurotrophic factor (CNTF) and is killed by FeTf. The developmental switch in CG neuron sensitivity to FeTf suggests that susceptibility of neurons to transferrinmediated apoptosis is likely to be a normal developmental event that is regulated by cell-cell interactions. The investigator proposes to study the molecular basis for the differential sensitivity of neurons to killing caused by transferrin-mediated iron transport. These studies are likely to lead to important clues as to how the process may go awry in neurodegenerative disease. The specific aims are: (1) to test the hypothesis that neurons become sensitive to killing by FeTf when they fail to downregulate transferrin receptor, human transferrin receptor will be overexpressed in insensitive neuronal populations in order to test whether it confers sensitivity to killing by human FeTf; (2) to test the hypothesis that susceptibility to FeTf is mediated by reduced levels of ferritin, the intracellular iron binding protein, ferritin heavy chain will be overexpressed in order test whether neurons are protected from death induced by FeTf; (3) to test the hypothesis that intracellular iron induces apoptosis by accumulating in mitochondria through reduced levels of frataxin, a protein that stimulates iron transport out of mitochondria, frataxin will be overexpressed in neurons in order to determine if they can be protected from killing by FeTf; and (4) to test the hypothesis that intracellular iron kills cells by generating excess free radicals which damage mitochondria, it will be determined if: (1) FeTf generates free radicals; (2) anti-oxidants rescue neurons from FeTf; (3) inhibitors of oxidative phosphorylation induce apoptosis

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with the same characteristics as FeTf; (4) cytochrome c is released by FeTf treated neurons; (5) overexpression of the mitochondrial anti-apoptotic protein Bcl-2 protects cells from FeTf; and (6) caspase inhibitors rescue neurons from FeTf. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IRON METABOLISM AND PHOSPHORYLATION OF IRPS BY PKC Principal Investigator & Institution: Eisenstein, Richard S.; Associate Professor; Nutritional Sciences; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-JAN-1994; Project End 31-DEC-2002 Summary: Iron is an essential but potentially toxic nutrient for virtually all organisms. Iron deficiency is the most common human nutritional deficiency disease. At the same time excessive iron stores have been associated with increased occurrence of neurological disorders and certain cancers. Mammalian iron metabolism is modulated through the action of two regulatory RNA binding proteins, iron regulatory protein 1 (IRP1) and IRP2. IRPs bind to iron responsive elements (IRE) in ferritin (iron storage) and transferrin receptor (TfR) (iron uptake) mRNAs and regulate their translation or stability, respectively. IRP1 is an Fe-S protein and the presence or absence of the Fe-S cluster modulates the RNA binding activity of the protein. Iron regulates the RNA binding activity of a related protein, IRP2, by inducing its degradation. Because IRPs are pivotal regulators of iron metabolism, and directed changes in iron metabolism occur in human health and disease, it is important to better understand how iron and other factors affect IRP function. Our overall goal is to determine how iron metabolism is modulated through the action of intracellular and extracellular effectors that influence IRP action. We have begun to elucidate a novel mechanism by which protein kinase C (PKC)-dependent phosphorylation of IRPs serves as a means through which hormones, growth factors and other agents can act to influence cellular iron metabolism. We propose to: 1) use a structure/function approach to determine how phosphorylation affects IRP function in vitro; 2) determine the cellular role of phosphorylation in the function and compartmentalization of IRPs; and 3) determine the effect of iron and oxidative stress on the cellular function of phosphorylated IRPs. Our broad goal with regard to IRP1 is to understand how regulated changes in assembly and stability of its Fe-S cluster affect its function as an iron-regulated RNA protein. Our overall goal for IRP2 is to delineate how phosphorylation affects the redox and iron-regulation of its proteasomal degradation. Our studies provide a comprehensive approach from the molecular to the whole animal level that will: 1) delineate a novel mechanism for regulated changes in stability of Fe-S clusters in mammals; 2) describe a unique example of how phosphoregulation and iron-regulation overlap to establish the steady state level of the regulatory RNA binding proteins, IRP1 and IRP2; 3) further define the molecular pathways through which mammalian iron metabolism can be regulated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IRON METABOLISM IN MOSQUITOS Principal Investigator & Institution: Winzerling, Joy J.; Nutritional Sciences; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 15-AUG-1998; Project End 30-JUN-2004 Summary: Iron is an essential mineral for all species. We are studying iron metabolism in the disease vector, Aedes aegypti. Ferritin and the iron regulatory protein 1 (IRP1) are important proteins of vertebrate iron metabolism. Ferritin is required for intracellular

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iron storage, and IRP1 is an important translational regulatory control factor for ferritin expression. Our work indicates that both proteins are also present in mosquitos. Our central hypothesis is that changes in the expression of ferritin and in IRP1 activity contribute to the ability of the females to adapt to the iron load of a blood meal. Our specific aims are to study the structure and function of Ae. aegypti IRP1 (aIRP1), to determine whether the aIRP1 regulates translation of the Ae. aegypti ferritin subunits, and to evaluate the effect of iron availability on the in vivo expression of ferritin and IRP1, and on aIRP1 activity in mosquito cells. We will accomplish these aims by studying the in vitro formation of an iron sulfur cluster in the IRP1, aconitase activity of aIRP1, aIRP1 control of in vitro translation of ferritin messages, and the expression of ferritin, IRP1 and IRP1/IRE binding activity in Ae. aegypti Aag2 cells in response to iron deprivation and excess. Our long term goals are: (1) to study the effects of an iron load on the expression of iron-binding proteins in mosquitos; (2) to study changes in the expression of these proteins in mosquitos during development; and (3) to evaluate the potential effects of nitric oxide and oxidants on the synthesis and function of these proteins in mosquito cells. This work will provide information that could apply to the areas of (1) vector intracellular iron metabolism, (2) vector/parasite relationships, (3) vector defense mechanisms and (4) mosquito development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IRON METABOLISM IN PLASMODIUM Principal Investigator & Institution: Sullivan, David J.; Assistant Professor; Molecular Microbiol and Immun; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: An increase in antimalarial drug resistance is an important contributing component to the current escalating mortality due to Plasmodium falciparum malaria. Two major classes of currently used antimalarials, the quinolines like chloroquine and the endoperoxides like artmesinin, interfere with iron metabolism to kill the parasite. Iron chelators, while cytostatic for bacterial and mammalian cells, actually kill Plasmodium despite the availability of millimolar heme iron in the parasitized erythrocyte. This indicates that the amount of bioavailable iron is limited and crucial for parasite survival. Therefore, interference with iron metabolism is an important and promising chemotherapeutic target for Plasmodium. The long term objectives of this proposal are to improve targeted antimalarial chemotherapy by further definition of the vital sources of parasitic iron and by characterization of iron transport to essential compartments. Preliminary data implicate erythrocytic ferritin as a source of iron. Recent cloning of the P. falciparum homologue to the mammalian iron transporter Natural Resistance Associated Macrophage Protein (NRAMP) will enable characterization of parasite iron transport. The specific aims are to test erythrocytic iron as an iron source, to localize the compartments in which PfNRAMP resides, to assess the specificity of divalent metal cations transported by PfNRAMP, to evaluate the kinetics and inhibition of this proton/cation symporter and to analyze its level of expression amongst quinoline-sensitive and -resistant parasites. The techniques of Plasmodium culture in resealed erythrocytes, recombinant gene expression, immunolocalization, cell transfection, and site-directed mutagenesis will be used to achieve these aims. The significant impact of this research is to improve the understanding of Plasmodium iron metabolism that is perturbed by antimalarial drugs. To improve the present antimalarial armamentarium for the US military and travelers as well as endemic populations is an essential component of malarial control.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IRON PRIMES HEPATIC ACTIVATION AND CYTOKINE EXPRESSION

MACROPHAGES

FOR

NF-KB

Principal Investigator & Institution: Tsukamoto, h; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002 Summary: Hepatic macrophages (HM) function as the primary effector cells in alcoholic liver injury via the release of cytotoxic and pro-inflammatory mediators. Expression of many of these mediators are transcriptionally regulated by a redox-sensitive transacting factor, NF-kappaB. We have shown that the treatment of cultured Kupffer cells with a lipophilic iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one (L1) abolishes LPSstimulated NF-kappaB activation and expression of TNFalpha and IL-6. Administration of L1 to rats with cholestatic liver injury leads to abrogation of HM NF- kappaB activation and TNFalpha mRNA expression with resultant amelioration of liver injury. HM from rat5s with alcoholic liver injury, exhibit NF-kappaB activation, TNFalpha upregulation, and an increased non-heme iron content. Ex vivo treatment of the cells with L1 normalizes all thee changes. The expanded iron storage in HM of these animals was accompanied by the increased content of ferritin L-chain mRNA and ferritin protein, as well as splenic iron accumulation. These cells also show enhanced hemeoxygenase -I mRNA expression, suggesting increased heme metabolism. Based on these results, we hypothesize that an increased iron storage primes HM for NF-kappaB mediated responses in alcoholic liver injury. We further advance the hypothesis to state that intracellular chelatable iron which is liberated from stored iron by oxidative stress, participates in NF-kappaB activation an that the activities of iron-regulated mRNA binding proteins, IRP (iron regulatory proteins), provide feed back regulation for this process via their known control over a catalytically active iron pool. To test these hypotheses, we will examine: 1) in vitro effects of iron status on temporal changes in the levels of chelatable iron, NF-kappaB and IRP mediated responses in LPS-stimulated cultured Kupffer cells; 2) in vivo temporal changes in cellular iron, NF-kappaB and IRP mediated responses in HM during evolution of alcoholic liver injury; 4) n vivo effects of HM iron depletion with liposome encapsulated iron chelators on NF- kappaB mediated responses and alcoholic liver injury; and 5) effects of splenectomy on iron storage and NF-kappaB activation by HM in alcoholic liver injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IRON STATUS AND RISK OF CHD AND COLON CANCER Principal Investigator & Institution: Ma, Jing; Assistant Professor of Medicine; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2003 Summary: (Adapted from Investigator's Abstract) The investigators propose to examine prospectively the relation between iron status (intake, body stores, and genetic susceptibility for hemochromatosis) and risk of myocardial infarction (MI) and colorectal cancer in three large cohorts. Iron intake was assessed by semiquantitative food frequency questionnaire (SFFQ) in 1980 in the Nurses' Health Study (NHS, n=121,700 women) and in 1986 in the NHS and in the Health Professionals Follow-up Study (HPFS, n=51,529 men). Blood samples were collected in both of these cohorts: from the NHS in 1989-90 (n=32,825 women), and the HPFS in 1993-94 (n=18,000 men). In addition, samples also were collected from participants in the Physicians' Health Study

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in 1982 (PHS, n=14,916 men). These men and women initially free of cardiovascular disease and cancer and have been followed prospectively for the occurrence of cardiovascular disease and cancer. The investigators plan to assay the samples, in a nested case-control design, for biomarkers of body iron stores (iron, total iron binding capacity, ferritin) and genetic marker of hemochromatosis, an inherited disease of iron overload (C282Y, a missense mutation in HLA-H gene). The iron-CHD/cancer hypotheses have been supported by laboratory and animal studies, but findings from small, less comprehensive epidemiologic studies are inconsistent. They propose to evaluate the individual associations of intake, biomarker levels, and genotype with risk of MI and colorectal cancer, as well as the combined effects. Further, they will evaluate other dietary and lifestyle factors that may account for or modify the association between iron and MI/colorectal cancer. The ongoing three cohorts will provide high yield follow-up participation and high quality end-point verification in addition to information on important variables (e.g., smoking, vitamin supplement use, dietary factors) for the proposed study. These analyses will take advantage of existing blood banks of these well-characterized cohorts, and part of the plasma ferritin measurements (the NHS and PHS) are funded through other sources. The investigators state that hence, this application provides a well-focused, efficient cost-effective, and comprehensive approach to evaluate the hypothesized but unproven role of iron as a risk factor for future cardiovascular disease and cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IRON STATUS IN WOMEN OF REPRODUCTIVE AGE Principal Investigator & Institution: Ramakrishnan, Usha; International Health; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 15-MAY-1998; Project End 30-APR-2004 Summary: (Adapted from Investigator's Abstract) The overall objective of this application is to characterize current patterns and determinants of iron status in women of reproductive age (12-49 years), using nationally representative data from the recently completed (1988-94) NHANES III. Iron status will be defined in terms of biochemical indicators: serum ferritin, transferrin saturation, erythrocyte porphyrin, mean corpuscular volume and hemoglobin. The Specific Aims include the identification of subgroups at risk for iron deficiency or excess, quantification of trends in iron status over the past 20 years by comparison to results from previous NHANES surveys and assessment of the contributions of supplement use and dietary sources (especially fortified products) to iron intake and status. Dietary data will be based on 24 hour recall and food frequency questionnaires. The sociodemographic correlates of iron deficiency and excess will be identified using multivariate techniques such as logistic regression and general linear models. Sample weights and Strata and Pseudo Primary Sampling Units will be used for calculating variance estimates using the program SUDAAN, which can account for the complex study design of the HANES datasets. Similarly, all the final logistic and ordinary least squares models will also be tested using SUDAAN. The investigators state that this project will help ascertain whether iron deficiency remains a major public health problem in the United States. It will provide an up-to-date picture of iron status among women, including the prevalence of iron excess, which is regarded as an emerging health problem. High iron stores are perceived to increase the risks of hereditary hemochromatosis and chronic disease. Although causality cannot be established due to the limitations of the NHANES, the examination of the strength and direction of the associations of iron excess with predisposing factors for and/or chronic disease is expected to improve significantly current understanding of this emerging area

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of concern and will be useful for identifying groups at risk and for guiding future research. The investigators state that in summary, the project is expected to provide information that can be used to examine policy options and develop guidelines to ensure adequate but safe iron status for women of reproductive age. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IRON, NO, AND LIPID PEROXIDES IN PHOTODYNAMIC THERAPY Principal Investigator & Institution: Girotti, Albert W.; Professor; Biochemistry; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 15-DEC-1996; Project End 30-JUN-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LONG-TERM EFFECTS OF IRON DEFICIENCY Principal Investigator & Institution: Coe, Christopher L.; Professor; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002 Summary: This project in the P01 application will use a unique nonhuman primate model to evaluate the long-term consequences of iron deficiency during infancy during infancy on behavior and the central nervous system (CNS). The infant monkey model of iron deficiency (ID) will be generated by breeding adult female rhesus monkeys prescreened for iron deficiency prior to conception. Previous research has established that these females generate infants that have low ferritin levels at birth, and the infants' low iron store ultimately predispose them to an iron deficiency anemia (IDA) between 4-8 months postpartum. Three studies are proposed to evaluate the consequences of this IDA for behavioral and CNS development across the first 1.5 years of life. The second and third studies will evaluate the benefits of early and late iron repletion for preventing or ameliorating the effects of IDA on CNS functions related to dopamine, myelination, and hippocampal memory processes. Across a 5-year period, 3 studies involving 90 mother-infant dyads will be conducted. The first study will assess the developmental and hematological profiles of infants generated from 15 iron deficient (ID) and 15 iron sufficient (IS) adult females. The outcome measures focuses on 4 domains: Physical Growth, Hematology, Cognitive Performance, and CNS measures. It is predicted that ID infants will show delayed neuromotor maturation, less adept fine motor control, greater emotionality, and poor performance on cognitive tasks. CNS functioning will be evaluated both by electrophysiological techniques (Auditory Brainstem Event Related Potentials (ABR) and neuroimaging of biochemical markers of myelination by proton Magnetic Resonance Spectroscopy (MRS). The second study will assess the benefits of early iron supplementation beginning at either 1 or 4 months postpartum for preventing IDA and any effects on behavioral and CNS development. Finally, Study 3 will extend this evaluation to investigate the therapeutic gains of iron repletion in the older infant, either at 6 or 9 months of age, which is after the onset of IDA in the monkey. It is hypothesized that some cognitive and CNS effects will continue to be manifest in the latter groups of infant monkeys. This project would provide valuable information on the persistent sequelae of ID using an established nonhuman primate model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MAGNETIC FIELD & APPLICATION FOR MR SUSCEPTIBILITY QUANTIFICATION Principal Investigator & Institution: Li, Lin; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002 Summary: We are developing a number of strategies for monitoring gene therapy. The first approach is to monitor the specific phenotype of the genetic disease. For example, in mucopolysaccharidosis type VII (MPS VII) the genetic defect is failure to produce glucuronidase. We are synthesizing glucuronides of fluorinated phenols. When the glycosidic bond is cleaved by -glucuronidase , the 19F chemical shift of the liberated phenol is expected to change by about 10ppm; furthermore, since the liberated fragment is anionic, it is expected to be trapped in the cell. In cystic fibrosis the genetic defect is in the chloride transporter (CFTR). This is known to result in an increase in the sodium and chloride concentrations in air passage fluids. We, therefore, are developing multiple quantum 23Na methods to detect and quantitate this alteration in sodium concentration. In hypercholesteremia the genetic defect is the lack of LDL receptors. We are developing methods to label LDL mole cules with magnetite so that delivery of LDL to liver lysosomes could be detected by MRI. These examples demonstrate how magnetic resonance methods can be developed to monitor genetic defects in enzymes, ion transport and receptors. However, we recognize that development of methods to monitor phenotypes of genetic defects will required an immense amount of effort and will not be completely reliable since similar genotypes may be expressed as different phenotypes or may be expressed to different extents. A more general approach is to develop a suitable marker gene that could be attached to the transfection vector and expressed by the same promotor. An ideal marker for MRI detection would be magnetite, which increases the relaxivity of water, which is 110 M in protons. Magnetite also has about a thousandfold higher relaxivity than an equivalent amount of iron (such as if found in the iron core of ferritin). Certain bacteria have the unique ability to produce magnetite from iron. T he protein responsible for this activity has been cloned and expressed in both bacterial and mammalian cells. We are exploring the utility of this protein as a marker for gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MAGNETIC RESONANCE MEASUREMENT OF HEART AND LIVER IRON Principal Investigator & Institution: Brittenham, Gary M.; Professor of Medicine; Pediatrics; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 30-JUN-2007 Summary: (provided by applicant): The proposed research will integrate radiological, clinical and laboratory efforts in the development and validation of quantitative magnetic resonance methods for the measurement of heart and liver iron. We propose to acquire a fundamental theoretical and physical understanding of the resonance effects of tissue iron as a guide in the development of novel MR techniques that will provide clinically applicable methods for the quantitative measurement of hepatic and cardiac iron. These studies will take advantage of a unique convergence of resources and expertise at Columbia University, including the Hatch MR Research Center, active programs of liver and heart transplantation, the Iron Reference Laboratory, and the SQUID biosusceptometry facility where hundreds of patients with diverse forms of iron overload are seen each year. The proposed research has three specific aims: (1) to

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investigate systematically in and ex vivo the resonance behavior of ferritin and hemosiderin iron in diverse hepatic and cardiac disorders in patients undergoing organ transplantation, using candidate MR methods including conventional spin- and gradient-echo sequences, spectroscopic techniques, and projection reconstruction-based pulse sequences designed to facilitate capture of short T2* components; and ( 2 ) to examine selected MR methods for measurement of hepatic and cardiac iron in patients with iron overload of diverse severity and etiologies (hereditary hemochromatosis, chronic transfusion for thalassmia major, sickle cell disease, aplastic and other refractory anemia) in conjunction with SQUID biosusceptometry in vivo, magnetic susceptometry ex vivo, ultrastructural and biochemical studies of explant tissue; and (3) to prospectively validate optimized MR measurements of hepatic and cardiac iron concentrations with the results of biochemical analysis of tissue from heart and liver explants in series of adult and pediatric patients with and without disorders affecting iron metabolism. The development of validated, clinically applicable MR methods for the non-invasive measurement of hepatic and cardiac iron would be a major advance in the diagnosis and management of patients with iron overload that would find immediate and widespread diagnostic use both in the U.S. and worldwide. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM MINERALIZATION

OF

FERRITIN

FERROXIDATION

AND

Principal Investigator & Institution: Huynh, Boi-Hanh V.; Professor of Physics; Physics; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: Iron is an important nutrient, required in almost every aspect of cellular function. However, at physiological pH and under oxidizing condition, it is not very soluble. How living organisms sequester iron for cellular utilization is therefore a fundamental question of vital importance. Also, in the presence Of 02, free Fe2+ ions are extremely toxic, capable of generating hydrogen peroxide, superoxide, and other reactive oxygen species that can attack and destroy important cellular molecules. Ferritin is unique in the sense that it performs dual functions of iron detoxification, by oxidizing the Fe2+ ions in solution, and iron sequestration, by storing the oxidized Fe3+ ions in its inner protein cavity in the form of ferrihydrite mineral. However, despite the importance of ferritin functions and decades of research efforts, the mechanism by which ferritin catalyzes the Fe2+ oxidation (ferroxidation) and directs the oxidized products to form the mineral core (mineralization) is still poorly understood. This is partly due to the complexity of the ferritin molecule and partly due to the fact that the methods used in previous studies were either indirect or lacked the required spectroscopic resolution to monitor the complex reaction catalyzed by ferritin. In this application, we propose to employ M ssbauer spectroscopy in conjunction with the rapid freeze-rapid quench kinetic technique to investigate the mechanism of ferritin ferroxidation and mineralization. Three different recombinant ferritins, the frog H and M ferritins, and the E. coli bacterioferritin, are to be examined. Results obtained from our preliminary studies demonstrate that this combined kinetic/spectroscopic approach provides the necessary time resolution for obtaining kinetic information and the required spectroscopic resolution for distinguishing, quantifying and characterizing the multiple Fe species generated during the ferroxidation and mineralization processes. Other complementary spectroscopies, such as EPR, ENDOR, EXAFS, and resonance Raman will also be employed to obtain further structural information on these reaction intermediates. Site-specific mutants will be engineered, produced and subjected to

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Ferritin

kinetic/spectroscopic investigations for the purpose of defining the ferroxidase site, the Fe transport pathways, and the functional roles of certain key residues. A series of double-mixing rapid freeze-quench Mossbauer investigations using 57Fe and 56Fe isotopes are particularly designed to address questions concerning the dynamics of the ferritin function. Detailed mechanistic insights into the processes involved in ferritin ferroxidase reaction and mineral core formation are expected to emerge from these proposed studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF BINUCLEAR NON-HEME IRON ENZYMES Principal Investigator & Institution: Clay, Michael D.; Chemistry; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2006 Summary: (provided by applicant): Binuclear non-heme iron active sites are present in a wide variety of proteins and enzymes which perform different biological functions. This proposal will specifically investigate those sites present in sMMO, R2, D9D and frog Mferritin to elucidate their differences in dioxygen reactivity (i.e. hydroxylation, radical generation, desaturation and ferroxidation). These differences have led to the identification of various diiron peroxy (P) and high-valent (Q and X) intermediates. While these enzymatic intermediates have been investigated, relatively little is known about their geometric and electronic structure and, more importantly, how their structure relates to reactivity. Therefore, the major objectives of this research proposal are to use biophysical spectroscopic techniques (EPR, resonance Raman and UVvis/Near IR absorption/CDNTVH MCD) to characterize the geometric, electronic and magnetic properties of the various diiron peroxy (P) and high-valent (Q and X) intermediates in these enzymes and relevant model complexes and apply computational methodologies to gain greater insight into the mechanistic conversion between these intermediates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF THROMBIN-INDUCED TOLERANCE TO BRAIN INJURY Principal Investigator & Institution: Xi, Guohua; Associate Director; Neurosurgery; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 05-FEB-2000; Project End 31-JAN-2007 Summary: (provided by applicant): Intracerebral hemorrhage (ICH) is a common and often fatal subtype of stroke and produces severe neurologic deficits in survivors. Brain injury after ICH appears to involve several phases. These include an early phase involving the clotting cascade and thrombin production and a later phase involving erythrocyte lysis and hemoglobin toxicity. Although high concentrations of thrombin cause brain edema and cell death, low concentrations are neuroprotective. Thus, we have found that prior treatment with a low dose of thrombin attenuates the brain edema induced by thrombin or hemorrhage, and significantly reduces the infarct size in a rat middle cerebral artery occlusion model. We have termed this phenomenon thrombin preconditioning (TPC). In our recent studies, we have found that TPC not only reduces brain edema induced by high dose thrombin, but also attenuates edema induced by lysed erythrocytes and FeCl[2]. TPC appear to involve activation of thrombin receptor, HIF-1alpha upregulation and increased transferrin, transferrin receptor and ferritin

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levels. This suggests that thrombin release during an ICH might induce protective mechanisms against factors released upon clot lysis. This data has led us to the following Specific Aims: 1) To determine whether TPC reduces hemorrhagic brain injury caused by lysis of erythrocytes. 2) To determine whether protease-activated receptors (PARs) play a key role in TPC. 3) To determine whether TPC modulates iron transport and storage protein levels in the brain, which then affects iron homeostasis after ICH. The purpose of our project is to investigate the mechanisms involved in TPC. An examination of TPC will also help our understanding of ischemic preconditioning since preliminary data suggests that TPC is a component of that phenomenon. It should be noted that TPC seems to be receptor mediated, greatly facilitating analysis compared to ischemic preconditioning. The long-term goal of these studies is to find mechanisms that can be used to limit brain injury after ICH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR AND CELLULAR CONTROL MECHANISMS IN IRON LOADED HEPATOCYTES Principal Investigator & Institution: Isom, Harriet C.; Distinguished Professor; Pennsylvania State Univ Hershey Med Ctr 500 University Drive Hershey, Pa 170332390 Timing: Fiscal Year 2002 Summary: Hemochromatosis is the termed used to describe a state of iron overload in an individual. Our goal is to address the isolated issue of how iron- overload alters the function of well-differentiated hepatocytes in the absence of the other liver cell types. We have carried out preliminary studies to determine whether primary hepatocytes in long-term DMSO culture can be loaded with iron. We conclude from these studies: (1) Primary rat hepatocytes in long-term DMSO culture can be iron-induced by exposure to iron in the form of ferrous sulfate or (3,5,5-trimethylhexanoyl) ferrocene (TMHferrocene) but not with holotransferrin at the concentrations tested. (2) Because iron loading can be carried out over long time periods (months) in hepatocytes in DMSO it is possible to obtain iron loading using concentrations as low as 2.5 muM TMH-ferrocene. When exposed to 25muM TMH-ferrocene, hepatocytes continued to load increasing amounts for iron for two months before the cells died; when exposed to lower concentrations such as 2.5 or 5.0 muM TMH-ferrocene, hepatocytes were able to continuously load iron and remain viable for more than two months. (3) The cellular deposition of iron was different in hepatocytes exposed to TMH-ferrocene compared to those exposed to ferrous sulfate; exposure to TMH-ferrocene resulted in the presence of more ferritin cores within lysosome. (4) Iron loading distorted nuclear shape in hepatocytes; the amount of nuclear distortion was greater in hepatocytes exposed to ferrous sulfate than in those exposed to TMH-ferrocene. (5) TMH-ferrocene produced a normal physiologic induction of ferritin. In summary, we have demonstrated that hepatocytes in long-term DMSO culture can be iron loaded and represent a flexible system for studying the effects of chronic iron loading on the cells. The hypothesis being tested in this proposal is: Iron loading of hepatocytes in long-term DMSO culture induces specific types of cellular changes may be potentiated is the cells are treated with cytokines. We will use iron over-loaded hepatocytes in long term DMSO culture: 1. To characterize the time- and concentration-dependent characteristics of TMH-ferrocene treatment with respect to cellular iron content, ferritin expression, IRE function, and markers of oxidative damage. 2. To characterize the mechanisms whereby alphatocopherol produces an increase in ferritin expression. 3. To assess the ability of our changes induced by iron overload are reversed by iron chelation. 4. To characterize the

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effects of chronic iron loading on the TNF-alpha signaling pathway with regard to NKkappaB expression and induction of apoptosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR PATHWAYS OF IRON DETOXIFICATION IN THE LUNG Principal Investigator & Institution: Yang, Funmei; Cellular & Structural Biology; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Iron the most abundant transition metal in living organisms can be released from tissues during injury. Accumulation of released catalytic reactive iron has been demonstrated in a number of diseased lungs, for examples, ARDS and cystic fibrosis. Conversely, sequestration of iron in a catalytically less reactive form is fundamentally important in lung defense. Better and more effective iron-chelating drugs, which do not inflict damage on healthy tissues, have not been developed. A lack of knowledge of iron metabolism in the lung hampers a complete understanding of its role in both normal and diseased states, and precludes the development of a lungspecific therapeutic intervention. Our long-term goal is to understand the molecular mechanisms involved in the maintenance of normal iron homeostasis in the lung. Our central hypothesis is that two recently identified transmembrane iron transporters, DMT1 (divalent metal transporter 1) and MTP1 (metal transporter protein 1), are key constituents of a novel mechanism for the detoxification of iron in the lung. In this process, iron is taken up by lung cells via DMT1-mediated transfer and re-exported by the same cells in less harmful protein-bound forms via MTP1-mediated pathway. This hypothesis is formulated based on the data from our laboratories that include 1) DMT1 and MTP1 genes are activated by iron in airway epithelial cells and alveolar macrophages, 2) the levels of DMT1 and MTP1 are elevated after endotoxin exposure and in some diseased lungs, 3) MTP1 protein is localized uniquely to the apical membrane in airway epithelial cells, and 4) in human bronchial epithelial cells cultured on a porous membrane, elemental iron taken up across the apical surface by these cells is later re-released across the same apical surface in protein-bound forms. We will test our hypothesis using cultured airway epithelial cells and mutant mice defective in DMT1/MTP1 mediated iron transport. This study will lead to a better understanding of iron dysfunction in diseased lungs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MRI QUANTITATION OF TISSUE IRON IN HEMATOLOGIC DISORDERS Principal Investigator & Institution: Song, Hee K.; Radiology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; 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 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

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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. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NANOSCALE IRON PHASES IN NEURODEGENERATIVE DISEASES Principal Investigator & Institution: Dobson, Jon P.; Keele University Keele St5 5Bg, England Keele, Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): AIMS:. To develop multi-modal imaging methods for high-resolution mapping of iron in neurodegenerative brain tissue. To examine the magnetic properties of neurodegenerative tissue for the possible presence of anomalous magnetic iron oxides. To examine the effects of biogenic, magnetic iron biominerals (primarily magnetite) on amyloid-beta aggregation in vitro. Research Design & Methods: The primary method for mapping iron distribution in tissue sections is via synchrotron x-ray scanning which will be conducted at Argonne National Laboratory. This technique will be used to identify iron anomalies eventually on a cellular level. And to compose composit images using a variety of imaing techniques. This work will enable correlation of iron anomalies and structural form to specific cellular and tissue structures for the first time. Examination of the magnetic properties of neurodegenerative tissue will be carried out pdmarily using Superconducting Quantum Interference Device (SQUID) magnetometry and Magnetic Force Microscopy (MFM). Using these methods the magnetic iron biominerals in the tissue will be characterized and compared to published data on non-pathologic and epileptic tissue samples. This will provide information on the relative abundance and type of magnetic iron biomineral present in the tissue and will help to either confirm or refute preliminary studies of nanoscale magnetic iron biominerals in Alzheimer's disease (AD) tissue. The effects of strong, local magnetic fields generated by nanoscale magnetic iron biominerals on amyloid-beta peptide aggregation rates will be examined using thioflavin-T assay and TEM imaging of peptide aggregates. Aggregation rates will be assessed in control solutions, solutions of peptide with coated magnetic nanoparticles and sham solutions containing the same concentrations of non-magnetic nanoparticles with the same size distribution and surface chemistry. Gla: FOREIGN GRANT: As the PI is a US citizen based at Keele University in the United Kingdom, the project will be administered through a foreign institution - Keele. The PI has considerable and unique experience in the analysis of magnetic iron biominerals in the brain (he has led all of the previous work described in this proposal) and is one of the few people in the wodd working in

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this field. The proposed project is highly interdisciplinary, incorporating aspects of biophysics, chemistry, neurobiology and biomedical engineering. The PI has a uniquely diverse background related to the proposed research, having worked in physics, chemistry and biomedical engineering departments and the UF Brain Institute since obtaining his PhD in 1991. He has published extensively in nanoscale magnetic iron biomineralization in the brain and his work has been featured by the media in such journals as Science,The Economist, Fact/Switzerland, The Los Angeles Times/Washington Post wire service as well as newspaper, radio and television coverage in six countries. The Pl's combination of skills and experience related to the research proposed here is unique and unavailable in the US. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OXIDATIVE STRESS, ANTIOXIDANT STATUS & PREGNANCY OUTCOME Principal Investigator & Institution: Scholl, Theresa O.; Professor; Obstetrics and Gynecology; Univ of Med/Dent Nj-Sch Osteopathic Med Osteopathic Medicine Stratford, Nj 08084 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: (Adapted from the Investigator's Abstract) The investigators propose a prospective study of 1000 low income and minority gravidas from Camden, NJ, to test the hypothesis that risk of poor pregnancy outcome is associated with an increased level of oxidative stress. They propose to measure oxidative stress, iron and iron-associated compounds, and antioxidant status at entry to care, 20 and 28 weeks gestation during pregnancy. Infant birth weight and the frequency of other poor pregnancy outcomes in the study population will serve as the outcomes. The primary objective is to determine the prognostic importance of indices for oxidative stress, specifically isoprostane 8-isoPGF2a and 8-hydroxydeoyguanosine excretion, on low birth weight and other poor pregnancy outcomes. Secondary outcomes are: (a) to determine the prognostic importance of indices for maternal antioxidant status (total, endogenous, exogenous) on low birth weight and other poor pregnancy outcomes; (b) to determine whether indices for oxidative stress (isoprostane 8-iso-PGF2a and 8-hydroxydeoyguanosine excretion) are related to serum cotinine (a biomarker for smoking), diet (antioxidant and tracemineral intake), ethnicity and other maternal characteristics during pregnancy; (c) to determine whether indices of oxidative stress during pregnancy are associated with biomarkers for maternal iron status and associated compounds (serum ferritin, hemoglobin, serum iron, total iron binding capacity, transferrin saturation) and 2,3 DPG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OXYGEN ACTIVATION BY METALLOENZYMES Principal Investigator & Institution: Loehr, Thomas M.; Professor; Environmental and Biomolecular Systems; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-MAY-1978; Project End 28-FEB-2005 Summary: This research project describes the investigation of oxygen activation by nonheme diiron enzymes. Four metalloenzymes are selected for study: (i) protein R2 of ribonucleotide reductase, (ii) the hydroxylase component of methane monooxygenase, (iii) stearoyl-acyl carrier protein delta9-desaturase, and (iv) the fast ferroxidase site in ferritin. These enzymes are evolutionarily related, possess structurally similar metal sites, and activate oxygen, but they catalyze diverse oxidation reactions. Crystal

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structures exist for the reduced and/or resting native enzymes and some mutants, but only sparse structural information is available on reaction intermediates. A hypothesis to be explored is that the iron centers adopt a common reaction pathway, namely, that the diferrous enzyme binds oxygen to form an initial peroxodiferric species, P, and 0-0 bond cleavage leads to a high-valent diiron(IV) intermediate. In MMOH, the diiron(IV) species, Q, is the active catalyst and is proposed to have a diamond-core structure. In protein R2, one-electron reduction leads to mixed valence [F(II)F(III)] intermediate, X, as the catalytically competent species. In ferritin, the peroxodiferric species may lose hydrogen peroxide to leave an oxidized metal cluster for mineralization. We describe the use of resonance Raman, optical absorption, EPR, and Mossbauer spectroscopy to investigate the structures of intermediates P, Q, and X. Enzyme intermediates can be trapped by rapid freeze-quench methods for spectroscopic analysis. Vibrational modes of iron-oxo and radical species known or suspected to occur during these reactions can be identified. Oxygen isotopes will be used to assign vibrational modes from massdependent shifts and to provide details on chemical bonding and binding geometry. The present proposal builds on the first successful identification of a common mu-1,2-peroxo intermediate in wild-type ferritin freeze-trapped at 25 milliseconds, as well as in a mutant of R2, and chemically reduced delta9-desaturase. An overall aim is to understand how enzymes with similar active sites carry out diverse reactions. This research will expand our knowledge of oxygen activation as well as mechanisms of oxygen and free-radical toxicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREVALENCE OF HEREDITARY HEMOCHROMATOSIS GENE IN PTS W HEPATITIS C VIRUS Principal Investigator & Institution: Nunes, Frederick A.; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROTECTIVE ROLE OF HEME OXYGENASE IN ISCHEMIC BRAIN Principal Investigator & Institution: Maines, Mahin D.; Professor; Biochemistry and Biophysics; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: A complication of stroke is cerebral hemorrhage. The heme oxygenase (HO) system, which plays a key role in cellular defense mechanisms, catalyses oxidation of hemoglobin heme to biologically active molecules: bile pigments and CO. We have identified two active forms of the enzyme: HO-1 and HO-2. HO-2 is a hemoprotein and may function as a "sink" for NO, an effector molecule in inflammation and immune response. We have developed transgenic (Tg) mice that overexpress HO-1 or HO-2. HO1 Tg mice brain, when compared with nonTg mice, show increased neuronal cGMP levels and expression of HO-1 in the lining of blood vessels. And, after pMCAo, they show decreases in brain stroke volume and in lipid peroxidation. Also, Tg mice neurons are resistant to H2O2 and glutamate toxicity. Initial studies with the HO-2 Tg line show increase in neuronal HO-2 expression and decrease in brain lipid peroxidation. To date, no data are available on the effect of HO-2 overexpression on the outcome of stroke. Deletion of the gene, however, exacerbates such injury. Also, the effect of HO-1 gene transfer on CNS injury has not been examined. Although, upregulation of HO-1 gene

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expression, using adenovirus (Ad)-mediated gene transfer, is known to protect against oxidative stress-mediated systemic tissue injury. The overall objective of this proposal is to further explore the role of HO isozymes in neuronal protection against stroke and cerebral hemorrhage. Specific aims are: 1) Using the HO-1 and HO-2 Tg mice to investigate the effect of HO gene overexpression on the outcome of transient focal ischemia (tMCAo), and on subarachnoid hemorrhage (SAH) caused by injection of lysed blood into the subarachnoid space. The tMCAo model will be evaluated for progression of ischemic injury and markers of stress: lipid peroxidation and redox available iron; also, for heme and bilirubin levels. The SAH model will be evaluated for vasospasm and necrotic/ apoptotic cell death. 2) To evaluate in the above models the potential therapeutic benefits of Ad-HO-1 and Ad-HO-2 gene transfer in stroke and cerebral hemorrhage. Genes will be delivered by CSF or by intracarotid route and the same indeces will be evaluated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF INTESTINAL IRON TRANSFER Principal Investigator & Institution: Haile, David J.; Cellular & Structural Biology; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 01-MAR-2002; Project End 28-FEB-2007 Summary: Iron is the most abundant transition metal in the human body and an essential nutrient. Toxicity results when cellular free iron catalyzes the formation of destructive free radicals. Aging, atherosclerosis, arthritis, are some of the increasing list of human conditions in which iron catalyzed generation of free radicals is suspected to contribute to tissue injury. To minimize toxicity, the iron content of the body tightly regulates uptake of iron through the duodenal epithelium. The central hypothesis of this application is that the control of duodenal iron export is primarily transcriptional and that this transcriptional control is independent of duodenal epithelial cell iron content. This hypothesis has been formulated on the basis of strong preliminary evidence from my laboratory that a) the regulation of MTP1 by iron is the opposite of the regulation observed with other 5' IRE containing genes, such as ferritin, b) the duodenal epithelial expression of MTP1 is independent of iron content of the epithelial cell itself. I plan to test the hypothesis and accomplish the objectives of this grant proposal by completing the following specific aims: 1. Measure MTP1 mRNA and protein levels and transcription rates in duodenal sections of normal, mk, sla and hpx mice with varying amounts of total body iron. 2. Determine the structure of the 5' UTR of the MTP1 mRNA induced with iron deprivation in duodenal epithelial cells. 3. Characterize the role of the 5' UTR IRE of MTP1 in the iron dependent regulation of the gene. This approach is expected to yield the following results: a) Identification of the mode of regulation of MTP1 by iron in the duodenum. b) Characterization of the role of the differing 5' UTRs of MTP1 in the iron dependent regulation of the gene. Identification of the mechanisms of the regulation by iron of components responsible for iron absorption will result in a better understanding of overall iron metabolism and will lead to better therapeutic strategies for limiting cellular damage secondary to iron derived free radicals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF IRON HOMEOSTASIS IN OXIDATIVE STRESS Principal Investigator & Institution: Tsuji, Yoshiaki; Environ & Molecular Toxicology; North Carolina State University Raleigh 2230 Stinson Drive Raleigh, Nc 27695 Timing: Fiscal Year 2002; Project Start 24-SEP-2002; Project End 31-AUG-2006

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Summary: (provided by applicant): Induction of detoxification enzymes is an important mechanism of cytoprotection against carcinogens and chemical/oxidative stress. Transcriptional activation of antioxidant detoxification genes by oxidative stress is driven by a cis-acting element, termed the antioxidant response element (ARE), however, the molecular mechanisms by which the ARE enhancer is activated by oxidative stress are not fully elucidated.Ferritin, composed of 24 subunits of the H and L types, is a ubiquitous and highly conserved iron-storage protein that plays a prominent role in maintaining iron homeostasis. Sequestration of intracellular free iron by Ferritin is an important cellular defense mechanism because it limits iron-catalyzed generation of hydroxyl radicals that elicit oxidative stress and cell damage. Indeed, others and we demonstrated that oxidative stress activates transcription of the ferritin H and L genes. However, the molecular mechanisms by which ferritin transcription is activated by oxidative stress remain unexplored. The overall goal of this research proposal is to understand molecular mechanisms underlying transcriptional activation of the ferritin H gene in response to oxidative stress. We propose that oxidative stress activates specific transcription factors by posttranslational modifications, which then bind to the 75 bp oxidative stress response element (OSRE) composed of two bidirectional ARE motifs in the ferritin H gene. Moreover, depending on oxidative conditions of the cells, the two ARE motifs in the ferritin H OSRE may function as both double strand and single strand (stem loop) DNA enhancer elements. To test this hypothesis we will, 1) identify the transcription factors and adaptor proteins that bind to the OSRE and activate transcription of the ferritin H gene in response to oxidative stress, and 2) elucidate oxidative stress-mediated posttranslational modifications of transcription factors and signaling pathways leading to transcriptional activation of the ferritin H gene.These studies will provide significant information for our understanding of molecular mechanisms by which transcription of the ferritin H gene is activated via ARE motifs in response to oxidative stress, and ultimately by which iron homeostasis is tuned to minimize oxidative cell damage under prooxidant conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-JAN-1995; Project End 31-JAN-2006 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 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

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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. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SYNDROME

RESPONSE

TO

IRON

TREATMENT

FOR

RESTLESS

LEG

Principal Investigator & Institution: Earley, Christopher J.; Associate Professor; Neurology and Neurosurgery; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2005 Summary: Restless Legs Syndrome (RLS) is a common, dopamine- responsive, sensorymotor disorder whose symptoms predominant at night and often lead to significant sleep loss and changes in one's quality of life. Altered CNS iron metabolism may play a pivotal role in RLS. Decreasing serum ferritin has been shown to correlate with increasing RLS symptoms. RLS patients have been found to have decreased CSF ferritin and increased CSF transferrin, which suggests a decrease in brain iron stores. Finally, open-labeled, non-controlled iron therapy has been effective in treating some patients with RLS. We have developed preliminary data strongly supporting our basic model that RLS results from altered dopaminergic mechanisms, which are precipitated by a relative or absolute reduction of iron in the brain. We have also developed data that indicate there may be a decrease in the normal transfer of iron from serum to brain tissue possibly related to abnormal transport across the blood brain barrier. This indicates that the use of IV iron might at least partly correct the brain iron deficits in RLS. We will, therefore, test the hypothesis that: (1) IV iron therapy will improve the CNS iron status. (2) IV iron therapy will improve symptoms in RLS patients. (3) Improvements in CNS iron status with IV iron treatment will parallel improvements measures of RLS. And, (4) the response to IV iron therapy differs based upon age at onset of RLS symptoms. A 1000 mg of iron or placebo will be given as a single intravenous dose to RLS patients in a randomized, double-blind trial. It is anticipated that a single IV treatment will provide relief of RLS symptoms for an extended period of time (2-12 months). Post-infusion changes in CNS iron status will be evaluated using CSF measurements of ferritin and other iron- related proteins and MRI measurements of brain iron stores. Post-infusion changes in RLS will be assessed using standard subjective (Diary; rating scale) and objective (PSG, SIT, Leg Activity Meters) measures of clinical status. CSF and serum iron values, MRI measures of brain iron and full clinical evaluations with sleep and immobilization tests will be obtained prior to treatment, two weeks after treatment and again at 12 months later or when symptoms return. Clinical ratings, Leg Activity Meter recordings and serum ferritin will be obtained monthly after

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treatment. CSF ferritin changes will be compared to those predicted from our prior studies. Symptoms will be correlated with CSF ferritin and MRI iron values. Our studies demonstrated possible differences in response to iron for early-and late-onset RLS. So treatment response based on the age of symptom onset will be evaluated separately. An expected finding that IV iron reduces the brain iron insufficiency and dramatically reduces the RLS symptoms strongly supports our model of RLS caused by brain iron insufficiency. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RNA THERAPEUTICS AND ABETA PRECURSOR PROTEIN TRANSLATION Principal Investigator & Institution: Rogers, Jack T.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): The Alzheimer's Amyloid Precursor Protein (APP), like ferritin, is a ubiquitously expressed metaloprotein that is regulated at the level of message translatation. We showed that the primary inflammatory cytokine, Interleukin1 (IL-1), up-regulated APP synthesis by up to 15-fold in the complete absence of changes to steady-state levels of APP mRNA. IL-1 and iron levels significantly regulate APPmRNA translation (and ABeta peptide levels) correlated with changed interaction between Iron Regulatory Protein (IRPs) and APP 5'UTR sequences (IRE-Type II sequences). Iron influx is known to release ferritin mRNAs from translational repression by removal of IRP from 5' untranslated region specific RNA stemloops that are related to APP 5'UTR sequences. Understanding regulation conferred by the APP 5'UTR will enable us to better identify medicinal compounds that reduce APP translation and Abeta-peptide levels. RNA-directed strategies have recently been developed for the use of small molecules to suppress viral infections, including a strategy to target the internal ribosome entry site Hepatitis-C virus. The iron chlelator desferrioxamine (Df) (Mw 650) and the novel anticholinesterase, phenserine (Ps) (Mw 480) suppress APP 5'UTR driven translation of APP to reduce amyloid output, exemplifying the use of this sequence as a therapeutic target for Alzheimer's disease. We will: 1. Define the location and functional action of cis-acting IL-1- and iron-responsive RNA enhancers in APP mRNA and examine functional interactions between 5'UTR and 3'UTR sequences. 2. Determine how the unique folding of RNA encoded by the APP 5'UTR offers a therapeutic target for small molecules exemplified by desferrioxamine and the anticholinesterase, phenserine. 3. Test the hypothesis that altering the binding of Iron-regulatory proteins (IRP-1 and IRP-2) to RNA structures in APP 5"UTR mediates IL-1 signals to increase APP translation. Small molecules could well act by this pathway to decrease APP synthesis and concomitant ABeta-peptide output. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF CERULOPLASMIN IN IRON METABOLISM AND OVERLOAD Principal Investigator & Institution: Fox, Paul L.; Associate Staff; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 27-SEP-2000; Project End 31-JUL-2003 Summary: (adapted from the application) The importance of iron is underscored by its participation in many cellular processes involving oxygen or redox reactions. Iron in excess of cellular needs is toxic; dietary overload or hereditary hemochromatosis leads

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to tissue iron deposition and injury, most likely due to redox activity of iron and consequent free radical reactions. The precise balance required to maintain appropriate cellular and tissue iron levels has led to mechanisms that regulate the synthesis of iron transport and storage proteins, e.g., transferrin receptor and ferritin. A role for copper in iron metabolism has been known for about 70 years. The important role for ceruloplasmin (Cp) in iron metabolism in vivo has been reinforced by the identification of "aceruloplasminemia" patients with Cp gene defects and massive iron deposits in many tissues, including the brain. This function for Cp has received support from studies showing that two Cp homologues, fet3p in yeast and hephaestin in mouse, play key roles in iron homeostasis. We have shown that the rate of Cp synthesis by HepG2 and Hep3B cells is tightly regulated by cellular iron status. Iron deficiency markedly increases Cp protein synthesis and gene expression. Nuclear "run-on" and mRNA stability studies indicate that regulation is by a transcriptional mechanism. We have new evidence that Cp transcription is regulated by hypoxia-inducible factor (HIF)-1 responsive elements since transcription is regulated by hypoxia and other HIF-1 activators. In addition, an enhancer element in the human Cp gene 5'-regulatory region contains HIF-1 responsive elements which increase reporter gene expression about 10fold. In contrast to the stimulatory activity of iron deficiency, excess iron decreases Cp synthesis of HepG2 cells; surprisingly, a post-transcriptional mechanism has been observed in which Cp mRNA is destabilized by iron. These results support the important role of Cp in maintenance of cellular iron homeostasis. We hypothesize that the rate of hepatic Cp synthesis, like that of other proteins involved in iron transport, is regulated by cell iron status. In this application we will test the following specific aims: that a specific trans-activating factor(s) in iron-deficient HepG2 cells binds to a cis-acting element in the Cp 5'-regulatory region, thereby increasing Cp transcription. Furthermore, iron in excess alters the activity of a specific trans-acting factor(s) that binds to a region of the Cp 3'-UTR, thereby destabilizing the Cp mRNA. The long-term goal of this research is to understand the specific function of Cp in iron homeostasis, and especially its role in primary (genetic) and secondary (dietary) iron overload states. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF IRON AND GLUTATHIONE IN PARKINSON'S DISEASE Principal Investigator & Institution: Andersen, Julie; Assistant Professor; Buck Institute for Age Research Novato, Ca 94945 Timing: Fiscal Year 2002; Project Start 20-APR-1994; Project End 31-JAN-2006 Summary: (From the Applicant's Abstract): A growing body of evidence has implicated oxidative stress as an important factor in the neuropathology associated with Parkinson's disease (PD). Dopaminergic nigrostriatal neurons, the predominant cell type lost in PD, are believed to be highly prone to free radical damage due to the propensity for dopamine to auto-oxidize and thereby produce elevated levels of hydrogen peroxide and catecholamine quinones. In vitro analysis suggests this reaction may be catalyzed by transition metals such as iron. Hydrogen peroxide formed during this process can either be converted by iron to form highly reactive and toxic hydroxyl radicals or removed through reduction by glutathione (GSH). GSH can also conjugate with quinones formed during dopamine oxidation preventing them from facilitating the release of iron from the iron-storage molecule ferritin. Alterations in both iron storage and glutathione (GSH) levels in the SN have been correlated with the neuronal degeneration accompanying PD but a direct causative role for either has yet to be definitively proved in vivo. We propose to use genetically engineered mouse lines generated in our laboratory as in vivo models to examine the role that alterations in

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GSH and free iron levels may play in the differential neurodegeneration of dopaminergic neurons of the substantia nigra in PD and how these two parameters may interact with one another to bring this about. This include the use of transgenic mice with altered SN expression levels of either ferrritin or glutamul cysteine synthetase (GCS), the rate limiting enzyme in GSH synthesis. We will use these in conjunction with the well-established MPTP toxicity model of PD to test whether chronic alterations in these molecules in vivo results in changes in neuronal loss associated with toxin treatment and/or aging and to delineate the specific biochemical processes responsible. Such in vivo systems should allow us not only to explore the mechanisms by which in vivo changes in these components may contribute to the neuropathology associated with PD but may also provide useful information for the design of future drug and genetic therapies for this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SECONDARY HEMOCHROMATOSIS IN BETA THALASSEMIA AND SCD Principal Investigator & Institution: Vichinsky, Elliott P.; Director; Children's Hospital & Res Ctr at Oakland Research Center at Oakland Oakland, Ca 946091809 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: (adapted from the application) The purpose of this study is to determine whether the pathologic effects of iron overload secondary to hypertransfusion are different in SCD and beta thalassemia. Iron-related organ injury and death are common in patients with beta thalassemia. Similar organ pathology and mortality have not been reported in SCD after hypertransfusion. Differences in organ and cellular iron localization, cellular processing of iron, inflammatory state, or the generation of reactive low molecular weight iron might explain the differences in disease response. Pilot data shows that the severity of iron overload is similar in hypertransfused patients with SCD and beta thalassemia, yet the rate of organ dysfunction (heart, endocrine) is much greater in beta thalassemia. The primary hypothesis of this study is that hypertransfused patients with SCD show less organ damage than patients with beta thalassemia. The specific aims of the study are: 1) to determine the organ and cellular distribution of iron in hypertransfused patients with beta thalassemia and SCD, 2) to determine whether severe organ damage occurs less frequently in hypertransfused patients with SCD than in patients with beta thalassemia and to evaluate whether markers for early organ dysfunction can be identified and used to guide chelation therapy, 3) to determine the molecular differences in ferritin between SCD and beta thalassemia which could account for a difference in iron deposition in response to chronic RBC transfusion. Organ and cellular iron distribution will be determined 1) post-mortem by histologic and chemical analyses of tissues obtained from hypertransfused patients with SCD or beta-thalassemia matched for age, transfusion volume, sex, and 2) pre-mortem, at an earlier stage of morbidity, by quantitative and histologic analyses of liver biopsy and bone marrow aspirates. Quantitative CT will be used to compare the organ distribution of iron in the two diseases. The frequency of severe organ damage (heart disease, diabetes, spinal fracture) will be determined prospectively over 3 years in a multicenter study (200 patients) to confirm the primary hypothesis. Evidence for early organ dysfunction will be sought using sensitive markers in patients (20 patients) followed prospectively for 4 years at CHO. In summary, if this study is successful and demonstrates a strong difference in the toxicity of severe iron overload in SCD as compared to beta thalassemia, it will change the approach to chelation therapy in

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hypertransfused patients with SCD, lead to reduced chelator-related toxicity, and improve quality of life in these patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SFT FUNCTION AND REGULATION IN HEMOCHROMATOSIS Principal Investigator & Institution: Wessling-Resnick, Marianne; Professor; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 15-SEP-1999; Project End 31-AUG-2004 Summary: Hereditary hemochromatosis is a genetic disorder that promotes increased intestinal absorption and progressive tissue deposition of iron resulting in cirrhosis of the liver, hepatic carcinoma, congestive heart failure, endocrinopathies and premature death. It is estimated that 1 in 200-to-400 people in the US are homozygous for this disease which is the most common defective genetic trait known in humans, more prevalent than cystic fibrosis, phenylketonuria and muscular dystrophy combined. Iron assimilation is a tightly regulated process that is limited to prevent harmful effects due to overload of this toxic metal and therefore a reciprocal relationship exists between body iron stores and dietary iron absorption, although the molecular basis for ion homeostasis remains unknown. Many studies of the molecular basis for hemochromatosis have evaluated the expression of factors involved in iron metabolism , including transferrin, transferrin receptor, ferritin and IRPs, but strong evidence to support their abnormal regulation in this disease is lacking. We recently identified SFT (Stimulator of Fe Transport) as a facilitator of non-transferrin-bound iron uptake. Our preliminary results demonstrate that SFT expression is down- regulated at both the mRNA and protein level in response to iron-loading. However, in the course of these studies, we made the significant discovery that SFT mRNA is 5-fold higher in liver from hemochromatosis patients despite the deposition of iron that occurs in this tissue. Thus, our working hypothesis is that malregulated expression of SFT contributes to the etiology of hemochromatosis. The proposed research will specifically evaluate our hypothesis through the following goals: 1) determination of SFT activity in iron transport by hepatocytes and intestinal enterocytes; 2) examination of interactions of interactions with the hemochromatosis protein Hfe that may modulate SFT expression and function in these cells; and 3) characterization of the mechanism that regulates SFT expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SILIPHOS IN HEPATITIS C Principal Investigator & Institution: Kowdley, Kris V.; Professor of Medicine; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-APR-2004 Summary: (provided by applicant): Aim: To gather evidence for the safety and tolerability of an oral silybin-phosphatidylcholine phytosome (SiliphosTM) at three doses: 360 mg tid, 720 mg tid, and 1080 mg tid in subjects with chronic hepatitis C with stages II, III and IV of liver fibrosis and who are non-responders to or poor candidates for interferon-based regimens and have persistently abnormal serum alanine aminotransferase (ALT) levels.Study Design: This is a phase I/II open label, randomized dose-finding study. It has three arms corresponding to three different SiliphosTM doses: 360-mg tid, 720-mg tid, and 1080-mg tid. Each arm has 12 subjects diagnosed with chronic hepatitis C. Each arm is stratified to four subjects with fibrosis stage II (periportal fibrosis), four subjects with fibrosis stage III (bridging fibrosis) and four

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subjects with fibrosis stage IV (compensate cirrhosis). Each stratified subject is randomized to one of the three dose arms. The treatment duration is 12 weeks. Subjects will be followed for an additional four weeks after treatment cessation to assess residual effects of measured parameters.Endpoints: The primary endpoint is to gather evidence for dose-dependent safety and tolerability of SiliphosTM at the three proposed doses in the study cohort. Safety and tolerability will be measured by number and severity of Adverse Events (AEs) that occur during 12 weeks of treatment and four weeks of follow-up. Secondary endpoints include changes during treatment and follow-up in serum alanine aminotransferase (ALT), transferrin iron saturation, transferrin receptor, ferritin, hyaluronic acid, procollagen III peptide, transforming growth factot beta-1 and plasma chondrex (YLK-40) levels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURE AND FUNCTION OF PARALLEL CHANNELS IN THE FOVEA Principal Investigator & Institution: Sterling, Peter; Professor; Neuroscience; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2004; Project Start 01-APR-1989; Project End 31-MAR-2009 Summary: (provided by applicant): Our broad goal is to investigate key 'design' principles by which the primate retina transfers large amounts of information to the brain. Its 106 axons are strikingly heterogeneous. They comprise 15 channels, spanning a 50-fold range in axon diameter and a 10-fold range in spike rate. Noting that foveal circuits are strongly constrained for space and energy, we hypothesize that multiple channels exist in order to relay information at least cost in "wire volume' and metabolic energy. Preliminary studies suggest that channels transmitting at low information rates (few bits/second) are more efficient (more bits/spike) and physically smaller, thus using less space and probably less energy per bit. Thus central nuclei, which acquire information at different rates (e.g. geniculate M vs. K layers), can receive their messages at least cost. To test this, AIM 1 will measure for several ganglion cell types: (a) 'natural information rate' (bits/spike and bits/s in response to natural images); (b) total wire volume (soma + dendrites + axon + terminal arbor)(cell density); (c) relative energy costs, i.e., mitochondrial content. We predict that natural information rates differ strongly across channels and that 'low-rate' channels use less space and energy per bit. Noting that OFF channels are spatially finer and denser than ON channels and that 'blue/yellow' channels also occur on two spatial scales, we hypothesize that receptive field sizes and sampling rates are tuned to the distribution of information in natural scenes. To test this, AIM 2 will measure achromatic and chromatic information in natural images on scales corresponding to known receptive fields. We predict that in nature dark regions occupy higher spatial frequencies and contain more information per retinal area than bright regions and thus require finer channels with more synapses; there are analogous predictions for the blue/yellow channels. Noting that information transfer through the retina relies on 'ribbon' synapses, we hypothesize that they release and retrieve vesicles at very high rates. To test this, AIM 3 will measure release rates at the cone synapse (2-photon + electron microscopy of FM1-43 dye), and AIM 4 will measure the rates at the bipolar synapse (electrophysiology + EM of ferritin). Glaucoma, a major cause of blindness, has been attributed to both ganglion cell anoxia and reduced axonal transport. Our studies will relate ganglion cell signaling to both oxidative capacity and axonal transport capacity, and thus should extend the basic foundation for future clinical studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SYNTHETIC MODELS AND SPECTROSCOPY OF METAL-OXO PROTEINS Principal Investigator & Institution: Que, Lawrence; Professor; Chemistry; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 01-APR-1999; Project End 31-MAR-2007 Summary: (provided by applicant): The diiron-oxo proteins have active sites consisting of metal centers bridged by oxo or hydroxo groups supported by carboxylate bridges. This expanding class of metalloproteins now includes proteins that perform a variety of functions in biology: dioxygen transport (hemerythrin), the conversion of ribonucleotides to deoxyribonucleotides (ribonucleotide reductase), iron storage (ferritin), phosphate ester hydrolysis (purple acid phosphatases), and oxidations of organic substrates via oxygen activation (methane monooxygenase, fatty acid desaturases, alkane and arene hydroxylases). Both soluble and membrane-bound forms are known. Many of the soluble enzymes have a sequence motif indicative of a carboxylate-rich diiron site, while the emerging membrane-bound subclass appears to have a histidine-rich diiron site. The focus of this proposal is to understand oxygen activation by diiron centers using a combination of biomimetic and biophysical approaches. Oxygen activation at a diiron active site is proposed to entail a common mechanism involving diiron(III)-peroxo intermediates and high-valent iron-oxo species derived therefrom. Building on past accomplishments in modeling structural and spectroscopic properties of such sites, it is proposed to synthesize precursor complexes that react with O2 or peroxides to afford metastable intermediates and characterize the spectroscopic and reactivity properties of these intermediates. Of great interest are intermediates such as O2 adducts of diiron(II) complexes, peroxo derivatives of iron(III), and species with Fe(III)Fe(IV) and Fe(IV)Fe(IV) formal oxidation states. These complexes will be characterized by x-ray crystallography whenever possible and by a variety of spectroscopic techniques such as NMR, EPR, UV-vis-NIR, Raman, Mossbauer, electrospray mass spectrometry, and EXAFS. Both stopped-flow and conventional kinetic methods will be used to characterize the mechanisms of formation and decomposition. The oxidative reactivities of these transient complexes towards a range of substrates will be investigated and compared with those of enzyme active sites. In parallel, EXAFS and resonance Raman studies of nonheme diiron enzyme intermediates themselves will be carried out to gain insight into their core structures. Of specific interest are the peroxo intermediates of stearoyl-ACP delta-9-desaturase and human H chain and E. coli ferritins as well as intermediates O, P, Q, and T in the methane monooxygenase cycle. These biophysical experiments dovetail well with the efforts to generate synthetic models for these enzyme intermediates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TRACE ELEMENT DYNAMICS IN THE VERTEBRATE EYE Principal Investigator & Institution: Mcgahan, Mary C.; Research Professor; Anatomy/Physiological Scis Rad; North Carolina State University Raleigh 2230 Stinson Drive Raleigh, Nc 27695 Timing: Fiscal Year 2002; Project Start 01-APR-1986; Project End 30-JUN-2006 Summary: (provided by applicant): Cataract is a significant health and economic problem worldwide. Oxidative damage has been implicated as a major causative factor in cataract formation. While iron (Fe) catalyzed free radical reactions are responsible for virtually all oxidative tissue damage, little information is available concerning Fe metabolism, storage and utilization in the lens. Storage of Fe in a non-reactive form in

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ferritin, prevents oxidative damage. Ferritin is made by the lens and a mutation resulting in dysregulation of the synthesis of ferritin subunits results in early bilateral cataracts in humans. The overlying Hypothesis of this proposal is that the uptake of Fe by lens epithelial cells and its movement between a cytoplasmic pool and sites of storage and utilization are carefully controlled under normal physiological conditions. Factors which increase the concentration of Fe in a low molecular weight cytoplasmic pool cause increased susceptibility to oxidative stress and UV irradiation, while a decrease in the size of this pool is protective. The first specific aim of this proposal is to determine how intracellular Fe dynamics, including Fe uptake and efflux, synthesis and concentration of ferritin, storage of Fe in ferritin and the amount of Fe in a low molecular weight cytoplasmic pool are altered by environmental factors and changes in ferritin subunit composition. The second specific aim is to determine whether disturbances in normal Fe distribution within lens epithelial cells result in altered cellular metabolism and affect their ability to withstand oxidative stress or UV irradiation. The results of these studies will provide information essential to our understanding of the metabolism and safe storage of Fe, the central component of damaging oxidative reactions. Such information could lead to the development of effective therapeutic interventions for the delay or prevention of cataract progression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRAINING: HEMATOLOGY, IMMUNOLOYG & STEM CELL BIOLOGY Principal Investigator & Institution: Lubin, Bertram H.; Director of Medical Research; Children's Hospital & Res Ctr at Oakland Research Center at Oakland Oakland, Ca 946091809 Timing: Fiscal Year 2002; Project Start 01-JUL-2000; Project End 30-JUN-2005 Summary: (Adapted from applicant's abstract) This is a proposal to establish an interdisciplinary postdoctoral training program in molecular and cellular biology with a focus on hematology, immunology and stem cell biology at the Children's Hospital Oakland Research Institute (CHORI). Support for six postdoctoral fellows is requested in each year of this grant. Trainees with Ph.D., M.D./Ph.D. or M.D. degrees are eligible for the program. Trainees are expected to have a strong background in either cell or molecular biology, genetic, biochemistry or physiology in order to be accepted into the program. The program emphasis hands-on bench work in the laboratory of an experienced, NIH supported investigator. A committee composed of the mentors at CHORI will select the candidates and will determine the laboratory in which they will work. Each trainee will develop a research hypothesis and write a mini proposal which will be reviewed by the P.I. and Co-PI of this application. Trainees will participate in core curriculum activities and will meet on a monthly basis to discuss progress on individual projects and to present data. In addition, trainees will participate in weekly laboratory meetings directed by their mentors, weekly journal clubs directed by the P.I. and Co-P.I., and weekly seminar series conducted at CHORI. Trainees will be expected to present their research at national meetings. All trainees will be expected to prepare a research proposal seeking extramural funding during their second or third year of training. The mentor will assist in preparing this application. Research training opportunities in this program will include: 1) Learning how to conduct clinical research in hematology with a focus on sickle cell anemia and thalassemia, 2) Studying red cell membrane structure and function studies using molecular, biochemical and biophysical techniques, 3) studying immunologic development, immune response to peptide mimetics, molecular analysis of the HLA system and their relationship to immune

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defects in patients with hemoglobinopathies, 4) Studies in iron metabolism and molecular regulation of ferritin, 5) studies of lipid mediated signal transduction in cell biology, 6) studies of genetic manipulation of cells, particularly hematopoietic stem cells, using adeno-associated viral vectors, and 7) studies of hematopoietic stem cell biology, with a focus on cord blood hematopoietic stem cells. This spectrum of research conducted by NIH funded M.D.s and Ph.D.s will provide a rich experience for trainees and will address the need for young scientists with a particular interest in hematology research that applies to the field of hemoglobinopathies. 1 Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSCRIPTIONAL REGULATION OF INSECT FERRITIN Principal Investigator & Institution: Pham, Daphne Q.; Biological Sciences; University of Wisconsin Parkside Kenosha, Wi 53141 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2004 Summary: Iron plays an essential role in numerous enzymatic processes. However, Fe+3 can catalyze dangerous oxidative reactions. Thus, all living organisms have developed proteins to transport, store and scavenge this indispensable yet hazardous metal. Numerous studies in vertebrates have associated the development of infection and neoplasia with excessive exposure to iron. Vertebrate data indicate that ferritin, an ironbinding protein, plays an essential role in the maintenance of cellular iron homeostasis in differentiating and malignant cells. The regulation of ferritin expression in these cases in mainly at the transcriptional level. Currently, the actual molecular machinery that activates this response remains unknown. Recent data attest to similarities between insect and vertebrate iron metabolism. Knowledge of insect iron metabolism however is limited. Our preliminary data indicated that transcriptional control is germane to the expression of ferritin in the yellow fever mosquito Aedes aegypti. The objective of this application is to dissect the transcriptional regulation of the mosquito A.aegypti ferritin. To accomplish the objective of this application, we will pursue three specific aims: 1) Obtain genomic clone containing approximately 20 kilobases of the 5' upstream region of the ferritin gene, 2) Map the cis-regulatory elements at the 5' upstream region and/or within the ferritin gene, 3) Partially identify of trans-regulatory factors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TRANSGENIC FERRITIN H IMPACTS IRON AND OXIDANT STRESS Principal Investigator & Institution: Wilkinson Iv, John; Cancer Biology; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2004; Project Start 01-MAR-2004; Project End 30-NOV-2006 Summary: (provided by applicant): This is an application for an NIDDK mentored career development award for John Wilkinson IV. Free or labile iron is a central mediator of oxidative stress. Ferritin, the primary cellular iron storage protein, is thought to buffer free iron flux and moderate the generation of oxygen free radicals. The role of ferritin in this critical process has been demonstrated in elegant cellular model systems, but has not been directly tested in vivo. To assess the function of ferritin in vivo, we have constructed conditional ferritin H transgenic mice in which ferritin H expression can be temporally controlled and targeted to specific organs. The ferritin H transgene contains a mutation in the iron responsive element that enables it to escape from translational control. We hypothesize that modulation of ferritin H regulates oxidative stress through its impact on cellular iron levels; thus, by regulating ferritin

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expression in vivo we can alter iron metabolism and the ability of iron to cause oxidative stress-induced cellular damage. To test this hypothesis we will conduct experiments according to the following aims: In Specific Aim One we will use the transgenic ferritin H model to understand the relationship between ferritin and iron metabolism. In Specific Aim Two we will use this model to assess the relationship between ferritin, accessible iron, and oxidative stress. In Specific Aim Three the model will be used to characterize the impact of ferritin on cellular oxidant defenses. Accomplishing these aims will increase our understanding of the role of ferritin in iron metabolism, will help define the scope of the influence ferritin can have on oxidant stress, and will establish an important model system for the study of diseases which involve oxidative stress such as atherosclerosis, cancer, diabetes, hematologic disorders, renal dysfunction, and neurodegeneration. The candidate's career development plan includes weekly meetings with his mentors, quarterly meetings with an advisory committee, attendance at several career development oriented workshops and seminars, training in the responsible conduct of science via an ethics course, and animal and radioactive safety training, and the development of collegial interactions through administration of a journal club which is topically pertinent to the studies conducted, as well as through presentation of his work at national meetings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSLOCATION AND FUNCTION OF NUCLEAR FERRITIN Principal Investigator & Institution: Connor, James R.; Professor; Neuroscience and Anatomy; Pennsylvania State Univ Hershey Med Ctr 500 University Drive Hershey, Pa 170332390 Timing: Fiscal Year 2002; Project Start 15-AUG-2001; Project End 31-JUL-2005 Summary: Iron is an essential component of life. However, iron is also a potent biological toxin. Thus the bioavailability of iron must be stringently regulated. At the cellular level, if there is too little iron, a cell will lack the ability to meet its metabolic and biosynthetic requirements. If there is too much iron the cell become vulnerable to oxidative stress. Iron requiring metabolic reactions are found in both nuclei and cytoplasm and molecules in both compartments are vulnerable to oxidative stress. Indeed, iron-binding sites have been reported on DNA and iron induced DNA damage is well established. In the cytoplasm, ferritin regulates iron bioavailability. Recently, we and two other groups have provided evidence that ferritin is present in the nuclei of some cells. By virtue of its ability to take up and release iron, ferritin may be uniquely suited to both deliver iron to the nucleus as well as provide protection from iron induced oxidative stress. Our preliminary data show that nuclear ferritin is found in many cell types, not just in corneal epithelium and cell lines in culture as reported in the literature. In addition we provide evidence that nuclear ferritin is inducible in specific cell nuclei. The objective of this proposal is to characterize and elucidate the contribution of ferritin to nuclear functions and genomic stability. We propose to achieve this objective by use four specific aims to test four hypotheses: (i) test the hypothesis that cell stress results in recruitment of cytoplasmic ferritin to the nucleus, (ii) test the hypothesis that ferritin cytoplasm to nucleus translocation of ferritin is regulated and that H-rich ferritin is preferred to L-rich ferritin for translocations, (iii) test the hypothesis that ferritin binds DNA and determine if there is a preferred DNA sequence and ferritin subunit for binding (iv) test the hypothesis that ferritin protects DNA from iron-induced oxidative damage. At the conclusion of these studies, we expect to: 1) demonstrate that the translocation of ferritin to the nucleus is a dynamic process. 2) identify conditions that influence the translocation of ferritin to the nucleus 3)

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identify the mechanism by which ferritin is translocated to the nucleus and the preferred composition of nuclear ferritin, 4) determined if there is a preferred DNA sequence for ferritin binding and 5) identify mechanisms by which ferritin contributes to genomic stability. This work will lead to novel insights into the role of ferritin in cell biology and may have unparalled significance in the context of accessibility of metals to DNA. Because iron overload is associated with many forms of cancer, the outcome of the proposed studies could form the basis of therapeutic strategies for iron mediated diseases and may be useful in the development of an improved antitumor chemotherapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “ferritin” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for ferritin in the PubMed Central database: •

A cis-acting element is necessary and sufficient for translational regulation of human ferritin expression in response to iron. by Hentze MW, Rouault TA, Caughman SW, Dancis A, Harford JB, Klausner RD.; 1987 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299157

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Both subunits of rat liver ferritin are regulated at a translational level by iron induction. by Aziz N, Munro HN.; 1986 Jan 24; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=339473

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Cloning, characterization, expression, and chromosomal localization of a human ferritin heavy-chain gene. by Hentze MW, Keim S, Papadopoulos P, O'Brien S, Modi W, Drysdale J, Leonard WJ, Harford JB, Klausner RD.; 1986 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=386688

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Conditional Derepression of Ferritin Synthesis in Cells Expressing a Constitutive IRP1 Mutant. by Wang J, Pantopoulos K.; 2002 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133884

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Conservation of ferritin heavy subunit gene structure: implications for the regulation of ferritin gene expression. by Murray MT, White K, Munro HN.; 1987 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299311

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

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

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Coordinate Transcriptional and Translational Regulation of Ferritin in Response to Oxidative Stress. by Tsuji Y, Ayaki H, Whitman SP, Morrow CS, Torti SV, Torti FM.; 2000 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86059

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Crosslinking of hemin to a specific site on the 90-kDa ferritin repressor protein. by Lin JJ, Patino MM, Gaffield L, Walden WE, Smith A, Thach RE.; 1991 Jul 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=52023

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Cytoplasmic protein binds in vitro to a highly conserved sequence in the 5' untranslated region of ferritin heavy- and light-subunit mRNAs. by Leibold EA, Munro HN.; 1988 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=279951

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Electron probe x-ray analysis of single ferritin molecules. by Shuman H, Somlyo AP.; 1976 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=430227

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Enhanced Iron Uptake of Saccharomyces cerevisiae by Heterologous Expression of a Tadpole Ferritin Gene. by Shin YM, Kwon TH, Kim KS, Chae KS, Kim DH, Kim JH, Yang MS.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=92725

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Essential Role of Ferritin Pfr in Helicobacter pylori Iron Metabolism and Gastric Colonization. by Waidner B, Greiner S, Odenbreit S, Kavermann H, Velayudhan J, Stahler F, Guhl J, Bisse E, van Vliet AH, Andrews SC, Kusters JG, Kelly DJ, Haas R, Kist M, Bereswill S.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128114

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Expression of Heteropolymeric Ferritin Improves Iron Storage in Saccharomyces cerevisiae. by Kim HJ, Kim HM, Kim JH, Ryu KS, Park SM, Jahng KY, Yang MS, Kim DH.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154789

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FER-1, an enhancer of the ferritin H gene and a target of E1A-mediated transcriptional repression. by Tsuji Y, Akebi N, Lam TK, Nakabeppu Y, Torti SV, Torti FM.; 1995 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230762

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Ferritin Synthesis is Controlled by Iron-Dependent Translational Derepression and by Changes in Synthesis/Transport of Nuclear Ferritin RNAs. by Coulson RM, Cleveland DW.; 1993 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47192

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Formation of the ferritin iron mineral occurs in plastids. by Waldo GS, Wright E, Whang ZH, Briat JF, Theil EC, Sayers DE.; 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=161379

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Haemoglobin and ferritin concentrations in men and women: cross sectional study. by Waalen J, Felitti V, Beutler E.; 2002 Jul 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117231

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High Prevalence of Helicobacter pylori in the Alaska Native Population and Association with Low Serum Ferritin Levels in Young Adults. by Parkinson AJ, Gold BD, Bulkow L, Wainwright RB, Swaminathan B, Khanna B, Petersen KM, Fitzgerald MA.; 2000 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95979

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Human ferritin gene is assigned to chromosome 19. by Caskey JH, Jones C, Miller YE, Seligman PA.; 1983 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=393402

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Identification and characterization of a receptor for tissue ferritin on activated rat lipocytes. by Ramm GA, Britton RS, O'Neill R, Bacon BR.; 1994 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296276

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Influence of altered transcription on the translational control of human ferritin expression. by Rouault TA, Hentze MW, Dancis A, Caughman W, Harford JB, Klausner RD.; 1987 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299070

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Inhibition of the growth of Neisseria meningitidis by reduced ferritin and other ironbinding agents. by Calver GA, Kenny CP, Kushner DJ.; 1979 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=414530

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Iron availability dramatically alters the distribution of ferritin subunit messages in Drosophila melanogaster. by Georgieva T, Dunkov BC, Harizanova N, Ralchev K, Law JH.; 1999 Mar 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15835

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Iron Content and Ferritin in Leaves of Iron Treated Xanthium pensylvanicum Plants. by Seckbach J.; 1969 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=396169

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Iron mobilization from ferritin by superoxide derived from stimulated polymorphonuclear leukocytes. Possible mechanism in inflammation diseases. by Biemond P, van Eijk HG, Swaak AJ, Koster JF.; 1984 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=437068

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Iron regulates ferritin mRNA translation through a segment of its 5' untranslated region. by Aziz N, Munro HN.; 1987 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299567

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Iron regulatory protein 1 is not required for the modulation of ferritin and transferrin receptor expression by iron in a murine pro-B lymphocyte cell line. by Schalinske KL, Blemings KP, Steffen DW, Chen OS, Eisenstein RS.; 1997 Sep 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23447

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Iron uptake in ferritin is blocked by binding of [Cr(TREN)(H2O)(OH)]2 +, a slow dissociating model for [Fe(H2O)6]2 +. by Barnes CM, Theil EC, Raymond KN.; 2002 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122745

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Iron-independent induction of ferritin H chain by tumor necrosis factor. by Miller LL, Miller SC, Torti SV, Tsuji Y, Torti FM.; 1991 Jun 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=51784

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Isolation and characterization of a cDNA clone for human ferritin heavy chain. by Boyd D, Jain SK, Crampton J, Barrett KJ, Drysdale J.; 1984 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=391568

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Model for intermediate steps in monocytic differentiation: c-myc, c-fms, and ferritin as markers. by Cayre Y, Raynal MC, Darzynkiewicz Z, Dorner MH.; 1987 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299351

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Modulation of ferritin H-chain expression in Friend erythroleukemia cells: transcriptional and translational regulation by hemin. by Coccia EM, Profita V, Fiorucci G, Romeo G, Affabris E, Testa U, Hentze MW, Battistini A.; 1992 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=364515

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Multiple post-transcriptional regulatory mechanisms in ferritin gene expression. by Mattia E, den Blaauwen J, Ashwell G, van Renswoude J.; 1989 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=286792

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Mutated recombinant human heavy-chain ferritins and myelosuppression in vitro and in vivo: a link between ferritin ferroxidase activity and biological function. by Broxmeyer HE, Cooper S, Levi S, Arosio P.; 1991 Feb 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=50895

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Nitric Oxide Signaling to Iron-Regulatory Protein: Direct Control of Ferritin mRNA Translation and Transferrin Receptor mRNA Stability in Transfected Fibroblasts. by Pantopoulos K, Hentze MW.; 1995 Feb 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42500

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Nitrogen monoxide-mediated control of ferritin synthesis: Implications for macrophage iron homeostasis. by Kim S, Ponka P.; 2002 Sep 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129424

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Novel mechanism for translational control in regulation of ferritin synthesis by iron. by Zahringer J, Baliga BS, Munro HN.; 1976 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=336018

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Nuclear Ferritin Protects DNA From UV Damage in Corneal Epithelial Cells. by Cai CX, Birk DE, Linsenmayer TF.; 1998 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25328

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Nucleotide sequence of cDNA encoding rabbit ferritin L chain. by Daniels-McQueen S, Ray A, Walden WE, Ray BK, Brown PH, Thach RE.; 1988 Aug 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=338463

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Nucleotide sequence of the mouse ferritin H chain gene. by Yachou AK, Renaudie F, Grandchamp B, Beaumont C.; 1989 Oct 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=334923

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ON THE PRESENCE OF FERRITIN IN THE PERIPHERAL BLOOD OF PATIENTS WITH HEPATOCELLULAR DISEASE. by Reissmann KR, Dietrich MR.; 1956 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=441628

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Opening protein pores with chaotropes enhances Fe reduction and chelation of Fe from the ferritin biomineral. by Liu X, Jin W, Theil EC.; 2003 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152977

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Paracrystalline inclusions of a novel ferritin containing nonheme iron, produced by the human gastric pathogen Helicobacter pylori: evidence for a third class of ferritins. by Frazier BA, Pfeifer JD, Russell DG, Falk P, Olsen AN, Hammar M, Westblom TU, Normark SJ.; 1993 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=193008

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Posttranscriptional regulation of ferritin during nodule development in soybean. by Kimata Y, Theil EC.; 1994 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=159185

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Redox reactivity of bacterial and mammalian ferritin: is reductant entry into the ferritin interior a necessary step for iron release? by Watt GD, Jacobs D, Frankel RB.; 1988 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282210

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Regulation of ferritin and heme oxygenase synthesis in rat fibroblasts by different forms of iron. by Eisenstein RS, Garcia-Mayol D, Pettingell W, Munro HN.; 1991 Feb 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=50878

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Regulation of transferrin receptor expression and ferritin content in human mononuclear phagocytes. Coordinate upregulation by iron transferrin and downregulation by interferon gamma. by Byrd TF, Horwitz MA.; 1993 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=288049

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Role of RNA secondary structure of the iron-responsive element in translational regulation of ferritin synthesis. by Kikinis Z, Eisenstein RS, Bettany AJ, Munro HN.; 1995 Oct 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=307361

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Sequence of Xenopus laevis ferritin mRNA. by Moskaitis JE, Pastori RL, Schoenberg DR.; 1990 Apr 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=330710

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Solid-Phase Conjugation of Ferritin to Fab-Fragments of Immunoglobulin G for Use in Antigen Localization on Thin Sections. by Kraehenbuhl JP, Jamieson JD.; 1972 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=426799

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Structural requirements of iron-responsive elements for binding of the protein involved in both transferrin receptor and ferritin mRNA post-transcriptional regulation. by Leibold EA, Laudano A, Yu Y.; 1990 Apr 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=330601

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Structure and expression of ferritin genes in a human promyelocytic cell line that differentiates in vitro. by Chou CC, Gatti RA, Fuller ML, Concannon P, Wong A, Chada S, Davis RC, Salser WA.; 1986 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=367547

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Structure and expression of the chicken ferritin H-subunit gene. by Stevens PW, Dodgson JB, Engel JD.; 1987 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=365276

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Structure of human ferritin light subunit messenger RNA: comparison with heavy subunit message and functional implications. by Dorner MH, Salfeld J, Will H, Leibold EA, Vass JK, Munro HN.; 1985 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=397730

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Structure of the 5' untranslated regulatory region of ferritin mRNA studied in solution. by Wang YH, Sczekan SR, Theil EC.; 1990 Aug 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=331265

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The immunosuppressive human placental ferritin subunit p43 is produced by activated CD4+ lymphocytes. by Garty B, Kaminsky E, Moroz C.; 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170132

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The importance of a single G in the hairpin loop of the iron responsive element (IRE) in ferritin mRNA for structure: an NMR spectroscopy study. by Sierzputowska-Gracz H, McKenzie RA, Theil EC.; 1995 Jan 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=306642

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The mRNA-binding protein which controls ferritin and transferrin receptor expression is conserved during evolution. by Rothenberger S, Mullner EW, Kuhn LC.; 1990 Mar 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=330432

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The role of superoxide anion radical in the reduction of ferritin iron by xanthine oxidase. by Williams DM, Lee GR, Cartwright GE.; 1974 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=301512

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The Ultrastructure of Ferritin Macromolecules. The Lattice Structure of the Core Crystallites. by Massover WH, Cowley JM.; 1973 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=427342

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Transcriptional regulation of the ferritin heavy-chain gene: the activity of the CCAAT binding factor NF-Y is modulated in heme-treated Friend leukemia cells and during monocyte-to-macrophage differentiation. by Marziali G, Perrotti E, Ilari R, Testa U, Coccia EM, Battistini A.; 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231863

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Translation of ferritin light and heavy subunit mRNAs is regulated by intracellular chelatable iron levels in rat hepatoma cells. by Rogers J, Munro H.; 1987 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=304633

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Translational repression in eukaryotes: partial purification and characterization of a repressor of ferritin mRNA translation. by Walden WE, Daniels-McQueen S, Brown PH, Gaffield L, Russell DA, Bielser D, Bailey LC, Thach RE.; 1988 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282781

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Unification of the ferritin family of proteins. by Grossman MJ, Hinton SM, MinakBernero V, Slaughter C, Stiefel EI.; 1992 Mar 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=48669

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with ferritin, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “ferritin” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for ferritin (hyperlinks lead to article summaries):

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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.

Studies

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A comparison between the soluble transferrin receptor, transferrin saturation and serum ferritin as markers of iron state in hemodialysis patients. Author(s): Beerenhout C, Bekers O, Kooman JP, van der Sande FM, Leunissen KM. Source: Nephron. 2002 September; 92(1): 32-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12187081

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A relationship between serum ferritin and the insulin resistance syndrome is present in non-diabetic women but not in non-diabetic men. Author(s): Sheu WH, Chen YT, Lee WJ, Wang CW, Lin LY. Source: Clinical Endocrinology. 2003 March; 58(3): 380-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12608945

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A simple assay for determination of iron release from ferritin in neuroblastoma cells. Author(s): Baader SL, Bruchelt G, Handgretinger R, Niethammer D. Source: Journal of Biochemical and Biophysical Methods. 1992 August; 25(1): 11-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1430787

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Active human ferritin H/L-hybrid and sequence effect on folding efficiency in Escherichia coli. Author(s): Lee J, Kim SW, Kim YH, Ahn JY. Source: Biochemical and Biophysical Research Communications. 2002 October 25; 298(2): 225-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12387819

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Adolescents eating diets rich in either lean beef or lean poultry and fish reduced fat and saturated fat intake and those eating beef maintained serum ferritin status. Author(s): Snetselaar L, Stumbo P, Chenard C, Ahrens L, Smith K, Zimmerman B. Source: Journal of the American Dietetic Association. 2004 March; 104(3): 424-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14993866

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Age-associated increases in heme oxygenase-1 and ferritin immunoreactivity in the autopsied brain. Author(s): Hirose W, Ikematsu K, Tsuda R. Source: Legal Medicine (Tokyo, Japan). 2003 March; 5 Suppl 1: S360-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12935634

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An alternative model of H ferritin promoter transactivation by c-Jun. Author(s): Faniello MC, Chirico G, Quaresima B, Cuda G, Allevato G, Bevilacqua MA, Baudi F, Colantuoni V, Cimino F, Venuta S, Avvedimento VE, Costanzo F. Source: The Biochemical Journal. 2002 April 1; 363(Pt 1): 53-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11903046

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Analysis of the biologic functions of H- and L-ferritins in HeLa cells by transfection with siRNAs and cDNAs: evidence for a proliferative role of L-ferritin. Author(s): Cozzi A, Corsi B, Levi S, Santambrogio P, Biasiotto G, Arosio P. Source: Blood. 2004 March 15; 103(6): 2377-83. Epub 2003 November 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14615379

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Anthelmintic treatment improves the hemoglobin and serum ferritin concentrations of Tanzanian schoolchildren. Author(s): Bhargava A, Jukes M, Lambo J, Kihamia CM, Lorri W, Nokes C, Drake L, Bundy D. Source: Food Nutr Bull. 2003 December; 24(4): 332-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14870620

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Anthracyclines induce accumulation of iron in ferritin in myocardial and neoplastic cells: inhibition of the ferritin iron mobilization pathway. Author(s): Kwok JC, Richardson DR. Source: Molecular Pharmacology. 2003 April; 63(4): 849-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12644586

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Antibodies for denatured human H-ferritin stain only reticuloendothelial cells within the bone marrow. Author(s): Ruggeri G, Santambrogio P, Bonfiglio F, Levi S, Bugari G, Verardi R, Cazzola M, Invernizzi R, Zambelli LM, Albertini A, et al. Source: British Journal of Haematology. 1992 May; 81(1): 118-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1381604

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Antiferritin VL homodimer binds human spleen ferritin with high specificity. Author(s): Nymalm Y, Kravchuk Z, Salminen T, Chumanevich AA, Dubnovitsky AP, Kankare J, Pentikainen O, Lehtonen J, Arosio P, Martsev S, Johnson MS. Source: Journal of Structural Biology. 2002 June; 138(3): 171-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12217656

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Antioxidant action of L-alanine: heme oxygenase-1 and ferritin as possible mediators. Author(s): Grosser N, Oberle S, Berndt G, Erdmann K, Hemmerle A, Schroder H. Source: Biochemical and Biophysical Research Communications. 2004 February 6; 314(2): 351-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14733911

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Antisense ferritin oligonucleotides inhibit growth and induce apoptosis in human breast carcinoma cells. Author(s): Yang DC, Jiang X, Elliott RL, Head JF. Source: Anticancer Res. 2002 May-June; 22(3): 1513-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12168831

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Assessment of the prevalence of iron deficiency anemia, by serum ferritin, in pregnant women of Southern Iran. Author(s): Karimi M, Kadivar R, Yarmohammadi H. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2002 July; 8(7): Cr488-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12118195

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Association between high serum ferritin levels and carotid atherosclerosis in the study of health in Pomerania (SHIP). Author(s): Wolff B, Volzke H, Ludemann J, Robinson D, Vogelgesang D, Staudt A, Kessler C, Dahm JB, John U, Felix SB. Source: Stroke; a Journal of Cerebral Circulation. 2004 February; 35(2): 453-7. Epub 2004 January 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14726541

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Association between serum ferritin and measures of inflammation, nutrition and iron in haemodialysis patients. Author(s): Kalantar-Zadeh K, Rodriguez RA, Humphreys MH. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2004 January; 19(1): 141-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14671049

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Association of ferritin and lipids with C-reactive protein. Author(s): Mainous AG 3rd, Wells BJ, Everett CJ, Gill JM, King DE. Source: The American Journal of Cardiology. 2004 March 1; 93(5): 559-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14996579

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Association of high serum ferritin concentration with glucose intolerance and insulin resistance in healthy people. Author(s): Haap M, Fritsche A, Mensing HJ, Haring HU, Stumvoll M. Source: Annals of Internal Medicine. 2003 November 18; 139(10): 869-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14623634

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Association of increased levels of heavy-chain ferritin with increased CD4+ CD25+ regulatory T-cell levels in patients with melanoma. Author(s): Gray CP, Arosio P, Hersey P. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 July; 9(7): 2551-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12855630

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Bacterioferritin: a hemoprotein member of the ferritin family. Author(s): Stiefel EI, Grossman MJ, Hinton SM, Minak-Bernero V, George GN, Prince RC, Bare RE, Watt GD. Source: Advances in Experimental Medicine and Biology. 1994; 356: 157-64. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7887220

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Beta-2-microglobulin and ferritin in cerebrospinal fluid for evaluation of patients with meningitis of different etiologies. Author(s): Takahashi S, Oki J, Miyamoto A, Moriyama T, Asano A, Inyaku F, Okuno A. Source: Brain & Development. 1999 April; 21(3): 192-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10372906

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Beta-2-microglobulin and ferritin values in cerebrospinal fluid of patients with acute leukemia. Author(s): Cudillo L, Pagano L, Storti S, Scribano D, De Stefano V, Leone G, Bizzi B. Source: Haematologica. 1986 March-April; 71(2): 109-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3087830

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Bilateral cataract and high serum ferritin: a new dominant genetic disorder? Author(s): Bonneau D, Winter-Fuseau I, Loiseau MN, Amati P, Berthier M, Oriot D, Beaumont C. Source: Journal of Medical Genetics. 1995 October; 32(10): 778-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8558554

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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. 1989 June; 96(6): 1539-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2714579

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Bilirubin, ferritin, D-dimers and erythrophages in the cerebrospinal fluid of patients with suspected subarachnoid haemorrhage but negative computed tomography scans. Author(s): Page KB, Howell SJ, Smith CM, Dabbs DJ, Malia RG, Porter NR, Thickett KJ, Wilkinson GM. Source: Journal of Clinical Pathology. 1994 November; 47(11): 986-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7829694

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Binding of a cytosolic protein to the iron-responsive element of human ferritin messenger RNA. Author(s): Rouault TA, Hentze MW, Caughman SW, Harford JB, Klausner RD. Source: Science. 1988 September 2; 241(4870): 1207-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3413484

Studies

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Biochemical analysis of ferritin subunits in sera from adult Still's disease patients. Author(s): Higashi S, Ota T, Eto S. Source: Rheumatology International. 1995; 15(2): 45-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7481479

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Biological variation of transferrin receptor and ferritin. Author(s): Masse J. Source: The American Journal of Clinical Nutrition. 1997 June; 65(6): 1897-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9174492

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Blood ferritin and isoferritins measurements may be helpful in acute respiratory distress syndrome patients. Author(s): Uzunhan Y, Guglielminotti J, Maury E, Berenbaum F, Offenstadt G. Source: Intensive Care Medicine. 2002 July; 28(7): 998. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12349824

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Blood ferritin concentrations in newborn infants and the sudden infant death syndrome. Author(s): Raha-Chowdhury R, Moore CA, Bradley D, Henley R, Worwood M. Source: Journal of Clinical Pathology. 1996 February; 49(2): 168-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8655686

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Blood letting in high-ferritin type 2 diabetes: effects on insulin sensitivity and betacell function. Author(s): Fernandez-Real JM, Penarroja G, Castro A, Garcia-Bragado F, HernandezAguado I, Ricart W. Source: Diabetes. 2002 April; 51(4): 1000-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11916918

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Blood letting in high-ferritin type 2 diabetes: effects on vascular reactivity. Author(s): Fernandez-Real JM, Penarroja G, Castro A, Garcia-Bragado F, Lopez-Bermejo A, Ricart W. Source: Diabetes Care. 2002 December; 25(12): 2249-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453969

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Blood leukocyte contribution to serum ferritin levels in patients on chronic hemodialysis. Author(s): Nuwayri-Salti N, Jabre F, Saab G, Daouk M, Salem Z. Source: Nephron. 1991; 57(2): 144-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2020340

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Blood transferrin and ferritin in Alzheimer's disease. Author(s): Fischer P, Gotz ME, Danielczyk W, Gsell W, Riederer P. Source: Life Sciences. 1997; 60(25): 2273-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9194682

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Body iron status in critically ill patients: significance of serum ferritin. Author(s): Bobbio-Pallavicini F, Verde G, Spriano P, Losi R, Bosatra MG, Braschi A, Iotti G, Chiaranda M, Villa S. Source: Intensive Care Medicine. 1989; 15(3): 171-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2738221

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Body iron stores decrease in boys during pubertal development: the transferrin receptor-ferritin ratio as an indicator of iron status. Author(s): Anttila R, Cook JD, Siimes MA. Source: Pediatric Research. 1997 February; 41(2): 224-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9029643

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Bovine ferritin iron bioavailability in man. Author(s): Skikne B, Fonzo D, Lynch SR, Cook JD. Source: European Journal of Clinical Investigation. 1997 March; 27(3): 228-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9088859

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Brain ferritin iron as a risk factor for age at onset in neurodegenerative diseases. Author(s): Bartzokis G, Tishler TA, Shin IS, Lu PH, Cummings JL. Source: Annals of the New York Academy of Sciences. 2004 March; 1012: 224-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15105269

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Brain iron and ferritin in Parkinson's and Alzheimer's diseases. Author(s): Jellinger K, Paulus W, Grundke-Iqbal I, Riederer P, Youdim MB. Source: J Neural Transm Park Dis Dement Sect. 1990; 2(4): 327-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2078310

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Caco-2 cell ferritin formation predicts nonradiolabeled food iron availability in an in vitro digestion/Caco-2 cell culture model. Author(s): Glahn RP, Lee OA, Yeung A, Goldman MI, Miller DD. Source: The Journal of Nutrition. 1998 September; 128(9): 1555-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9732319

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Calculated electrostatic gradients in recombinant human H-chain ferritin. Author(s): Douglas T, Ripoll DR. Source: Protein Science : a Publication of the Protein Society. 1998 May; 7(5): 1083-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9605313

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Cellular distribution of ferric iron, ferritin, transferrin and divalent metal transporter 1 (DMT1) in substantia nigra and basal ganglia of normal and beta2-microglobulin deficient mouse brain. Author(s): Moos T, Trinder D, Morgan EH. Source: Cell Mol Biol (Noisy-Le-Grand). 2000 May; 46(3): 549-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10872742

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Cerebrospinal fluid ferritin in glioblastoma: evidence for tumor synthesis. Author(s): Sato Y, Honda Y, Asoh T, Oizumi K, Ohshima Y, Honda E. Source: Journal of Neuro-Oncology. 1998 October; 40(1): 47-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9874185

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Characterization and distribution of ferritin binding sites in the adult mouse brain. Author(s): Hulet SW, Hess EJ, Debinski W, Arosio P, Bruce K, Powers S, Connor JR. Source: Journal of Neurochemistry. 1999 February; 72(2): 868-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9930764

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Chloramphenicol-induced mitochondrial dysfunction is associated with decreased transferrin receptor expression and ferritin synthesis in K562 cells and is unrelated to IRE-IRP interactions. Author(s): Leiter LM, Thatte HS, Okafor C, Marks PW, Golan DE, Bridges KR. Source: Journal of Cellular Physiology. 1999 September; 180(3): 334-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10430173

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Clinical usefulness of sialyl SSEA-1 antigen as tumor marker for ovarian cancer as compared with CA125, CA19-9, TPA, IAP, CEA and ferritin. Author(s): Yabushita H, Sawaguchi K, Hieda S, Ogawa A, Tomatsu A, Noguchi M, Ishihara M. Source: Nippon Sanka Fujinka Gakkai Zasshi. 1989 February; 41(2): 217-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2566639

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Clinical utility of the soluble transferrin receptor and comparison with serum ferritin in several populations. Author(s): Mast AE, Blinder MA, Gronowski AM, Chumley C, Scott MG. Source: Clinical Chemistry. 1998 January; 44(1): 45-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9550557

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Cloning and expression of a ferritin subunit for Galleria mellonella. Author(s): Kim BS, Yun CY, Yeo SM, Lee HJ, Kim HR. Source: Archives of Insect Biochemistry and Physiology. 2001 May; 47(1): 8-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11317331

76

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Commercially available dissociation-enhanced lanthanide fluoroimmunoassay kit evaluated for quantifying ferritin in serum. Author(s): Koskinen P, Irjala K. Source: Clinical Chemistry. 1989 February; 35(2): 327-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2914393

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Components of biological variation in serum soluble transferrin receptor: relationships to serum iron, transferrin and ferritin concentrations, and immune and haematological variables. Author(s): Maes M, Bosmans E, Scharpe S, Hendriks D, Cooremans W, Neels H, De Meyer F, D'Hondt P, Peeters D. Source: Scandinavian Journal of Clinical and Laboratory Investigation. 1997 February; 57(1): 31-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9127455

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Conditional derepression of ferritin synthesis in cells expressing a constitutive IRP1 mutant. Author(s): Wang J, Pantopoulos K. Source: Molecular and Cellular Biology. 2002 July; 22(13): 4638-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12052872

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Contrasting effects of excess ferritin expression on the iron-mediated oxidative stress induced by tert-butyl hydroperoxide or ultraviolet-A in human fibroblasts and keratinocytes. Author(s): Giordani A, Haigle J, Leflon P, Risler A, Salmon S, Aubailly M, Maziere JC, Santus R, Morliere P. Source: Journal of Photochemistry and Photobiology. B, Biology. 2000 January; 54(1): 4354. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10739142

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Cooperativity of mutational effects within a six amino acid residues substitution that induces a major conformational change in human H ferritin. Author(s): Jappelli R, Cesareni G. Source: Biochemical and Biophysical Research Communications. 1998 September 18; 250(2): 342-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9753631

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Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age. Author(s): Tamura T, Goldenberg RL, Hou J, Johnston KE, Cliver SP, Ramey SL, Nelson KG. Source: The Journal of Pediatrics. 2002 February; 140(2): 165-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11865266

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Cord serum ferritin levels, fetal iron status, and neurodevelopmental outcomes: correlations and confounding variables. Author(s): Fleming RE. Source: The Journal of Pediatrics. 2002 February; 140(2): 145-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11865262

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Correlation of T1 and T2 relaxation rates in normal bone-marrow water with serum ferritin concentration. Author(s): Ishizaka H, Ishijima H. Source: Acta Radiologica (Stockholm, Sweden : 1987). 1997 November; 38(6): 1076-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9394673

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Correlation of tomographic liver density with serum ferritin levels in multipletransfused children with thalassemia major. Author(s): Bavdekar SB, Ahuja P, Vaswani LK. Source: Indian Pediatrics. 1999 April; 36(4): 383-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10717698

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Crystal structure and biochemical properties of the human mitochondrial ferritin and its mutant Ser144Ala. Author(s): Langlois d'Estaintot B, Santambrogio P, Granier T, Gallois B, Chevalier JM, Precigoux G, Levi S, Arosio P. Source: Journal of Molecular Biology. 2004 July 2; 340(2): 277-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15201052

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Cytosolic aconitase and ferritin are regulated by iron in Caenorhabditis elegans. Author(s): Gourley BL, Parker SB, Jones BJ, Zumbrennen KB, Leibold EA. Source: The Journal of Biological Chemistry. 2003 January 31; 278(5): 3227-34. Epub 2002 November 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12438312

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Day to day variability in the transferrin receptor/ferritin index in female athletes. Author(s): Stupnicki R, Malczewska J, Milde K, Hackney AC. Source: British Journal of Sports Medicine. 2003 June; 37(3): 267-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12782555

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Decreased serum ferritin and alopecia in women. Author(s): Rushton DH. Source: The Journal of Investigative Dermatology. 2003 November; 121(5): Xvii-Xviii. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14708588

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Decreased serum ferritin is associated with alopecia in women. Author(s): Kantor J, Kessler LJ, Brooks DG, Cotsarelis G. Source: The Journal of Investigative Dermatology. 2003 November; 121(5): 985-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14708596

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Deficient ferritin immunoreactivity in tissues from niemann-pick type C patients: extension of findings to fetal tissues, H and L ferritin isoforms, but also one case of the rare Niemann-Pick C2 complementation group. Author(s): Christomanou H, Vanier MT, Santambrogio P, Arosio P, Kleijer WJ, Harzer K. Source: Molecular Genetics and Metabolism. 2000 July; 70(3): 196-202. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10924274

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Denatured H-ferritin subunit is a major constituent of haemosiderin in the liver of patients with iron overload. Author(s): Miyazaki E, Kato J, Kobune M, Okumura K, Sasaki K, Shintani N, Arosio P, Niitsu Y. Source: Gut. 2002 March; 50(3): 413-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11839724

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Deposits of fibrillar A beta do not cause neuronal loss or ferritin expression in adult rat brain. Author(s): Bishop GM, Robinson SR. Source: Journal of Neural Transmission (Vienna, Austria : 1996). 2003 April; 110(4): 381400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12658366

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Deteriorating ischaemic stroke. cytokines, soluble cytokine receptors, ferritin, systemic blood pressure, body temperature, blood glucose, diabetes, stroke severity, and CT infarction-volume as predictors of deteriorating ischaemic stroke. Author(s): Christensen H, Boysen G, Johannesen HH, Christensen E, Bendtzen K. Source: Journal of the Neurological Sciences. 2002 September 15; 201(1-2): 1-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163186

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Determination of serum ferritin in the evaluation of iron depletion and iron over load in chronic twin-to-twin transfusion syndrome. Author(s): Caglar MK, Kollee LA. Source: Journal of Perinatal Medicine. 1989; 17(5): 357-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2625656

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Developing human erythroid cells grown in transferrin-free medium utilize iron originating from extracellular ferritin. Author(s): Leimberg JM, Konijn AM, Fibach E. Source: American Journal of Hematology. 2003 July; 73(3): 211-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12827660

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Development of an automated immunoturbidimetric ferritin assay. Author(s): Borque L, Rus A, Bellod L, Seco ML. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 1999 September; 37(9): 899-905. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10596956

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Diabetes and serum ferritin concentration among U.S. adults. Author(s): Ford ES, Cogswell ME. Source: Diabetes Care. 1999 December; 22(12): 1978-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10587829

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Diagnosis of iron deficiency anemia in the elderly by transferrin receptor-ferritin index. Author(s): Rimon E, Levy S, Sapir A, Gelzer G, Peled R, Ergas D, Sthoeger ZM. Source: Archives of Internal Medicine. 2002 February 25; 162(4): 445-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11863478

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Diagnostic capability of CSF ferritin in children with meningitis. Author(s): Kim YO, Kang JS, Youm MH, Jong Woo Y. Source: Pediatric Neurology. 2003 April; 28(4): 271-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12849879

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Diagnostic value of ferritin and glycosylated ferritin in adult onset Still's disease. Author(s): Fautrel B, Le Moel G, Saint-Marcoux B, Taupin P, Vignes S, Rozenberg S, Koeger AC, Meyer O, Guillevin L, Piette JC, Bourgeois P. Source: The Journal of Rheumatology. 2001 February; 28(2): 322-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11246670

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Differentiation between hemosiderin- and ferritin-bound brain iron using nuclear magnetic resonance and magnetic resonance imaging. Author(s): Vymazal J, Urgosik D, Bulte JW. Source: Cell Mol Biol (Noisy-Le-Grand). 2000 June; 46(4): 835-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10875444

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Dinuclear center of ferritin: studies of iron binding and oxidation show differences in the two iron sites. Author(s): Treffry A, Zhao Z, Quail MA, Guest JR, Harrison PM. Source: Biochemistry. 1997 January 14; 36(2): 432-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9003196

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Distribution of ferritin and redox-active transition metals in normal and cataractous human lenses. Author(s): Garner B, Roberg K, Qian M, Eaton JW, Truscott RJ. Source: Experimental Eye Research. 2000 December; 71(6): 599-607. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11095912

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Diurnal variation of serum iron, iron-binding capacity, transferrin saturation, and ferritin levels. Author(s): Dale JC, Burritt MF, Zinsmeister AR. Source: American Journal of Clinical Pathology. 2002 May; 117(5): 802-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12090432

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Double-gradient denaturing gradient gel electrophoresis assay for identification of Lferritin iron-responsive element mutations responsible for hereditary hyperferritinemia-cataract syndrome: identification of the new mutation C14G. Author(s): Cremonesi L, Fumagalli A, Soriani N, Ferrari M, Levi S, Belloli S, Ruggeri G, Arosio P. Source: Clinical Chemistry. 2001 March; 47(3): 491-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11238302

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Effect of ascorbic acid administration in hemodialysis patients on in vitro oxidative stress parameters: influence of serum ferritin levels. Author(s): Chen WT, Lin YF, Yu FC, Kao WY, Huang WH, Yan HC. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2003 July; 42(1): 158-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12830468

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Effect of cell proliferation on H-ferritin receptor expression in human T lymphoid (MOLT-4) cells. Author(s): Moss D, Powell LW, Arosio P, Halliday JW. Source: The Journal of Laboratory and Clinical Medicine. 1992 August; 120(2): 239-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1323634

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Effect of retinoic acid on ferritin H expression during brain development and neuronal differentiation. Author(s): VanLandingham JW, Levenson CW. Source: Nutritional Neuroscience. 2003 February; 6(1): 39-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12608735

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Effects of haemoglobin and serum ferritin on cognitive function in school children. Author(s): Sungthong R, Mo-suwan L, Chongsuvivatwong V. Source: Asia Pacific Journal of Clinical Nutrition. 2002; 11(2): 117-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12074177

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Effects of hypoxia and nitric oxide on ferritin content of alveolar cells. Author(s): Smith JJ, O'Brien-Ladner AR, Kaiser CR, Wesselius LJ. Source: The Journal of Laboratory and Clinical Medicine. 2003 May; 141(5): 309-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12761474

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Elevated amniotic fluid ferritin levels are associated with inflammation-related pregnancy loss following mid-trimester amniocentesis. Author(s): Ramsey PS, Andrews WW, Goldenberg RL, Tamura T, Wenstrom KD, Johnston KE. Source: J Matern Fetal Neonatal Med. 2002 May;11(5):302-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12389670

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Elevated serum ferritin level in acute myocardial infarction. Author(s): Moroz C, Bessler H, Katz M, Zahavi I, Salman H, Djaldetti M. Source: Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 1997; 51(3): 126-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9181048

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Enhanced expression and functional characterization of the human ferritin H- and Lchain genes in Saccharomyces cerevisiae. Author(s): Seo HY, Chung YJ, Kim SJ, Park CU, Kim KS. Source: Applied Microbiology and Biotechnology. 2003 November; 63(1): 57-63. Epub 2003 May 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12768248

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Erythrocyte ferritin in patients with chronic renal failure and heterozygous betathalassemia. Author(s): Christopoulou V, Varsou A, Travlou A, Drivas G. Source: Nephron. 2002 July; 91(3): 463-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12119478

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Erythrocyte incorporation of iron by infants: iron bioavailability from a low-iron infant formula and an evaluation of the usefulness of correcting erythrocyte incorporation values, using a reference dose or plasma ferritin concentrations. Author(s): Davidsson L, Ziegler EE, Kastenmayer P, Hurrell RF. Source: The British Journal of Nutrition. 2000 December; 84(6): 847-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11177201

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Evaluation of a new measurement procedure for the concentration of ferritin in serum. Author(s): Palencia-Dominguez T, Martinez-Cervera JM, Fuentes-Arderiu X. Source: Eur J Clin Chem Clin Biochem. 1997 February; 35(2): 117-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9056755

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Evaluation of enhanced luminescence immunoenzymometric assays (LIA) for ferritin and free T4. Author(s): Armbruster DA, Jirinzu DC, Williams JV. Source: Journal of Clinical Laboratory Analysis. 1989; 3(2): 78-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2659758

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Evaluation of serum ferritin as a marker for adult Still's disease activity. Author(s): Schwarz-Eywill M, Heilig B, Bauer H, Breitbart A, Pezzutto A. Source: Annals of the Rheumatic Diseases. 1992 May; 51(5): 683-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1616341

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Evaluation of serum ferritin in screening for iron deficiency in tuberculosis. Author(s): Kotru M, Rusia U, Sikka M, Chaturvedi S, Jain AK. Source: Annals of Hematology. 2004 February; 83(2): 95-100. Epub 2003 October 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14551742

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Evaluation of the changes in serum lipid profile and ferritin concentrations in relation to body ascorbic acid status in healthy pre- and postmenopausal women. Author(s): Oner P, Mutlu-Turkoglu U, Omer B. Source: J Nutr Sci Vitaminol (Tokyo). 1997 February; 43(1): 1-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9151236

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Examination of the mechanism(s) involved in doxorubicin-mediated iron accumulation in ferritin: studies using metabolic inhibitors, protein synthesis inhibitors, and lysosomotropic agents. Author(s): Kwok JC, Richardson DR. Source: Molecular Pharmacology. 2004 January; 65(1): 181-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722250

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Expected value of serum soluble transferrin receptor, erythropoietin and ferritin and their correlation among healthy non-anemic Thai children. Author(s): Wiwanitkit V, Preechakas P, Bhokaisawan N, Boonchalermvichian C. Source: J Med Assoc Thai. 2002 June; 85 Suppl 1: S241-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12188418

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Expression of ferritin, transferrin receptor, and non-specific resistance associated macrophage proteins 1 and 2 (Nramp1 and Nramp2) in the human rheumatoid synovium. Author(s): Telfer JF, Brock JH. Source: Annals of the Rheumatic Diseases. 2002 August; 61(8): 741-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12117685

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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. 2004 June 11; 279(24): 25085-92. Epub 2004 March 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15044462

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Expression of transferrin receptor and ferritin H-chain mRNA are associated with clinical and histopathological prognostic indicators in breast cancer. Author(s): Yang DC, Wang F, Elliott RL, Head JF. Source: Anticancer Res. 2001 January-February; 21(1B): 541-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11299801

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Ferritin and cardiovascular risk. Author(s): Williams MJ, Poulton R, Williams S. Source: Atherosclerosis. 2003 March; 167(1): 171. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12618283

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Ferritin and serum iron levels in adult patients with sickle cell anaemia at Ibadan, Nigeria. Author(s): Aken'Ova YA, Adeyefa I, Okunade M. Source: Afr J Med Med Sci. 1997 March-June; 26(1-2): 39-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10895227

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Ferritin and serum transferrin receptor predict iron deficiency in anemic patients with rheumatoid arthritis. Author(s): Bultink IE, Lems WF, van de Stadt RJ, Dinant HJ, Leyte A, Park DS, de Koning MH, Dijkmans BA. Source: Arthritis and Rheumatism. 2001 April; 44(4): 979-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11315939

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Ferritin and venous cannula sepsis in TPN. Author(s): Cooney C, McCarthy E, Bourke J, Phelan D. Source: Anaesthesia and Intensive Care. 1992 May; 20(2): 250-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1595872

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Ferritin binds to light chain of human H-kininogen and inhibits kallikrein-mediated bradykinin release. Author(s): Parthasarathy N, Torti SV, Torti FM. Source: The Biochemical Journal. 2002 July 1; 365(Pt 1): 279-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12071855

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Ferritin concentrations in dried serum spots from capillary and venous blood in children in Sri Lanka: a validation study. Author(s): Ahluwalia N, de Silva A, Atukorala S, Weaver V, Molls R. Source: The American Journal of Clinical Nutrition. 2002 February; 75(2): 289-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11815320

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Ferritin expression in maturing normal human erythroid precursors. Author(s): Vaisman B, Meyron-Holtz EG, Fibach E, Krichevsky AM, Konijn AM. Source: British Journal of Haematology. 2000 August; 110(2): 394-401. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10971397

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Ferritin immunohistochemistry as a marker for microglia. Author(s): Kaneko Y, Kitamoto T, Tateishi J, Yamaguchi K. Source: Acta Neuropathologica. 1989; 79(2): 129-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2596262

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Ferritin is more cost-effective than transferrin receptor-ferritin index for the diagnosis of iron deficiency. Author(s): Ruivard M, Gerbaud L, Doz M, Philippe P. Source: Archives of Internal Medicine. 2002 August 12-26; 162(15): 1783. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12153390

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Ferritin levels in adult Still's disease: any sugar? Author(s): Fautrel B. Source: Joint, Bone, Spine : Revue Du Rhumatisme. 2002 June; 69(4): 355-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12184429

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Ferritin oxidation in vitro: implication of iron release and degradation by the 20S proteasome. Author(s): Rudeck M, Volk T, Sitte N, Grune T. Source: Iubmb Life. 2000 May; 49(5): 451-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10902578

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Ferritin regulation by oxidants and chemopreventive xenobiotics. Author(s): Wilkinson J 4th, Pietsch EC, Torti SV, Torti FM. Source: Advances in Enzyme Regulation. 2003; 43: 135-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791388

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Ferritin release by mononuclear cells in hereditary hemochromatosis. Author(s): Flanagan PR, Lam D, Banerjee D, Valberg LS. Source: The Journal of Laboratory and Clinical Medicine. 1989 February; 113(2): 145-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2783721

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Ferritin, a potent threat for acute myocardial infarction? Author(s): Silvia WD, Biswas S, Uthappa S, Shetty P. Source: J Assoc Physicians India. 2003 October; 51: 947-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14719581

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Ferritin, iron homeostasis, and oxidative damage. Author(s): Arosio P, Levi S. Source: Free Radical Biology & Medicine. 2002 August 15; 33(4): 457-63. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12160928

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Ferritin: at the crossroads of iron and oxygen metabolism. Author(s): Theil EC. Source: The Journal of Nutrition. 2003 May; 133(5 Suppl 1): 1549S-53S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12730463

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Ferrous ion binding to recombinant human H-chain ferritin. An isothermal titration calorimetry study. Author(s): Bou-Abdallah F, Arosio P, Santambrogio P, Yang X, Janus-Chandler C, Chasteen ND. Source: Biochemistry. 2002 September 17; 41(37): 11184-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12220183

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Functional expression and production of human H-ferritin in Pichia pastoris. Author(s): Lee JL, Song HS, Kim HJ, Park JH, Chung DK, Park CS, Jeoung D, Kim HY. Source: Biotechnology Letters. 2003 July; 25(13): 1019-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12889808

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Functional roles of the ferritin receptors of human liver, hepatoma, lymphoid and erythroid cells. Author(s): Moss D, Fargion S, Fracanzani AL, Levi S, Cappellini MD, Arosio P, Powell LW, Halliday JW. Source: Journal of Inorganic Biochemistry. 1992 August 15-September; 47(3-4): 219-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1331322

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Gender difference in cord serum ferritin concentrations. Author(s): Tamura T, Hou J, Goldenberg RL, Johnston KE, Cliver SP. Source: Biology of the Neonate. 1999; 75(6): 343-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10325437

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Genes for the 'H' subunit of human ferritin are present on a number of human chromosomes. Author(s): Cragg SJ, Drysdale J, Worwood M. Source: Human Genetics. 1985; 71(2): 108-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3862645

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Genetic mapping of the mouse ferritin light chain gene and 11 pseudogenes on 11 mouse chromosomes. Author(s): Filie JD, Buckler CE, Kozak CA. Source: Mammalian Genome : Official Journal of the International Mammalian Genome Society. 1998 February; 9(2): 111-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9457670

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Gestational anemia and serum ferritin. Author(s): Ishikawa K, Narita O, Saito H. Source: Kaku Igaku. 1984 April; 21(4): 305-10. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6471597

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Glycosylated serum ferritin in patients with hematological malignancies before and after bone marrow transplantation. Author(s): Konijn AM, Kaplan R, Or R, Matzner Y. Source: Leukemia & Lymphoma. 1992 May; 7(1-2): 151-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1472927

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Growth stimulation of ferritin of human leukemia cells in vitro. Author(s): Kikyo N, Hagiwara K, Yazaki Y, Okabe T. Source: Journal of Cancer Research and Clinical Oncology. 1995; 121(2): 76-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7883778

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Haem, haem oxygenase and ferritin in vascular endothelial cell injury. Author(s): Balla J, Vercellotti GM, Nath K, Yachie A, Nagy E, Eaton JW, Balla G. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2003 July; 18 Suppl 5: V8-12. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12817058

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Haemochromatosis mutations and ferritin in myocardial infarction: a case-control study. Author(s): Claeys D, Walting M, Julmy F, Wuillemin WA, Meyer BJ. Source: European Journal of Clinical Investigation. 2002 March; 32 Suppl 1: 3-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11886425

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Haemoglobin and ferritin concentrations in men and women: cross sectional study. Author(s): Waalen J, Felitti V, Beutler E. Source: Bmj (Clinical Research Ed.). 2002 July 20; 325(7356): 137. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12130609

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Haptoglobin polymorphism and serum ferritin concentration in ageing subjects. Author(s): Langlois MR, De Buyzere ML, Vlierberghe HV, Delanghe JR. Source: British Journal of Haematology. 2004 February; 124(4): 555-6; Author Reply 5567. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14984507

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HBsAg carrier status and the association between gestational diabetes with increased serum ferritin concentration in Chinese women. Author(s): Lao TT, Tse KY, Chan LY, Tam KF, Ho LF. Source: Diabetes Care. 2003 November; 26(11): 3011-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14578232

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Heavy chain ferritin enhances serine hydroxymethyltransferase expression and de novo thymidine biosynthesis. Author(s): Oppenheim EW, Adelman C, Liu X, Stover PJ. Source: The Journal of Biological Chemistry. 2001 June 8; 276(23): 19855-61. Epub 2001 March 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11278996

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Helicobacter pylori infection and serum ferritin: A population-based study among 1806 adults in Germany. Author(s): Berg G, Bode G, Blettner M, Boeing H, Brenner H. Source: The American Journal of Gastroenterology. 2001 April; 96(4): 1014-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11316140

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Hemochromatosis caused by mutations in the iron-regulatory proteins ferroportin and H ferritin. Author(s): Press RD. Source: Molecular Diagnosis : a Journal Devoted to the Understanding of Human Disease Through the Clinical Application of Molecular Biology. 2001 December; 6(4): 347. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11774199

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Hepatic iron concentration combined with long-term monitoring of serum ferritin to predict complications of iron overload in thalassaemia major. Author(s): Telfer PT, Prestcott E, Holden S, Walker M, Hoffbrand AV, Wonke B. Source: British Journal of Haematology. 2000 September; 110(4): 971-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11054091

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Hepatic iron deposition on MR imaging in patients with chronic liver disease: correlation with serial serum ferritin concentration. Author(s): Kim MJ, Mitchell DG, Ito K, Hann HW, Park YN, Kim PN. Source: Abdominal Imaging. 2001 March-April; 26(2): 149-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11178691

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Hepatitis C virus infection, increased serum ferritin and hyperinsulinemia. Author(s): Garrido Serrano A, Guerrero Igea FJ, Lepe Jimenez JA, Palomo Gil S, Grilo Reina A. Source: Rev Esp Enferm Dig. 2001 October; 93(10): 639-48. English, Spanish. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11767488

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High ferritin and low glycosylated ferritin may also be a marker of excessive macrophage activation. Author(s): Lambotte O, Cacoub P, Costedoat N, Le Moel G, Amoura Z, Piette JC. Source: The Journal of Rheumatology. 2003 May; 30(5): 1027-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12734900

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High level of ferritin light chain mRNA in lens. Author(s): Cheng Q, Gonzalez P, Zigler JS Jr. Source: Biochemical and Biophysical Research Communications. 2000 April 13; 270(2): 349-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10753629

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High maternal hemoglobin and ferritin values as risk factors for gestational diabetes. Author(s): Tarim E, Kilicdag E, Bagis T, Ergin T. Source: International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics. 2004 March; 84(3): 259-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15001377

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High prevalence of Helicobacter pylori in the Alaska native population and association with low serum ferritin levels in young adults. Author(s): Parkinson AJ, Gold BD, Bulkow L, Wainwright RB, Swaminathan B, Khanna B, Petersen KM, Fitzgerald MA. Source: Clinical and Diagnostic Laboratory Immunology. 2000 November; 7(6): 885-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11063492

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High serum ferritin is not identical to high iron stores. Author(s): Hallberg L, Hulthen L. Source: The American Journal of Clinical Nutrition. 2003 December; 78(6): 1225-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14668287

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How to approach an elevated ferritin level? Author(s): Mallory MA, Kowdley KV. Source: Postgraduate Medicine. 2002 June; 111(6): 10, 117. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12082914

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HTLV-I-associated myelopathy: are ferritin, S100beta protein, or guanine nucleotides CSF markers of disease? Author(s): Regner A, Bianchini O, Jardim C, Menna-Barreto M. Source: Journal of Neurovirology. 2002 February; 8(1): 64-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11847594

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Human liver ferritin as a new tracer for studying glomerular permeability. Author(s): Ota Z, Kumagai I, Shikata K, Makino H. Source: Acta Medica Okayama. 1989 December; 43(6): 363-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2624144

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Iatrogenic ferroma: a cause of failure of serum ferritin to respond to phlebotomy. Author(s): Plumb R, Levine E, Skikne B. Source: The American Journal of Medicine. 1997 February; 102(2): 220-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9217576

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Identification and minimization of nonideal binding effects in BIAcore analysis: ferritin/anti-ferritin Fab' interaction as a model system. Author(s): Oddie GW, Gruen LC, Odgers GA, King LG, Kortt AA. Source: Analytical Biochemistry. 1997 January 15; 244(2): 301-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9025947

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Identification of a mechanism by which lens epithelial cells limit accumulation of overexpressed ferritin H-chain. Author(s): Goralska M, Holley BL, McGahan MC. Source: The Journal of Biological Chemistry. 2003 October 31; 278(44): 42920-6. Epub 2003 August 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12920121

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Immunohistochemical identification of ferritin, lactoferrin and transferrin in leprosy lesions of human skin biopsies. Author(s): Momotani E, Wuscher N, Ravisse P, Rastogi N. Source: Journal of Comparative Pathology. 1992 April; 106(3): 213-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1602055

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Immunoreactivity for ferritin in Leydig cells of human testis. Author(s): Koeva YA. Source: Folia Med (Plovdiv). 2002; 44(3): 24-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12580527

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Importance of serum ferritin levels in patients with renal failure. Author(s): Gulcelik NE, Kayatas M. Source: Nephron. 2002 September; 92(1): 230-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12187111

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Increased expression of cytokeratin and ferritin-H genes in tumorigenic clones of the SW 613-S human colon carcinoma cell line. Author(s): Modjtahedi N, Frebourg T, Fossar N, Lavialle C, Cremisi C, Brison O. Source: Experimental Cell Research. 1992 July; 201(1): 74-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1377134

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Increased serum ferritin is common in men with essential hypertension. Author(s): Piperno A, Trombini P, Gelosa M, Mauri V, Pecci V, Vergani A, Salvioni A, Mariani R, Mancia G. Source: Journal of Hypertension. 2002 August; 20(8): 1513-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12172312

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Increased serum ferritin levels in active Behcet's disease. Author(s): Odabas AR, Karakuzu A, Cetinkaya R, Selcuk Y, Keles S, Bilen H. Source: Int J Clin Pract. 2002 May; 56(4): 310-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12074217

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Induction of ferritin and lipid peroxidation by coal samples with different prevalence of coal workers' pneumoconiosis: role of iron in the coals. Author(s): Zhang Q, Huang X. Source: American Journal of Industrial Medicine. 2002 September; 42(3): 171-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12210686

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Induction of ferritin expression by oxalomalate. Author(s): Santamaria R, Irace C, Festa M, Maffettone C, Colonna A. Source: Biochimica Et Biophysica Acta. 2004 May 3; 1691(2-3): 151-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15110995

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Influence of parenteral iron preparations on non-transferrin bound iron uptake, the iron regulatory protein and the expression of ferritin and the divalent metal transporter DMT-1 in HepG2 human hepatoma cells. Author(s): Scheiber-Mojdehkar B, Sturm B, Plank L, Kryzer I, Goldenberg H. Source: Biochemical Pharmacology. 2003 June 15; 65(12): 1973-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12787877

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Insulin resistance and ferritin as major determinants of nonalcoholic fatty liver disease in apparently healthy obese patients. Author(s): Hsiao TJ, Chen JC, Wang JD. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2004 January; 28(1): 167-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14610526

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Insulin resistance/beta-cell function and serum ferritin level in non-diabetic patients with hepatitis C virus infection. Author(s): Furutani M, Nakashima T, Sumida Y, Hirohama A, Yoh T, Kakisaka Y, Mitsuyoshi H, Senmaru H, Okanoue T. Source: Liver International : Official Journal of the International Association for the Study of the Liver. 2003 August; 23(4): 294-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12895270

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Interactions and reactions of ferritin with DNA. Author(s): Surguladze N, Thompson KM, Beard JL, Connor JR, Fried MG. Source: The Journal of Biological Chemistry. 2004 April 9; 279(15): 14694-702. Epub 2004 January 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14734543

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Intracellular ferritin accumulation in neural and extraneural tissue characterizes a neurodegenerative disease associated with a mutation in the ferritin light polypeptide gene. Author(s): Vidal R, Ghetti B, Takao M, Brefel-Courbon C, Uro-Coste E, Glazier BS, Siani V, Benson MD, Calvas P, Miravalle L, Rascol O, Delisle MB. Source: Journal of Neuropathology and Experimental Neurology. 2004 April; 63(4): 36380. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15099026

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Iron status markers, serum ferritin and hemoglobin in 1359 Danish women in relation to menstruation, hormonal contraception, parity, and postmenopausal hormone treatment. Author(s): Milman N, Kirchhoff M, Jorgensen T. Source: Annals of Hematology. 1992 August; 65(2): 96-102. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1511065

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Is there really no clear association between low serum ferritin and chronic diffuse telogen hair loss? Author(s): Rushton DH, Dover R, Norris MJ. Source: The British Journal of Dermatology. 2003 June; 148(6): 1282-4; Author Reply 1284. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12828773

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Isolation of point mutations that affect the folding of the H chain of human ferritin in E.coli. Author(s): Luzzago A, Cesareni G. Source: The Embo Journal. 1989 February; 8(2): 569-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2656256

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Lack of a relationship between serum ferritin levels and coronary atherosclerosis evaluated by coronary arteriography. Author(s): Manfroi WC, Zago AJ, Cruz R, Oliveira J, Kirschnick LS, Ordovas K, Candiago RH, Souza J, Ribeiro LW, Leitao C, Brizolara ML. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. 1999 March; 32(3): 303-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10347788

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Lack of association between ferritin level and measures of LDL oxidation: the ARIC study. Atherosclerosis Risk in Communities. Author(s): Iribarren C, Sempos CT, Eckfeldt JH, Folsom AR. Source: Atherosclerosis. 1998 July; 139(1): 189-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9699907

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Lack of magnetization transfer from the ferritin molecule. Author(s): Salustri C. Source: Journal of Magnetic Resonance. Series B. 1996 May; 111(2): 171-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8661275

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Lack of up-regulation of ferritin is associated with sustained iron regulatory protein-1 binding activity in the substantia nigra of patients with Parkinson's disease. Author(s): Faucheux BA, Martin ME, Beaumont C, Hunot S, Hauw JJ, Agid Y, Hirsch EC. Source: Journal of Neurochemistry. 2002 October; 83(2): 320-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12423242

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Latex agglutination test for ferritin measurement. Author(s): Kotajima N, Ishizaka M, Oshitani S, Fukumura Y, Ushijima Y, Murakami M. Source: Journal of Clinical Laboratory Analysis. 2003; 17(6): 223-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14614745

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Levels of serum ferritin and total body iron among infants with different feeding regimens. Author(s): Hokama T. Source: Acta Paediatr Jpn. 1993 August; 35(4): 298-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8379320

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LIAISON Ferritin--an automated chemiluminescent immunoassay for the determination of Ferritin. Author(s): Konig B, Oed M, Kunz A, Schlett R, Mack M. Source: Anticancer Res. 1999 July-August; 19(4A): 2739-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10470232

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Limitations of ferritin as a marker of anemia in end stage renal disease. Author(s): Dennison HA. Source: Anna J. 1999 August; 26(4): 409-14; Quiz 419-20. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10838972

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Lipid peroxidative damage in the erythrocytes and elevation of serum LDLcholesterol, apolipoprotein-B, ferritin and uric acid with age and in coronary heart disease patients. Author(s): El-Gebali HH, Tahir SA, Haider SS, El-Fakhri MM. Source: Saudi Med J. 2000 February; 21(2): 184-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11533779

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Liver density measured by DEXA correlates with serum ferritin in patients with betaThalassemia Major. Author(s): Chatterton BE, Thomas CM, Schultz CG. Source: Journal of Clinical Densitometry : the Official Journal of the International Society for Clinical Densitometry. 2003 Fall; 6(3): 283-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14514999

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Liver ferritin subunit ratios in neonatal hemochromatosis. Author(s): Hagar W, Vichinsky EP, Theil EC. Source: Pediatric Hematology and Oncology. 2003 April-May; 20(3): 229-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12637219

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Logarithmic quantitation model using serum ferritin to estimate iron overload in secondary haemochromatosis. Author(s): Gungor T, Rohrbach E, Solem E, Kaltwasser JP, Kornhuber B. Source: Archives of Disease in Childhood. 1996 April; 74(4): 323-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8669933

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Longitudinal changes in ferritin during chronic transfusion: a report from the Stroke Prevention Trial in Sickle Cell Anemia (STOP). Author(s): Files B, Brambilla D, Kutlar A, Miller S, Vichinsky E, Wang W, Granger S, Adams RJ. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2002 May; 24(4): 284-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11972097

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Loop mutations affect ferritin solubility causing non-native aggregation of subunits or precipitation of fully assembled polymers. Author(s): Jappelli R, Cesareni G. Source: Febs Letters. 1996 October 7; 394(3): 311-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8830664

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Low density lipoprotein oxidation by stimulated neutrophils and ferritin. Author(s): Abdalla DS, Campa A, Monteiro HP. Source: Atherosclerosis. 1992 December; 97(2-3): 149-59. Erratum In: Atherosclerosis 1993 January 25; 98(2): 257. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1334654

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Low-frequency low-field magnetic susceptibility of ferritin and hemosiderin. Author(s): Allen PD, St Pierre TG, Chua-anusorn W, Strom V, Rao KV. Source: Biochimica Et Biophysica Acta. 2000 February 21; 1500(2): 186-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10657588

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Lymphocyte labile iron pool, plasma iron, transferrin saturation and ferritin levels in colon cancer patients. Author(s): Gackowski D, Kruszewsk M, Banaszkiewicz Z, Jawien A, Olinski R. Source: Acta Biochimica Polonica. 2002; 49(1): 269-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12136950

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Lymphocyte-bearing ferritin in beta-thalassemia/Hb E. Author(s): Lamchaigdhase P, Pattanapanyasat K, Sritanaitipol A, Kuntamrongsri S, Fucharoen S. Source: J Med Assoc Thai. 1992 November; 75(11): 649-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1307389

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Magnetic properties of human liver and brain ferritin. Author(s): Dubiel SM, Zablotna-Rypien B, Mackey JB. Source: European Biophysics Journal : Ebj. 1999; 28(3): 263-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10192938

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Manganese absorption and retention by young women is associated with serum ferritin concentration. Author(s): Finley JW. Source: The American Journal of Clinical Nutrition. 1999 July; 70(1): 37-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10393136

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Massively elevated serum ferritin in an ill man with abnormal liver function tests. Author(s): Watson JP, Bramble MG, Ghosh SK. Source: Postgraduate Medical Journal. 1998 October; 74(876): 619-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10211364

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Maternal second-trimester serum ferritin concentrations and subsequent risk of preterm delivery. Author(s): Xiao R, Sorensen TK, Frederick IO, El-Bastawissi A, King IB, Leisenring WM, Williams MA. Source: Paediatric and Perinatal Epidemiology. 2002 October; 16(4): 297-304. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12445145

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Maternal serum ferritin and fetal growth. Author(s): Hou J, Cliver SP, Tamura T, Johnston KE, Goldenberg R. Source: Obstetrics and Gynecology. 2000 March; 95(3): 447-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10711561

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Maternal serum ferritin and gestational impaired glucose tolerance. Author(s): Lao TT, Tam KF. Source: Diabetes Care. 1997 September; 20(9): 1368-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9283781

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Measurement of ferritin levels: comparison of a commercial IRMA to an in-house ELISA method. Author(s): Zemelka S, Biesalski HK. Source: Journal of Immunoassay & Immunochemistry. 2001; 22(4): 371-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11816804

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Measuring serum ferritin under field conditions. Author(s): Monarrez-Espino J, Greiner T. Source: The American Journal of Clinical Nutrition. 2002 November; 76(5): 1138; Author Reply 1138-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12399290

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Mechanism of catalysis of Fe(II) oxidation by ferritin H chains. Author(s): Treffry A, Hirzmann J, Yewdall SJ, Harrison PM. Source: Febs Letters. 1992 May 11; 302(2): 108-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1353023

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Metal-dependent expression of ferritin and lactoferrin by respiratory epithelial cells. Author(s): Ghio AJ, Carter JD, Samet JM, Reed W, Quay J, Dailey LA, Richards JH, Devlin RB. Source: The American Journal of Physiology. 1998 May; 274(5 Pt 1): L728-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9612288

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Mineralization in ferritin: an efficient means of iron storage. Author(s): Chasteen ND, Harrison PM. Source: Journal of Structural Biology. 1999 June 30; 126(3): 182-94. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10441528

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Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia. Author(s): Cazzola M, Invernizzi R, Bergamaschi G, Levi S, Corsi B, Travaglino E, Rolandi V, Biasiotto G, Drysdale J, Arosio P. Source: Blood. 2003 March 1; 101(5): 1996-2000. Epub 2002 October 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12406866

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Mitochondrial ferritin: a new player in iron metabolism. Author(s): Drysdale J, Arosio P, Invernizzi R, Cazzola M, Volz A, Corsi B, Biasiotto G, Levi S. Source: Blood Cells, Molecules & Diseases. 2002 November-December; 29(3): 376-83. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12547228

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Moderately high serum ferritin concentration is not a sign of iron overload in dialysis patients. Author(s): Kalantar-Zadeh K, Luft FC, Humphreys MH. Source: Kidney International. 1999 August; 56(2): 758-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10432420

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Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations. Author(s): Hetet G, Devaux I, Soufir N, Grandchamp B, Beaumont C. Source: Blood. 2003 September 1; 102(5): 1904-10. Epub 2003 May 01. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12730114

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Molecular diffusion into ferritin: pathways, temperature dependence, incubation time, and concentration effects. Author(s): Yang X, Arosio P, Chasteen ND. Source: Biophysical Journal. 2000 April; 78(4): 2049-59. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10733983

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Monoclonal and polyclonal antibodies against human ferritin, a nonspecific tumor marker. Author(s): Chou SF, Chen CY. Source: Hybridoma. 2001 February; 20(1): 59-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11289229

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MR contrast of ferritin and hemosiderin in the brain: comparison among gradientecho, conventional spin-echo and fast spin-echo sequences. Author(s): Haque TL, Miki Y, Kanagaki M, Takahashi T, Yamamoto A, Konishi J, Nozaki K, Hashimoto N, Konishi J. Source: European Journal of Radiology. 2003 December; 48(3): 230-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14652139

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MRI evaluation of basal ganglia ferritin iron and neurotoxicity in Alzheimer's and Huntingon's disease. Author(s): Bartzokis G, Tishler TA. Source: Cell Mol Biol (Noisy-Le-Grand). 2000 June; 46(4): 821-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10875443

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Natural history of the C282Y homozygote for the hemochromatosis gene (HFE) with a normal serum ferritin level. Author(s): Yamashita C, Adams PC. Source: Clin Gastroenterol Hepatol. 2003 September; 1(5): 388-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15017658

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Neutrophil-activating protein (HP-NAP) versus ferritin (Pfr): comparison of synthesis in Helicobacter pylori. Author(s): Dundon WG, Polenghi A, Del Guidice G, Rappuoli R, Montecucco C. Source: Fems Microbiology Letters. 2001 May 15; 199(1): 143-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11356582

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Nitric oxide alters the expression of gamma-globin, H-ferritin, and transferrin receptor in human K562 cells at the posttranscriptional level. Author(s): Domachowske JB, Rafferty SP, Singhania N, Mardiney M 3rd, Malech HL. Source: Blood. 1996 October 15; 88(8): 2980-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8874195

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Nitric oxide donors modulate ferritin and protect endothelium from oxidative injury. Author(s): Juckett MB, Weber M, Balla J, Jacob HS, Vercellotti GM. Source: Free Radical Biology & Medicine. 1996; 20(1): 63-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8903680

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Non-allergenic antigen in allergic sensitization: responses to the mite ferritin heavy chain antigen by allergic and non-allergic subjects. Author(s): Epton MJ, Smith W, Hales BJ, Hazell L, Thompson PJ, Thomas WR. Source: Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology. 2002 September; 32(9): 1341-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12220473

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Nonglycosylated ferritin predominates in the circulation of women with preeclampsia but not intrauterine growth restriction. Author(s): Hubel CA, Bodnar LM, Many A, Harger G, Ness RB, Roberts JM. Source: Clinical Chemistry. 2004 May; 50(5): 948-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15105358

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Nonheme-iron absorption, fecal ferritin excretion, and blood indexes of iron status in women consuming controlled lactoovovegetarian diets for 8 wk. Author(s): Hunt JR, Roughead ZK. Source: The American Journal of Clinical Nutrition. 1999 May; 69(5): 944-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10232635

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Non-invasive liver iron quantification by SQUID-biosusceptometry and serum ferritin iron as new diagnostic parameters in hereditary hemochromatosis. Author(s): Nielsen P, Engelhardt R, Dullmann J, Fischer R. Source: Blood Cells, Molecules & Diseases. 2002 November-December; 29(3): 451-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12547235

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Normal serum iron and ferritin concentrations in patients with Friedreich's ataxia. Author(s): Wilson RB, Lynch DR, Fischbeck KH. Source: Annals of Neurology. 1998 July; 44(1): 132-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9667602

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Novel cellular defenses against iron and oxidation: ferritin and autophagocytosis preserve lysosomal stability in airway epithelium. Author(s): Persson HL, Nilsson KJ, Brunk UT. Source: Redox Report : Communications in Free Radical Research. 2001; 6(1): 57-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11333118

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Novel properties of L-type polypeptide subunits in mouse ferritin molecules. Author(s): Beaumont C, Torti SV, Torti FM, Massover WH. Source: The Journal of Biological Chemistry. 1996 April 5; 271(14): 7923-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8626471

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Okadaic acid stimulates H ferritin transcription in HeLa cells by increasing the interaction between the p300 CO-activator molecule and the transcription factor Bbf. Author(s): Bevilacqua MA, Faniello MC, Cimino F, Costanzo F. Source: Biochemical and Biophysical Research Communications. 1997 November 7; 240(1): 179-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9367906

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Oligodendrocyte progenitor cells internalize ferritin via clathrin-dependent receptor mediated endocytosis. Author(s): Hulet SW, Heyliger SO, Powers S, Connor JR. Source: Journal of Neuroscience Research. 2000 July 1; 61(1): 52-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10861799

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On the cytoprotective role of ferritin in macrophages and its ability to enhance lysosomal stability. Author(s): Garner B, Li W, Roberg K, Brunk UT. Source: Free Radical Research. 1997 November; 27(5): 487-500. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9518065

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Onset of cataract in early infancy associated with a 32G-->C transition in the iron responsive element of L-ferritin. Author(s): Campagnoli MF, Pimazzoni R, Bosio S, Zecchina G, DeGobbi M, Bosso P, Oldani B, Ramenghi U. Source: European Journal of Pediatrics. 2002 September; 161(9): 499-502. Epub 2002 August 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12200611

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Overexpression of myotonic dystrophy protein kinase in C2C12 myogenic culture involved in the expression of ferritin heavy chain and interleukin-1alpha mRNAs. Author(s): Watanabe T, Sasagawa N, Usuki F, Koike H, Saitoh N, Sorimachi H, Maruyama K, Nakase H, Takagi A, Ishiura S, Suzuki K. Source: Journal of the Neurological Sciences. 1999 August 1; 167(1): 26-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10500258

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Overexpression of the ferritin iron-responsive element decreases the labile iron pool and abolishes the regulation of iron absorption by intestinal epithelial (Caco-2) cells. Author(s): Garate MA, Nunez MT. Source: The Journal of Biological Chemistry. 2000 January 21; 275(3): 1651-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10636858

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Overexpression of wild type and mutated human ferritin H-chain in HeLa cells: in vivo role of ferritin ferroxidase activity. Author(s): Cozzi A, Corsi B, Levi S, Santambrogio P, Albertini A, Arosio P. Source: The Journal of Biological Chemistry. 2000 August 18; 275(33): 25122-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10833524

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Oxathiolene oxides: a novel family of compounds that induce ferritin, glutathione Stransferase, and other proteins of the phase II response. Author(s): Pietsch EC, Hurley AL, Scott EE, Duckworth BP, Welker ME, Leone-Kabler S, Townsend AJ, Torti FM, Torti SV. Source: Biochemical Pharmacology. 2003 April 15; 65(8): 1261-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12694867

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Oxidant stress and glioblastoma multiforme risk: serum antioxidants, gammaglutamyl transpeptidase, and ferritin. Author(s): Schwartzbaum JA, Cornwell DG. Source: Nutrition and Cancer. 2000; 38(1): 40-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11341043

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Oxidative damage to ferritin by 5-aminolevulinic acid. Author(s): Rocha ME, Dutra F, Bandy B, Baldini RL, Gomes SL, Faljoni-Alario A, Liria CW, Miranda MT, Bechara EJ. Source: Archives of Biochemistry and Biophysics. 2003 January 15; 409(2): 349-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12504902

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Patterns of immunocytochemical staining for ferritin and transferrin in the human spinal cord following traumatic injury. Author(s): Koszyca B, Manavis J, Cornish RJ, Blumbergs PC. Source: Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. 2002 May; 9(3): 298-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12093138

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Percentage of glycosylated serum ferritin remains low throughout the course of adult onset Still's disease. Author(s): Vignes S, Le Moel G, Fautrel B, Wechsler B, Godeau P, Piette JC. Source: Annals of the Rheumatic Diseases. 2000 May; 59(5): 347-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10784516

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Plasma ferritin in acute hepatocellular damage. Author(s): Bhagat CI, Fletcher S, Joseph J, Beilby JP. Source: Clinical Chemistry. 2000 June; 46(6 Pt 1): 885-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10839792

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Plasma ferritin in an elderly population living in the community. Author(s): Woo J, Mak YT, Law LK, Swaminathan R. Source: J Med. 1989; 20(2): 123-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2769082

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Plasmid DNA damage caused by methylated arsenicals, ascorbic acid and human liver ferritin. Author(s): Ahmad S, Kitchin KT, Cullen WR. Source: Toxicology Letters. 2002 July 7; 133(1): 47-57. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12076509

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PLIF, a novel human ferritin subunit from placenta with immunosuppressive activity. Author(s): Moroz C, Traub L, Maymon R, Zahalka MA. Source: The Journal of Biological Chemistry. 2002 April 12; 277(15): 12901-5. Epub 2002 January 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11821435

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Post-test probability that men in the community with raised plasma ferritin concentrations are hazardous drinkers. Author(s): Peach HG, Bath NE. Source: Journal of Clinical Pathology. 1999 November; 52(11): 853-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10690180

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Profiles of the acute-phase reactants C-reactive protein and ferritin related to the disease course of patients with systemic lupus erythematosus. Author(s): Hesselink DA, Aarden LA, Swaak AJ. Source: Scandinavian Journal of Rheumatology. 2003; 32(3): 151-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12892251

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Proteomic analysis and molecular characterization of tissue ferritin light chain in hepatocellular carcinoma. Author(s): Park KS, Kim H, Kim NG, Cho SY, Choi KH, Seong JK, Paik YK. Source: Hepatology (Baltimore, Md.). 2002 June; 35(6): 1459-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12029631

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Proteomic approach to coronary atherosclerosis shows ferritin light chain as a significant marker: evidence consistent with iron hypothesis in atherosclerosis. Author(s): You SA, Archacki SR, Angheloiu G, Moravec CS, Rao S, Kinter M, Topol EJ, Wang Q. Source: Physiological Genomics. 2003 March 18; 13(1): 25-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12644631

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Qualitative functional deficiency of affinity-purified lactoferrin from neutrophils of patients with chronic myelogenous leukemia, and lactoferrin/H-ferritin-cell interactions in a patient with lactoferrin-deficiency with normal numbers of circulating leukocytes. Author(s): Broxmeyer HE, Bicknell DC, Cooper S, Sledge G Jr, Williams DE, McGuire WA, Coates TD. Source: Pathobiology : Journal of Immunopathology, Molecular and Cellular Biology. 1991; 59(1): 26-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2043267

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Quantification of ferritin-secreting cells in patients with non-Hodgkin's lymphoma. Author(s): Ohnishi K, Shimizu K, Yamada H, Kunii A. Source: Acta Haematologica. 1985; 73(3): 145-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3929527

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Quantitation of ferritin iron in plasma, an explanation for non-transferrin iron. Author(s): Pootrakul P, Josephson B, Huebers HA, Finch CA. Source: Blood. 1988 April; 71(4): 1120-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3355890

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Quantitative and qualitative studies of red cell ferritin in refractory anemia of myelodysplastic syndrome. Author(s): Ohhara Y. Source: European Journal of Haematology. 1993 July; 51(1): 31-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8348942

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Quantitative determination of intracellular, ferritin-associated radioactive iron by high-performance liquid chromatography and immunoprecipitation. Author(s): Josic D, Mattia E, Ashwell G, van Renswoude J. Source: Analytical Biochemistry. 1986 January; 152(1): 42-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3456731

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Quantitative determination of non-haem iron and ferritin iron in bone marrow using flameless atomic absorption spectrophotometry. A comparative study on the cytological and chemical determination of the bone marrow iron content. Author(s): van Dieijen-Visser MP, Marell GJ, Coenen JL, Brombacher PJ. Source: Eur J Clin Chem Clin Biochem. 1991 June; 29(6): 381-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1912086

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Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection. Author(s): Distante S, Bjoro K, Hellum KB, Myrvang B, Berg JP, Skaug K, Raknerud N, Bell H. Source: Liver. 2002 June; 22(3): 269-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12100578

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Recent advance in molecular iron metabolism: translational disorders of ferritin. Author(s): Kato J, Niitsu Y. Source: International Journal of Hematology. 2002 October; 76(3): 208-12. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12416730

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Reference ranges for serum concentrations of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin, progesterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), cortisol and ferritin in neonates, children and young adults. Author(s): Elmlinger MW, Kuhnel W, Ranke MB. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 November; 40(11): 1151-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12521235

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Reference values for a heterogeneous ferritin assay and traceability to the 3rd International Recombinant Standard for Ferritin (NIBSC code 94/572). Author(s): Hamwi A, Endler G, Rubi K, Wagner O, Endler AT. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 April; 40(4): 365-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12059077

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Regulation of LIP level and ROS formation through interaction of H-ferritin with GCSF receptor. Author(s): Yuan X, Cong Y, Hao J, Shan Y, Zhao Z, Wang S, Chen J. Source: Journal of Molecular Biology. 2004 May 21; 339(1): 131-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15123426

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Relation between iron content of serum ferritin and clinical status factors extracted by factor analysis in patients with hyperferritinemia. Author(s): Yamanishi H, Iyama S, Yamaguchi Y, Kanakura Y, Iwatani Y. Source: Clinical Biochemistry. 2002 October; 35(7): 523-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12493580

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Relations among serum ferritin, C282Y and H63D mutations in the HFE gene and type 2 diabetes mellitus in the Czech population. Author(s): Kankova K, Jansen EH, Marova I, Stejskalova A, Pacal L, Muzik J, Vacha J. Source: Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association. 2002 August; 110(5): 2239. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12148086

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Relationship of serum ferritin with cardiovascular risk factors and inflammation in young men and women. Author(s): Williams MJ, Poulton R, Williams S. Source: Atherosclerosis. 2002 November; 165(1): 179-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12208485

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Repression of ferritin expression modulates cell responsiveness to H-ras-induced growth. Author(s): Kakhlon O, Gruenbaum Y, Cabantchik ZI. Source: Biochemical Society Transactions. 2002 August; 30(4): 777-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12196194

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Role of iron and ferritin in TNFalpha-induced apoptosis in HeLa cells. Author(s): Cozzi A, Levi S, Corsi B, Santambrogio P, Campanella A, Gerardi G, Arosio P. Source: Febs Letters. 2003 February 27; 537(1-3): 187-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12606055

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Screening of ferritin light polypeptide 460-461InsA mutation in Parkinson's disease patients in North America. Author(s): Chen R, Langston JW, Chan P. Source: Neuroscience Letters. 2002 December 25; 335(2): 144-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12459518

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Sequential changes of serum ferritin levels and their clinical significance in lamivudine-treated patients with chronic viral hepatitis B. Author(s): Liu ZW, Han QY, Zhang N, Kang W. Source: World Journal of Gastroenterology : Wjg. 2004 April 1; 10(7): 972-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15052677

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Serial ferritin concentrations in hemodialysis patients receiving intravenous iron. Author(s): Kirschbaum B. Source: Clinical Nephrology. 2002 June; 57(6): 452-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12078949

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Serum ferritin and Helicobacter pylori infection in children: a sero-epidemiologic study in Korea. Author(s): Seo JK, Ko JS, Choi KD. Source: Journal of Gastroenterology and Hepatology. 2002 July; 17(7): 754-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12121504

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Serum ferritin levels and early prognosis of stroke. Author(s): Erdemoglu AK, Ozbakir S. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2002 November; 9(6): 633-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453079

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Serum ferritin levels and transferrin saturation in men with prostate cancer. Author(s): Kuvibidila SR, Gauthier T, Rayford W. Source: Journal of the National Medical Association. 2004 May; 96(5): 641-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15160979

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Serum ferritin levels in West Nile encephalitis. Author(s): Cunha BA, Sachdev B, Canario D. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2004 February; 10(2): 184-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14759247

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Serum ferritin vs transferrin receptor-ferritin index. Author(s): Dosh SA. Source: Archives of Internal Medicine. 2002 August 12-26; 162(15): 1782; Author Reply 1782-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12153388

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Serum ferritin, alpha-tocopherol, beta-carotene and retinol levels in lymphatic filariasis. Author(s): Friis H, Kaestel P, Nielsen N, Simonsen PE. Source: Transactions of the Royal Society of Tropical Medicine and Hygiene. 2002 March-April; 96(2): 151-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12055804

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Soluble transferrin receptor (sTfR), ferritin, and sTfR/log ferritin index in anemic patients with nonhematologic malignancy and chronic inflammation. Author(s): Lee EJ, Oh EJ, Park YJ, Lee HK, Kim BK. Source: Clinical Chemistry. 2002 July; 48(7): 1118-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12089189

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The effect of maternal anemia and iron deficiency on fetal erythropoiesis: comparison between serum erythropoietin, hemoglobin and ferritin levels in mothers and newborns. Author(s): Erdem A, Erdem M, Arslan M, Yazici G, Eskandari R, Himmetoglu O. Source: J Matern Fetal Neonatal Med. 2002 May;11(5):329-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12389675

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The iron content of serum ferritin: physiological importance and diagnostic value. Author(s): ten Kate J, Wolthuis A, Westerhuis B, van Deursen C. Source: Eur J Clin Chem Clin Biochem. 1997 January; 35(1): 53-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9156568

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The mechanism of nitrogen monoxide (NO)-mediated iron mobilization from cells. NO intercepts iron before incorporation into ferritin and indirectly mobilizes iron from ferritin in a glutathione-dependent manner. Author(s): Watts RN, Richardson DR. Source: European Journal of Biochemistry / Febs. 2002 July; 269(14): 3383-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12135476

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The mengovirus leader protein suppresses alpha/beta interferon production by inhibition of the iron/ferritin-mediated activation of NF-kappa B. Author(s): Zoll J, Melchers WJ, Galama JM, van Kuppeveld FJ. Source: Journal of Virology. 2002 October; 76(19): 9664-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12208945

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The relation between serum ferritin and goiter, urinary iodine and thyroid hormone concentration. Author(s): Azizi F, Mirmiran P, Sheikholeslam R, Hedayati M, Rastmanesh R. Source: Int J Vitam Nutr Res. 2002 October; 72(5): 296-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12463104

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The relationship between serum ferritin levels and disease activity in systemic lupus erythematosus. Author(s): Beyan E, Beyan C, Demirezer A, Ertugrul E, Uzuner A. Source: Scandinavian Journal of Rheumatology. 2003; 32(4): 225-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14626629

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The role of cysteine residues in the oxidation of ferritin. Author(s): Welch KD, Reilly CA, Aust SD. Source: Free Radical Biology & Medicine. 2002 August 1; 33(3): 399-408. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12126762

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There is no clear association between low serum ferritin and chronic diffuse telogen hair loss. Author(s): Sinclair R. Source: The British Journal of Dermatology. 2002 November; 147(5): 982-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12410711

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Transgenic tobacco plants produce miniantibodies against human ferritin. Author(s): Semenyuk EG, Orlova IV, Stremovskii OA, Balandin TG, Nosov AM, Bur'yanov Y, Deev SM. Source: Doklady. Biochemistry and Biophysics. 2002 May-June; 384: 176-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12134516

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Ultraviolet A radiation induces immediate release of iron in human primary skin fibroblasts: the role of ferritin. Author(s): Pourzand C, Watkin RD, Brown JE, Tyrrell RM. Source: Proceedings of the National Academy of Sciences of the United States of America. 1999 June 8; 96(12): 6751-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10359784

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Unidirectional upregulation of the synthesis of the major iron proteins, transferrinreceptor and ferritin, in HepG2 cells by the acute-phase protein alpha1-antitrypsin. Author(s): Graziadei I, Weiss G, Bohm A, Werner-Felmayer G, Vogel W. Source: Journal of Hepatology. 1997 October; 27(4): 716-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9365048

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Unification of the ferritin family of proteins. Author(s): Grossman MJ, Hinton SM, Minak-Bernero V, Slaughter C, Stiefel EI. Source: Proceedings of the National Academy of Sciences of the United States of America. 1992 March 15; 89(6): 2419-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1549605

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Use of plasma ferritin concentration to diagnose iron deficiency in elderly patients. Author(s): Holyoake TL, Stott DJ, McKay PJ, Hendry A, MacDonald JB, Lucie NP. Source: Journal of Clinical Pathology. 1993 September; 46(9): 857-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8227438

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Use of the ferritin/alanine aspartate transaminase ratio as an iron overload marker independent of liver cell damage. Author(s): Triadou P, Regnat-Lusinchi A, Girot R. Source: European Journal of Haematology. 1989 November; 43(5): 423-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2612615

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Usefulness of glycosylated ferritin in atypical presentations of adult onset Still's disease. Author(s): Hamidou MA, Denis M, Barbarot S, Boutoille D, Belizna C, Le Moel G. Source: Annals of the Rheumatic Diseases. 2004 May; 63(5): 605. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15082500

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Usefulness of serum ferritin levels in the assessment of iron status in non-pregnant Zairean women of childbearing age. Author(s): Kuvibidila S, Yu L, Warrier RP, Ode D, Mbele V. Source: J Trop Med Hyg. 1994 June; 97(3): 171-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8007058

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Usefulness of serum transferrin receptor and serum ferritin in diagnosis of iron deficiency in infancy. Author(s): Olivares M, Walter T, Cook JD, Hertrampf E, Pizarro F. Source: The American Journal of Clinical Nutrition. 2000 November; 72(5): 1191-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11063448

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Using ferritin levels to determine iron-deficiency anemia in pregnancy. Author(s): Alper BS, Kimber R, Reddy AK. Source: The Journal of Family Practice. 2000 September; 49(9): 829-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11032208

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Utilization of intracellular ferritin iron for hemoglobin synthesis in developing human erythroid precursors. Author(s): Vaisman B, Fibach E, Konijn AM. Source: Blood. 1997 July 15; 90(2): 831-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9226184

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Validity of using capillary blood for the measurement of plasma ferritin. Author(s): Pawashe AB, Raman L, Nair M, Sarma J. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 1987 February 27; 163(1): 119-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3568410

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Value of ascitic fluid ferritin in the differential diagnosis of malignant ascites. Author(s): Kountouras J, Boura P, Tsapas G, Charisis K, Magoula I, Tsakiri I. Source: Anticancer Res. 1993 November-December; 13(6B): 2441-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8135481

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Value of serum alpha-fetoprotein and ferritin in the diagnosis of hepatocellular carcinoma. Author(s): Tatsuta M, Yamamura H, Iishi H, Kasugai H, Okuda S. Source: Oncology. 1986; 43(5): 306-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2429242

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Variation of soluble transferrin receptor and ferritin concentrations in human serum during recovery from exercise. Author(s): Nikolaidis MG, Michailidis Y, Mougios V. Source: European Journal of Applied Physiology. 2003 June; 89(5): 500-2. Epub 2003 April 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12712355

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Variations in erythropoiesis and serum ferritin during erythropoietin therapy for anaemia of end-stage renal disease. Author(s): Barosi G, Merlo C, Palestra P, Liberato NL, Guarnone R, Di Dio F, Piazza V, Salvadeo A. Source: Acta Haematologica. 1993; 90(1): 13-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8237268

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Variations in serum ferritin, serum iron, total iron binding capacity and saturation index in elderly hospitalized patients with iron deficiency anaemia after blood transfusion. Author(s): Joosten E, Linthoudt H, Pelemans W. Source: European Journal of Haematology. 1998 January; 60(1): 70-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9451433

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Very high serum ferritin levels in adult-onset Still's disease. Author(s): Akritidis N, Giannakakis Y, Sakkas L. Source: British Journal of Rheumatology. 1997 May; 36(5): 608-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9189070

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Vitamin B12, folic acid, ferritin and haematological variables among Thai construction site workers in urban Bangkok. Author(s): Tungtrongchitr R, Pongpaew P, Phonrat B, Chanjanakitskul S, Paksanont S, Migasena P, Schelp FP. Source: J Med Assoc Thai. 1995 January; 78(1): 5-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7622978

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Vitamin B12, folic acid, ferritin and haemoglobin status of rural women in childbearing age in northeast Thailand. Author(s): Tungtrongchitr R, Pongpaew P, Schelp FP, Phonrat B, Mahaweerawat U, Paksanont S, Sanchaisuriya P, Jotking P, Intarakhao C, Saowakhontha S. Source: J Med Assoc Thai. 1997 December; 80(12): 785-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9470332

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Welder's pneumoconiosis: diagnostic usefulness of high-resolution computed tomography and ferritin determinations in bronchoalveolar lavage fluid. Author(s): Yoshii C, Matsuyama T, Takazawa A, Ito T, Yatera K, Hayashi T, Imanaga T, Kido M. Source: Intern Med. 2002 December; 41(12): 1111-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12521198

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Why concentration of serum ferritin does not in all circumstances reflect storage iron but is still of value in its estimation. Author(s): Rajantie J, Siimes MA. Source: Scand J Haematol. 1983 July; 31(1): 20-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6867606

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Why should women have lower reference limits for haemoglobin and ferritin concentrations than men? Author(s): Rushton DH, Dover R, Sainsbury AW, Norris MJ, Gilkes JJ, Ramsay ID. Source: Bmj (Clinical Research Ed.). 2001 June 2; 322(7298): 1355-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11387188

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Zinc protoporphyrin/haem ratio and plasma ferritin in preterm infants. Author(s): Griffin IJ, Reid MM, McCormick KP, Cooke RJ. Source: Archives of Disease in Childhood. Fetal and Neonatal Edition. 2002 July; 87(1): F49-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091292

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Zinc, iron, copper, selenium, lactoferrin, and ferritin in human pus. Author(s): Bryant RE, Crouse R, Deagen JT. Source: The American Journal of the Medical Sciences. 2004 February; 327(2): 73-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14770022

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CHAPTER 2. NUTRITION AND FERRITIN Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and ferritin.

Finding Nutrition Studies on Ferritin The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “ferritin” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

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Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

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The following is a typical result when searching for recently indexed consumer information on ferritin: •

Ascorbic acid and ferritin catabolism. Source: Anonymous Nutr-Revolume 1989 July; 47(7): 218-9 0029-6643

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Diabetes and serum ferritin concentration among U.S. adults. Author(s): Division of Nutrition, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, USA. [email protected] Source: Ford, E S Cogswell, M E Diabetes-Care. 1999 December; 22(12): 1978-83 01495992

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Maternal serum ferritin and gestational impaired glucose tolerance. Author(s): University of Hong Kong, Hong Kong, China. Source: Lao, T.T. Tam, K.F. Diabetes-care (USA). (September 1997). volume 20(9) page 1368-1369. pregnancy diabetes blood sugar metalloproteins women 0149-5992

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The ferritin genes: their response to iron status. Author(s): USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111. Source: Munro, H Nutr-Revolume 1993 March; 51(3): 65-73 0029-6643

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

An atypical iron-responsive element (IRE) within crayfish ferritin mRNA and an iron regulatory protein 1 (IRP1)-like protein from crayfish hepatopancreas. Source: Huang, T.S. Melefors, O. Lind, M.I. Soderhall, K. Insect-biochem-mol-biol. Oxford, England : Elsevier Science Ltd. January 1999. volume 29 (1) page 1-9. 0965-1748

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Effect of dietary aluminum on tissue nonheme iron and ferritin levels in the chick. Author(s): Department of Food Science and Human Nutrition, University of Hawaii, Honolulu 96822, USA. Source: Han, J Han, J Dunn, M A Toxicology. 2000 January 3; 142(2): 97-109 0300-483X

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Effect of exercise on plasma ferritin concentrations: implications for the measurement of iron status. Author(s): Agrifood Research Finland, Animal Production, Equines, Ypaja. Source: Hyyppa, S Hoyhtya, M Nevalainen, M Poso, A R Equine-Vet-J-Suppl. 2002 September; (34): 186-90

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Effect of retinoic acid on ferritin H expression during brain development and neuronal differentiation. Author(s): Program in Neuroscience and Department of Nutrition, Food and Exercise Sciences, Florida State University, 237 Biomedical Research Facility, Tallahassee, FL 32306-4340, USA. Source: VanLandingham, J W Levenson, C W Nutr-Neurosci. 2003 February; 6(1): 39-45 1028-415X

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Effect of wine ethanol on serum iron and ferritin levels in patients with coronary heart disease. Author(s): Laboratoire du Stress Cardiovasculaire et Pathologies Associees, UFR de Medecine et Pharmacie, Domaine de la Merci, 38706 La Tronche, Grenoble, France. [email protected] Source: de Lorgeril, M Salen, P Boucher, F de Leiris, J Paillard, F Nutr-MetabCardiovasc-Dis. 2001 June; 11(3): 176-80 0939-4753

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Feasibility study on the detection of ferritin using surface plasmon resonance. Author(s): Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Source: Werawatgoompa, S Sriyudthsak, M J-Med-Assoc-Thai. 2001 June; 84 Suppl 1: S155-62 0125-2208

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Hematological parameters, ferritin and vitamin B12 in vegetarians. Author(s): Department of Clinical Microscopy, Faculty of Medical Technology, Rangsit University, Pathumthani, Thailand. Source: Pongstaporn, W Bunyaratavej, A J-Med-Assoc-Thai. 1999 March; 82(3): 304-11 0125-2208

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High ferritin values in malnourished children. Source: Golden, M.H.N. Golden, B.E. Bennett, F.I. Trace elements in man and animals : TEMA 5 : proceedings of the fifth International Symposium on Trace Elements in Man and Animals / editors C.F. Mills, I. Bremner, & J.K. Chesters. Farnham Royal, Slough : Commonwealth Agricultural Bureaux, c1985. page 775-779. ISBN: 085198553X

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Induction of ferritin and heat shock proteins by prostaglandin A1 in human monocytes. Evidence for transcriptional and post-transcriptional regulation. Author(s): Institute of Experimental Medicine, CNR, Roma, Italy. Source: Elia, G Polla, B Rossi, A Santoro, M G Eur-J-Biochem. 1999 September; 264(3): 736-45 0014-2956

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Low ferritin levels indicate the need for iron supplementation: strategy to minimize iron-depletion in regular blood donors. Author(s): Institute of Immunology and Transfusion Medicine, University of Lubeck School of Medicine, Germany. Source: Alvarez Ossorio, L Kirchner, H Kluter, H Schlenke, P Transfus-Med. 2000 June; 10(2): 107-12 0958-7578

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Novel cellular defenses against iron and oxidation: ferritin and autophagocytosis preserve lysosomal stability in airway epithelium. Author(s): Division of Pathology II, Faculty of Health Sciences, Linkoping University, Sweden. Source: Persso, H L Nilsson, K J Brunk, U T Redox-Repage 2001; 6(1): 57-63 1351-0002

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Regulation, mechanisms and proposed function of ferritin translocation to cell nuclei. Author(s): Department of Neuroscience and Anatomy, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, 17033, USA. [email protected] Source: Thompson, K J Fried, M G Ye, Z Boyer, P Connor, J R J-Cell-Sci. 2002 May 15; 115(Pt 10): 2165-77 0021-9533

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Serum ferritin and other haematological measurements in apparently healthy children with malaria parasitaemia in Lagos, Nigeria. Author(s): Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria. Source: Odunukwe, N N Salako, L A Okanny, C Ahmed, O A Mafe, A G Efinemokwu, C Raheem, T Y West-Afr-J-Med. 2001 Jan-March; 20(1): 42-5 0189-160X

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Serum ferritin as a measure of iron stores in the college girls. Author(s): Department of Food and Nutrition, College of Home Science, Punjab Agricultural University, Ludhiana 141 004. Source: Bains, K Mann, S K Indian-J-Med-Sci. 2000 September; 54(9): 375-9 0019-5359

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The association of low and high ferritin levels and anemia with pregnancy outcome. Source: O'Brien, H.T. Santure, M. Maziade, J. Can-j-diet-pract-res. Markham, ON : PG Communications, [1998-. Fall 2000. volume 61 (3)page 121-127. 1486-3847

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The effect of interferon and desferrioxamine on serum ferritin and hepatic iron concentrations in chronic hepatitis B. Author(s): Department of Gastroenterology, School of Medicine, Hacettepe University, Ankara, Turkey. Source: Bayraktar, Y Saglam, F Temizer, A Uzunalimodlu, B van Thiel, D H Hepatogastroenterology. 1998 Nov-December; 45(24): 2322-7 0172-6390

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The effect of intramuscular iron injections on serum ferritin levels and physical performance in elite netballers. Author(s): Department of Human Movement & Exercise Science, The University of Western Australia, Nedlands, Australia. Source: Blee, T Goodman, C Dawson, B Stapff, A J-Sci-Med-Sport. 1999 December; 2(4): 311-21 1440-2440

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The mechanism of nitrogen monoxide (NO)-mediated iron mobilization from cells. NO intercepts iron before incorporation into ferritin and indirectly mobilizes iron from ferritin in a glutathione-dependent manner. Author(s): The Iron Metabolism and Chelation Group, The Heart Research Institute, Camperdown, Sydney, New South Wales, Australia. Source: Watts, R N Richardson, D R Eur-J-Biochem. 2002 July; 269(14): 3383-92 0014-2956

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Transcriptional control is relevant in the modulation of mosquito ferritin synthesis by iron. Author(s): Department of Biochmistry, University of Arizona, Tucson, AZ, USA. [email protected] Source: Pham, D Q Winzerling, J J Dodson, M S Law, J H Eur-J-Biochem. 1999 November; 266(1): 236-40 0014-2956

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The following is a specific Web list relating to ferritin; 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: •

Minerals Calcium Source: Prima Communications, Inc.www.personalhealthzone.com Iron Source: Healthnotes, Inc.; www.healthnotes.com Manganese Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER 3. ALTERNATIVE MEDICINE AND FERRITIN Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to ferritin. 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 ferritin 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 “ferritin” (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 ferritin: •

5-Aminolevulinic acid induces iron release from ferritin. Author(s): Oteiza PI, Kleinman CG, Demasi M, Bechara EJ. Source: Archives of Biochemistry and Biophysics. 1995 January 10; 316(1): 607-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7840672

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Aerobic oxidation of aminoacetone, a threonine catabolite: iron catalysis and coupled iron release from ferritin. Author(s): Dutra F, Knudsen FS, Curi D, Bechara EJ. Source: Chemical Research in Toxicology. 2001 September; 14(9): 1323-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11559049

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Aminoacetone induces loss of ferritin ferroxidase and iron uptake activities. Author(s): Dutra F, Araki D, Bechara EJ.

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Source: Free Radical Research. 2003 October; 37(10): 1113-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14703801 •

Characterization and expression of the pseudomonas putida bacterioferritin alpha subunit gene. Author(s): Miller CD, Kim YC, Walsh MK, Anderson AJ. Source: Gene. 2000 April 18; 247(1-2): 199-207. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10773460

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Complexation of 1,2,4-benzenetriol with inorganic and ferritin-released iron in vitro. Author(s): Ahmad S, Rao GS. Source: Biochemical and Biophysical Research Communications. 1999 May 27; 259(1): 169-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10334934

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Decreased ferritin levels, despite iron supplementation, during erythropoietin therapy in anaemia of prematurity. Author(s): Bader D, Blondheim O, Jonas R, Admoni O, Abend-Winger M, Reich D, Lanir A, Tamir A, Eldar I, Attias D. Source: Acta Paediatrica (Oslo, Norway : 1992). 1996 April; 85(4): 496-501. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8740313

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Diallyl disulfide increases rat h-ferritin, L-ferritin and transferrin receptor genes in vitro in hepatic cells and in vivo in liver. Author(s): Thomas M, Zhang P, Noordine ML, Vaugelade P, Chaumontet C, Duee PH. Source: The Journal of Nutrition. 2002 December; 132(12): 3638-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12468600

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Differential regulation and expression of stress proteins and ferritin in human monocytes. Author(s): Bornman L, Baladi S, Richard MJ, Tyrrell RM, Polla BS. Source: Journal of Cellular Physiology. 1999 January; 178(1): 1-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9886484

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DNA damage by 5-aminolevulinic and 4,5-dioxovaleric acids in the presence of ferritin. Author(s): Di Mascio P, Teixeira PC, Onuki J, Medeiros MH, Dornemann D, Douki T, Cadet J. Source: Archives of Biochemistry and Biophysics. 2000 January 15; 373(2): 368-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10620361

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Effect of the microtubular inhibitor vinblastine on ferritin clearance and release in the rat. Author(s): Ramm GA, Powell LW, Halliday JW. Source: Journal of Gastroenterology and Hepatology. 1996 November; 11(11): 1072-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8985833

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Effects of low-dose iron supplementation in women with low serum ferritin concentration. Author(s): Fogelholm M, Suominen M, Rita H. Source: European Journal of Clinical Nutrition. 1994 October; 48(10): 753-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7835330

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Ethylenediaminetetraacetic acid (EDTA) does not increase iron uptake or ferritin synthesis by Caco-2 cells. Author(s): Garcia-Casal MN, Leets I, Layrisse M. Source: The Journal of Nutritional Biochemistry. 2004 May; 15(5): 261-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15135149

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Evaluation of transfusional iron overload before and during iron chelation by magnetic resonance imaging of the liver and determination of serum ferritin in adult non-thalassaemic patients. Author(s): Jensen PD, Jensen FT, Christensen T, Ellegaard J. Source: British Journal of Haematology. 1995 April; 89(4): 880-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7772526

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Ferritin assay performed on the Technicon Immuno 1 analyser using serum and plasma samples. Author(s): Cloete H, Kleinhans W, Mansvelt EP. Source: Clinical and Laboratory Haematology. 2002 October; 24(5): 281-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12358888

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Ferritin stimulation of hydroxyl radical production by rat liver nuclei. Author(s): Kukielka E, Cederbaum AI. Source: Archives of Biochemistry and Biophysics. 1994 January; 308(1): 70-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8311476

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Ferritin-dependent inactivation of microsomal glucose-6-phosphatase. Author(s): Puntarulo S, Cederbaum AI. Source: Biochimica Et Biophysica Acta. 1994 May 25; 1200(1): 41-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8186231

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Glycation of metal-containing proteins such as Cu,Zn-superoxide dismutase, ceruloplasmin, and ferritin: possible implication for DNA damage in vivo. Author(s): Taniguchi N, Kaneto H, Islam KN, Hoshi S, Myint T. Source: Contrib Nephrol. 1995; 112: 18-23. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7554989

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Hematological parameters, ferritin and vitamin B12 in vegetarians. Author(s): Pongstaporn W, Bunyaratavej A. Source: J Med Assoc Thai. 1999 March; 82(3): 304-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10410487

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Identification and characterization of the iron regulatory element in the ferritin gene of a plant (soybean). Author(s): Wei J, Theil EC. Source: The Journal of Biological Chemistry. 2000 June 9; 275(23): 17488-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10748212

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Influence of iron supplementation frequency on absorption efficiency and mucosal ferritin in anaemic rats. Author(s): Benito P, House W, Miller D. Source: The British Journal of Nutrition. 1997 September; 78(3): 469-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9306887

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Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia. Author(s): Tarng DC, Wei YH, Huang TP, Kuo BI, Yang WC. Source: Kidney International. 1999 June; 55(6): 2477-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10354297

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Investigation of the release of iron from ferritin by naturally occurring antioxidants. Author(s): Hynes MJ, Coinceanainn MO. Source: Journal of Inorganic Biochemistry. 2002 May 21; 90(1-2): 18-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12009251

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Iron bound to ferritin catalyzes ascorbate oxidation: effects of chelating agents. Author(s): Roginsky VA, Barsukova TK, Bruchelt G, Stegmann HB. Source: Biochimica Et Biophysica Acta. 1997 April 17; 1335(1-2): 33-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9133640

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Iron chelation can modulate UVA-induced lipid peroxidation and ferritin expression in human reconstructed epidermis. Author(s): Seite S, Popovic E, Verdier MP, Roguet R, Portes P, Cohen C, Fourtanier A, Galey JB.

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Source: Photodermatology, Photoimmunology & Photomedicine. 2004 February; 20(1): 47-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14738533 •

Iron overload in thalassemia: comparative analysis of magnetic resonance imaging, serum ferritin and iron content of the liver. Author(s): Mazza P, Giua R, De Marco S, Bonetti MG, Amurri B, Masi C, Lazzari G, Rizzo C, Cervellera M, Peluso A, et al. Source: Haematologica. 1995 September-October; 80(5): 398-404. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8566878

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Low ferritin levels indicate the need for iron supplementation: strategy to minimize iron depletion in regular blood donors. Author(s): Wood EM, Miller JP. Source: Transfusion Medicine (Oxford, England). 2001 February; 11(1): 59-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11328574

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Low ferritin levels indicate the need for iron supplementation: strategy to minimize iron-depletion in regular blood donors. Author(s): Alvarez-Ossorio L, Kirchner H, Kluter H, Schlenke P. Source: Transfusion Medicine (Oxford, England). 2000 June; 10(2): 107-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10849379

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Magnetic resonance imaging evaluation of the pituitary gland and hypothalamus in thalassaemic children with elevated serum ferritin levels. Author(s): Lau KY, Chan YL, Lam WW, Li CK, Metreweli C. Source: Journal of Paediatrics and Child Health. 1998 October; 34(5): 463-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9767512

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Metal binding and ferritin immunoreactivity in a high molecular weight fraction from rat brain. Author(s): San-Marina S, Nicholls DM. Source: Biochimica Et Biophysica Acta. 1996 February 29; 1310(3): 277-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8599605

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Metal binding properties of ferritin in Vigna mungo (L.) Hepper (black gram): possible role in heavy metal detoxification. Author(s): Rama Kumar T, Prasad MN. Source: Bulletin of Environmental Contamination and Toxicology. 1999 April; 62(4): 5027. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10094736

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Mobilization of iron from urban particulates leads to generation of reactive oxygen species in vitro and induction of ferritin synthesis in human lung epithelial cells. Author(s): Smith KR, Aust AE. Source: Chemical Research in Toxicology. 1997 July; 10(7): 828-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9250418

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Nrf2 mediates the induction of ferritin H in response to xenobiotics and cancer chemopreventive dithiolethiones. Author(s): Pietsch EC, Chan JY, Torti FM, Torti SV. Source: The Journal of Biological Chemistry. 2003 January 24; 278(4): 2361-9. Epub 2002 November 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12435735

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Occurrence and expression of members of the ferritin gene family in cowpeas. Author(s): Wardrop AJ, Wicks RE, Entsch B. Source: The Biochemical Journal. 1999 February 1; 337 ( Pt 3): 523-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9895297

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Purified ferritin and soybean meal can be sources of iron for treating iron deficiency in rats. Author(s): Beard JL, Burton JW, Theil EC. Source: The Journal of Nutrition. 1996 January; 126(1): 154-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8558296

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Roles of phosphate and an enoyl radical in ferritin iron mobilization by 5aminolevulinic acid. Author(s): Rocha ME, Ferreira AM, Bechara EJ. Source: Free Radical Biology & Medicine. 2000 December 15; 29(12): 1272-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11118817

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Selective iron supplementation based on serum ferritin values early in pregnancy: are the Norwegian recommendations satisfactory? Author(s): Sandstad B, Borch-Iohnsen B, Andersen GM, Dahl-Jorgensen B, Froysa I, Leslie C, Aas MH, Eig TR, Sandem SO. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 June; 82(6): 537-42. Erratum In: Acta Obstet Gynecol Scand. 2003 September; 82(9): 890. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12780424

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Sequential changes in serum iron and ferritin in patients undergoing high-dose chemotherapy and radiation with autologous bone marrow transplantation: possible implications for treatment related toxicity. Author(s): Gordon LI, Brown SG, Tallman MS, Rademaker AW, Weitzman SA, Lazarus HM, Kelley CH, Mangan C, Rubin H, Fox RM, et al.

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Source: Free Radical Biology & Medicine. 1995 March; 18(3): 383-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9101228 •

Serum ferritin and iron status in the general population of Singapore, 1993 to 1995. Author(s): Hughes K. Source: Ann Acad Med Singapore. 1998 July; 27(4): 507-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9791655

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Serum ferritin concentrations in transfusion dependent beta-thalassaemia. Author(s): George E, Wong HB, George R, Ariffin WA. Source: Singapore Med J. 1994 February; 35(1): 62-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8009283

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Serum iron, transferrin saturation, ferritin, and dietary data in age-related macular degeneration. Author(s): Richer S, Rudy D, Statkute L, Karofty K, Frankowski J. Source: American Journal of Therapeutics. 2002 January-February; 9(1): 25-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11782816

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Targeting higher ferritin concentrations with intravenous iron dextran lowers erythropoietin requirement in hemodialysis patients. Author(s): DeVita MV, Frumkin D, Mittal S, Kamran A, Fishbane S, Michelis MF. Source: Clinical Nephrology. 2003 November; 60(5): 335-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14640239

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The 2.6 A resolution structure of Rhodobacter capsulatus bacterioferritin with metalfree dinuclear site and heme iron in a crystallographic 'special position'. Author(s): Cobessi D, Huang LS, Ban M, Pon NG, Daldal F, Berry EA. Source: Acta Crystallographica. Section D, Biological Crystallography. 2002 January; 58(Pt 1): 29-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11752777

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The effect of putative nucleation sites on the loading and stability of iron in ferritin. Author(s): Juan SH, Aust SD. Source: Archives of Biochemistry and Biophysics. 1998 February 15; 350(2): 259-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9473300

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The effects of iron deficiency and iron and zinc supplementation on rat hippocampus ferritin. Author(s): Shoham S, Youdim MB.

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Source: Journal of Neural Transmission (Vienna, Austria : 1996). 2002 October; 109(10): 1241-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12373558 •

Variations of ferritin levels over a period of 15 years as a compliance chelation index in thalassemic patients. Author(s): Kattamis A, Dinopoulos A, Ladis V, Berdousi H, Kattamis C. Source: American Journal of Hematology. 2001 December; 68(4): 221-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11754409

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Weekly supplementation with iron and vitamin A during pregnancy increases hemoglobin concentration but decreases serum ferritin concentration in Indonesian pregnant women. Author(s): Muslimatun S, Schmidt MK, Schultink W, West CE, Hautvast JA, Gross R, Muhilal. Source: The Journal of Nutrition. 2001 January; 131(1): 85-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11303488

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

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

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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

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

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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html

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

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

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

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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

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

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HealthGate: http://www.tnp.com/

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

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

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

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The following is a specific Web list relating to ferritin; 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 Atherosclerosis Source: Healthnotes, Inc.; www.healthnotes.com Female Infertility Source: Healthnotes, Inc.; www.healthnotes.com Iron-Deficiency Anemia Source: Healthnotes, Inc.; www.healthnotes.com Parkinson's Disease Source: Healthnotes, Inc.; www.healthnotes.com Pregnancy and Postpartum Support Source: Healthnotes, Inc.; www.healthnotes.com Sickle Cell Anemia Source: Healthnotes, Inc.; www.healthnotes.com

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Herbs and Supplements Antacids Source: Prima Communications, Inc.www.personalhealthzone.com Lansoprazole Source: Healthnotes, Inc.; www.healthnotes.com Omeprazole Source: Healthnotes, Inc.; www.healthnotes.com

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

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CHAPTER 4. DISSERTATIONS ON FERRITIN Overview In this chapter, we will give you a bibliography on recent dissertations relating to ferritin. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “ferritin” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on ferritin, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Ferritin ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to ferritin. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

Cationic ferritin labeling of anionic sites at cellular surfaces by Brac, Timothy Victor; PhD from the University of Western Ontario (Canada), 1983 http://wwwlib.umi.com/dissertations/fullcit/NK58724

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Endocytosis of cationized ferritin by soybean (Glycine max L.) protoplasts by Tanchak, Michael Alan; PhD from the University of Saskatchewan (Canada), 1987 http://wwwlib.umi.com/dissertations/fullcit/NL35348

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

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CHAPTER 5. PATENTS ON FERRITIN 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.8 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 “ferritin” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on ferritin, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Ferritin By performing a patent search focusing on ferritin, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We

8Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on ferritin: •

Ferritin analogs Inventor(s): Monzyk; Bruce F. (Maryland Heights, MO) Assignee(s): Monsanto Company (St. Louis, MO) Patent Number: 5,304,382 Date filed: March 26, 1992 Abstract: Ferritin analogs comprising an apoferritin protein shell and a core substantially devoid of ferrihydrite, e.g. of inorganic composition such as aluminum hydroxide or organic composition such as acetaminophen. The protein shell can be removed from ferritin analog to produce spherules having a substantially monomodal nominal diameter between about 45 and 100 Angstroms. Excerpt(s): Disclosed herein are inventions relating to compositions encapsulated in a protein shell, more specifically such inventions comprise ferritin analogs, methods of making ferritin analogs and methods of using ferritin analogs, e.g. to produce nanosized (e.g. about 1-50 nanometers) particles and monolithic articles such as ceramics. Also disclosed are inventions relating to substantially uniform spherules of a monomodal size distribution prepared from ferritin analogs and methods of making and using such spherules. Among the tougher ceramic materials are those comprising ultra-small particles. Such particles are conventionally prepared by grinding larger particles and classifying the resultant mix of particles of wide ranging sizes and shapes, e.g. lumps, discs and needles, etc. The variety of shapes are difficult to separate and inhibit close packing of particles in use. For instance, when ceramics are produced from such particles, the disparate shapes provide discontinuities and stress risers which can result in failure of the ceramic article. Some attempts to produce high performance ceramics have focused on uniformity and fineness of particles. For instance, Eastman et al. in Research and Development pp 56-60 (January 1989) report the production of ultrafine powders of alumina, rutile etc. by condensing evaporated atoms in a low pressure inert gas, followed by compaction; the particles have a typical grain size distribution from about 5 to 25 nanometers (50-250 Angstroms). Also, Wusirika in U.S. Pat. No. 4,778,671 discloses the production of substantially unagglomerated metal oxide particles of up to about 1 micron mean diameter by precisely controlled precipitation of chelated solutes. The production of ultrafine particles of substantially monomodal size distribution has eluded practioners in the ceramics but remains an objective in efforts to provide high performance ceramics. Substantially uniform nanosized particles are ubiquitous in nature, i.e. in the form of the mineral core of the natural iron storage molecule, commonly known as "ferritin". Although iron is essential for most forms of plant and animal life, free or too much iron can be harmful. In nature ferritin serves to accumulate, store and dispense iron in response to the flux of iron entering or leaving the plant or animal. The structure and characteristics of ferritin is discussed by Ford et al. in "Ferritin: design and formation of an iron-storage molecule", B 304 Phil. Trans. R. Soc. Lond. 551-565 (1984). Ferritin is characterized as a hybrid polymer comprising a protein shell, assembled from 24 structurally equivalent protein subunits, forming a nearly spherical hollow shell surrounding a hydrous ferric oxide core, commonly known as "ferrihydrite", which is reported to have a diameter of about 5-8 nanometers (50 to 80 Angstroms) which corresponds to about 4500 iron atoms. It is believed that ions permeate through intersubunit channels in the protein shell to nucleation sites on

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the inside surface of the protein shell where the ferrihydrite core grows from the outside in. Web site: http://www.delphion.com/details?pn=US05304382__ •

Ferritin formation as an predictor of iron availability in foods Inventor(s): Glahn; Raymond P (Ithaca, NY) Assignee(s): The United States of America, as represented by the Secretary of (Washington, DC) Patent Number: 6,017,713 Date filed: March 12, 1999 Abstract: An in vitro system has been developed capable of effectively predicting the iron (Fe) availability of foods and food products. The system utilizes the formation of ferritin in intestinal epithelial cells as an indicator of Fe uptake from peptic and intestinal food digests. Excerpt(s): The invention relates to a method for effectively predicting the availability of iron (Fe) in foods utilizing ferritin formation in intestinal epithelial cells as an indicator. An intestinal epithelial cell line is a useful model for studies of iron uptake in humans. The Caco-2 cell line has been described as such a model in a number of studies (e.g. Glahn et al. 1994. FASEB Journal. vol. 8, no. 5, abstr. No. 4134; Wien et al. 1995. FASEB Journal. vol. 9, no. 4, abstr. No. 5711; Glahn et al. 1996. J. Nutr. vol. 126, pp. 332-339; Glahn et al. 1998. J. Nutr. vol. 128, pp. 257-264, all herein incorporated by reference). These applications all required the extrinsic radiolabeling of the food Fe. Intrinsic radiolabeling as a means of tracking Fe absorption for plant foods has also been utilized, however, it is a relatively expensive and time-consuming process which requires a facility and technical staff to support the growth of radiolabeled plant materials. In addition, it may be difficult to incorporate sufficient radioactivity into the food studied, particularly for use in in vitro systems. Thus, an in vitro model system that does not require radiolabeling of food Fe would be advantageous with respect to both time, cost, reliability and convenience. It would enable the measurement of food Fe availability in foods obtained directly from the producer or the supermarket shelf and would eliminate concerns of adequate radiolabeling of food Fe present in a complete meal. Web site: http://www.delphion.com/details?pn=US06017713__

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Ferritin with ferrimagnetically ordered ferrite core and method technical field Inventor(s): Mann; Stephen (Bath, GB) Assignee(s): Protein Magnetics (San Luis Obispo, CA) Patent Number: 5,491,219 Date filed: June 11, 1993 Abstract: Biocompatability and orders greater magnetic responsiveness characterize a uniquely useful new product, magnetoferritin, comprising ferritin having a ferrimagnetically ordered ferrite core in place of the naturally occurring ferrihydrite core. A method of preparation is disclosed.

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Excerpt(s): This invention has to do with the preparation of novel proteins useful in imaging of biological tissue, separations through labeling of cells and antibodies, and in a host of applications where magnetic properties are advantageously employed on a nanometer scale. More particularly, the invention provides a novel product: ferritin with a ferrimagnetically ordered, ferrite core. This product, sometimes referred to herein as magnetoferritin, affords a 10,000 fold and greater improvement in body or room temperature magnetic properties over naturally occurring ferritin, which has a paramagnetic core rather than the superparamagnetic core obtained in the invention. While the core of naturally occurring ferritin is comprised of the hydrous iron oxide ferrihydrite, the ferrimagnetic core is typically comprised of the iron-oxide ferrite magnetite, Fe.sub.3 O.sub.4, or maghemite,.gamma.-Fe.sub.2 O.sub.3, or an intermediate composition. Magnetite and maghemite are members of a series continuum of solid solutions. For ease of description reference will be made to magnetite as inclusive of maghemite as the ferrimagnetic constituent of the ferritin core in the compositions of the invention. The core can also be comprised of other transition metal ferrites. Ferritin, a protein naturally occurring in bacteria, fungi, plants, invertebrates and vertebrates including humans, is characterized by an ability to sequester and store iron in a bioavailable form. Chemically, the protein is a quaternary structure of 24 polypeptide units assembled into a spherical shell having an internal cavity about 8-10 nm in its longest dimension and penetrated by two types of intersubunit channels. In naturally occurring ferritin, the cavity contains up to 4500 iron atoms as a mineral core of the hydrous iron oxide ferrihydrite which is paramagnetic at ambient temperature. To my knowledge no one has substituted into the cavity of ferritin a ferrimagnetically ordered ferrite core with improved magnetic characteristics. Web site: http://www.delphion.com/details?pn=US05491219__ •

Five member ring sulfenate esters and thiosulfinate esters Inventor(s): Hurley; Allison L. (Atlanta, GA), Pietsch; Eva (Winston-Salem, NC), Torti; Frank M. (Winston-Salem, NC), Torti; Suzy V. (Winston-Salem, NC), Townsend; Alan J. (Winston-Salem, NC), Welker; Mark E. (Winston-Salem, NC) Assignee(s): Wake Forest University (Winston-Salem, NC) Patent Number: 6,242,478 Date filed: December 10, 1999 Abstract: Disclosed are novel sulfenate esters and thiosulfinate esters that induce the expression of metabolic enzymes, particularly Phase II enzymes such as glutathione-stransferase, DT-diaphorase and Ferritin H when administered to a subject. Also disclosed, such compounds are effective to displace a zinc ion from retroviral zinc finger nucleocapsid proteins effective to inhibit HIV replication. The present invention is further directed to novel methods of making these compounds, and any compounds produced by the process of making these novel compounds. Excerpt(s): The invention relates generally to novel sulfenate esters and thiosulfinate esters containing five membered rings, and to methods of making these compounds. The invention also relates to the field of therapeutic compositions for use as anti-cancer chemotherapeutic or chemoprotective agents, and as anti-HIV agents. Various types of cancers occur throughout the body, and affect large numbers of people. It is postulated that many of these cancers are caused by foreign substances, also referred to as xenobiotics. One method of limiting the carcinogenic effect of various xenobiotics is by promoting steps or increasing levels of substances in the metabolic pathway that allow

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carcinogens to be metabolized into neutral forms that are easily excreted from the body. A simplified description of how xenobiotics, compounds foreign to the body, are metabolized is that procarcinogens are metabolized by Phase I enzymes to either (i) electrophilic metabolites, which may cause DNA damage leading to DNA repair mechanisms or to cancer, or to (ii) nonelectrophilic metabolites that are further metabolized by Phase II enzymes to produce detoxification products. Several steps in this pathway potentially neutralize xenobiotics, and therefore could be considered as logical targets for chemoprevention of cancer. For example, the induction or inhibition of phase I enzymes might promote neutralizing metabolic steps, as could the induction of phase II enzymes. Alternatively, the promotion of DNA repair is a potentially promising means of preventing the carcinogenic effect of xenobiotics that are metabolized through Phase I enzymes to produce electrophilic metabolites which damage nucleic acid structures. Web site: http://www.delphion.com/details?pn=US06242478__ •

Homogeneous enzyme immunoassay for ferritin Inventor(s): Armenta; Richard (Mountain View, CA) Assignee(s): Syntex (U.S.A.) Inc. (Palo Alto, CA) Patent Number: 4,560,648 Date filed: September 23, 1983 Abstract: Composition and method are provided for enzyme immunoassays for high molecular weight proteins, such as ferritin. An enzyme is conjugated to the high molecular weight protein through a specific linking group. Usually, on the average, about 2 to 10 enzyme molecules are bonded to each protein molecule. In an assay, the conjugate competes with an unknown sample for receptor and the resulting enzymatic activity is compared to a standard for a determination of the presence and amount of protein in the unknown. Excerpt(s): High molecular weight proteins have drawn increasing attention in recent years as knowledge of their functions and their significance in medical diagnoses has grown. One such protein is ferritin, which is the main form of stored iron in tissue. The liver is the most important site in which this form of iron is found. Also, in some pathological conditions such as overload of iron by blood transfusions, inflammation, and certain tumors, changes in the ferritin content of tissues are found. Measurement of serum ferritin reflects the amount of total iron stored in the body. The need for sensitive and efficient assays for high molecular weight proteins such as ferritin has grown. To this end, various immunoassay techniques have been applied. The large size of these proteins, however, has heretofore limited the number of immunoassays which could provide a detectable signal. In particular, enzyme immunoassays have been limited to cumbersome procedures involving progressive binding reactions and phase separation. This is a serious limitation since enzyme immunoassays have the advantage of permitting spectrophotometric determinations and the potential of offering high sensitivity due to rapid substrate turnover rates which amplify the signal. A sensitive enzyme immunoassay is therefore needed which will permit the determination of large proteins in a simple and efficient manner. Solid phase sandwich enzyme immunoassays for ferritin, a protein with a molecular weight of aproximately 450,000 daltons, are disclosed in Theriault et al., Clin. Chem., 23/11:2142-2144 (1977); Fortier et al., Clin. Chem., 25/8:1466-1469 (1979); Conradie et al., S. Afr. Med. J., 57:282-287 (1980); Page et

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al., Scand. J. Clin. Lab. Invest., 40:641-645 (1980); Anderson et al., Clin. Chim. Acta., 116:405-408 (1981); and Linpisarn et al., Ann. Clin. Biochem., 18:48-53 (1981). Web site: http://www.delphion.com/details?pn=US04560648__ •

Method for measuring total body tissue iron stores Inventor(s): Herbert; Victor D. (New York, NY), Jayatilleke; Elizabeth (Englewood, NJ), Shaw; Spencer (Larchmont, NY) Assignee(s): Quixote Associates, Inc. (Katonah, NY) Patent Number: 5,552,268 Date filed: August 8, 1995 Abstract: A non-invasive method to measure total body tissue iron stores comprising recovering iron released from total ferritin contained in a body fluid sample derived from a host, measuring the ferritin-iron in the total ferritin and thereby determining total body tissue iron stores. Such an assay is utilized for diagnosing negative iron balance as well as positive iron balance, wherein the latter promotes cancer, coronary artery disease, atherosclerosis, and hepatic failure among other diseases, as well as the susceptibility to such diseases. Excerpt(s): Total body tissue iron stores are an important diagnostic indicator to the health professional of the presence of diseased states or a susceptibility to diseased states in an individual. Body iron is both a necessary component for cellular metabolism and a highly damaging agent when present in excess. For example, iron leashed to protein is an essential element in all cell metabolism and growth, but is toxic when unleashed (Herbert V., et al., Stem Cells, 92:1502-1509 (1994)). Because of its ability to switch back and forth between ferrous and ferric oxidation states, iron is both a strong biological oxidant and reductant. Ferric iron or Fe.sup.3+ is a relatively harmless form of iron. However, ferrous iron or Fe.sup.2+ plays a significant role in the generation of oxygen radicals, excess of which have been proven to be extremely harmful to the health of an individual. The human diet contains a multitude of natural chemicals which are carcinogens and anti-carcinogens, many of which act by generating oxygen radicals, which initiate degenerative processes related to cancer, heart disease and aging (Ames, B., Science, 221:1256-1264 (1993)). Among these many dietary chemicals are many redox agents, including vitamin C and beta carotene. Web site: http://www.delphion.com/details?pn=US05552268__

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Method for quantitatively measuring and mapping stored iron in tissue using MRI Inventor(s): Bartzokis; George (Los Angeles, CA), Phelan; Carolanne K. (Los Angeles, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 5,322,682 Date filed: August 6, 1992 Abstract: The invention provides a specific measure of iron stores in vivo using magnetic resonance imaging. T.sub.2 relaxation times in both lower-to-mid field strength magnetic resonance imaging instruments and a higher field strength instrument is evaluated. T.sub.2 obtained at the higher field strength instrument is

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subtracted from T.sub.2 obtained at the lower field strength instrument. This difference, T, is then correlated with a quantitative measure of the iron stores in vivo in the scanned tissue. A two-dimensional or multidimensional map of the scanned tissue is then constructed on the basis of T to visually identify different tissue types as being normal or abnormal, either through a visual determination based on gray scales or a numeric comparison based on quantitative measure. The introduction of artificial or nonbiological substances as opposed to natural ferritin, is permitted for further diagnostic use by application of this methodology. Excerpt(s): The invention relates to the field of the use of magnetic resonance in medicine to measure iron stores in tissue, and in particular to quantitatively and specifically measure in vivo ferritin and closely related substances in tissue. During the past decade, a number of studies have implicated iron as a central culprit in various diseases including some cancers. A genetic disease, hemochromatosis, which causes excessive accumulations of iron in tissue and which can be fatal, is estimated to occur or to be at risk in an estimated 1.4 million Americans. The accumulation of iron stores in tissue has also been implicated in various studies in liver damage, arthritis, diabetes, impotence, heart failure and various neurological disorders such as Alzheimer's and Parkinson's disease. Iron stores is understood to mean ferritin or ferritin like proteins, which is the biological form for storage of iron. The deleterious effects of excessive iron stores levels in tissue is thought to be related to its ability to catalyze the production of hydroxil radicals from other free radicals which naturally occur within the human body as well as direct toxic effects of iron itself. The largest part of iron stores in human tissue normally occurs in a complex protein called ferritin, the storage form of iron. Free radicals such as superperoxides, as well as other substances which occur in the body can remove the iron from ferritin, where it is harmless, to catalyze the formation of more destructive radicals which are believed to be linked to the above disease states. Web site: http://www.delphion.com/details?pn=US05322682__ •

Monoclonal antibodies to placental isoferritin for use in detecting oncofetal ferritin associated with breast cancer and Hodgkins disease Inventor(s): Moroz; Chaya (40 Yehuda Hanassi Street, Tel Aviv, IL) Assignee(s): none reported Patent Number: 4,882,270 Date filed: January 22, 1988 Abstract: There are provided monoclonal antibodies which react with human oncofetal ferritin and which do not react with human spleen ferritin or with liver ferritin; there are also provided monoclonal antibodies which react both with human placenta oncofetal ferritin and with human adult spleen ferritin. There is provided a process for producing clones producing such antibodies and such clones, and an assay for the detection of human breast cancer based on the determination of oncofetal ferritin, which assay is based on such monoclonal antibodies. Excerpt(s): The present invention relates to monoclonal antibodies which react with human embryonic ferritin derived from human placenta, which do not react with adult human spleen or liver ferritin; and to monoclonal antibodies which react with human placenta embryonic ferritin and which cross-react with human adult spleen ferritin. The invention further relates to an assay for the detection of human breast cancer and/or Hodgkins disease which comprises selectively determining when human oncofetal

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ferritin is present in the body tissues and/or lymphocytes of patients. According to a specific embodiment of the present invention the presence or absence of human oncofetal ferritin is determined by a cytotoxic assay. Web site: http://www.delphion.com/details?pn=US04882270__ •

Placental isoferritins for the prognosis and diagnosis of immunosuppression Inventor(s): Misrock; S. Leslie (Chappaqua, NY), Moroz; Chaya (Tel-Aviv, IL) Assignee(s): Daikin Industries Ltd. (Osaka, JP) Patent Number: 5,283,177 Date filed: March 18, 1992 Abstract: Methods for the diagnosis and prognosis of immunosuppressive conditions are disclosed, involving the detection of a particular isoform of ferritin, placental ferritin (PLF), in patient samples such as sera or on peripheral blood lymphocytes. PLF is elevated in immunosuppressed patients at early stages of disease; by contrast, adult insoferritins are elevated at late stages of immunodeficiency. Depending upon the nature of the disease associated with the immunodeficiency, the elevated levels of PLF detected at early stages may remain elevated or diminish as disease progresses. Examples are described in which elevated levels of PLF were detected at very early stages of of HIV-infection. The elevated levels diminished as disease progressed from ARC to AIDS. By contrast, adult isoforms of ferritin became elevated at late stages of disease. Excerpt(s): The present invention relates to methods for the diagnosis and prognosis of immunosuppressive conditions. The method of the invention involves the detection of placental ferritin (PLF) in patient samples such as serum, or on peripheral blood lymphocytes. Elevated levels of PLF are detected in patients at early stages of immunosuppression. Depending upon the nature of the disease associated with the patients, immunosuppressed condition, the elevated PLF levels may decline with progression of disease. The detection and measurement of PLF may be accomplished using monoclonal antibodies described herein. The invention is demonstrated by way of examples in which elevated PLF was detected in sera of subjects infected with human immunodeficiency virus (HIV). Individuals at early stages of disease exhibited the highest PLF levels which declined as the disease progressed. Ferritin is an iron storage protein which maintains iron in an available, non-toxic form. A variety of ferritin isoforms have been isolated from different tissues. The variability of ferritin characteristics appear to be mainly caused by the presence of different subunit types in the multimeric protein shell (Drysdale, 1977, Ciba Found. Symp. 51:41; Arosio, et al., 1978, J. Biol. Chem. 253:4451; Watanabe et al., 1981, Biochem. Biophys. Res. Comm. 103:207). In fact, three ferritin subunits have been described. The L subunit (19 Kd), prevalent in iron loaded tissues, the H subunit (21 Kd), predominant in iron poor and malignant cells (Drysdale, 1977, supra; Arosio, 1978, supra) and the glycosylated G subunit (24 Kd) isolated from serum (Cragg et al., 1981, Biochem. J. 199:565). Different isoferritins contain different proportions of L and H subunit types. More recently, preliminary analysis of cDNA clones revealed that the H and L subunits are encoded by rather complex families of genes (Brown et al., 1983, Proc. Natl. Acad. Sci. USA 73:857; Costanzo et al., 1984, EMBO J. 3:23), suggesting that the heterogeneity of ferritin molecules may be even greater than presently determined. Web site: http://www.delphion.com/details?pn=US05283177__

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Process for determining ferritin Inventor(s): Cowan; Stuart I. (Marston Mortaine, GB2), Niemann; Elfriede (Kriftel, DE), Stagg; Brian H. (Bletchley, GB2) Assignee(s): Hoechst Aktiengesellschaft (Frankfurt am Main, DE) Patent Number: 4,278,652 Date filed: October 26, 1978 Abstract: A process for the determination of ferritin in serum or in plasma is disclosed, which comprises incubating an antibody directed against an organ-specific isoferritin, which is covalently bound to nylon(polyamide 6,6), on the one hand with ferritin standard solutions and on the other hand with serum samples, decanting or aspirating the incubation solutions, washing the nylon-antibody-ferritin complex formed and subsequently incubating it with a iodine-labelled antibody directed against a second organ-specific isoferritin, isolating the nylon-antibody-ferritin-anti-body-.sup.125 Icomplex formed, counting its radioactivity in the gamma counter and comparing the standard samples with the serum samples. Excerpt(s): The present invention relates to a process for determining ferritin. The assay of ferritin in serum of mammals, especially of humans, has been shown to provide a means of accurately assessing iron storage in the body. According to J. W. Halliday et al. (cf. Clinica Chimica Acta 58, 207-214 (1975)) ferritin may be determined in serum using plastic tubes, which are coated inside with anti-liver ferritin antibodies. Either liver ferritin standards or serum samples are incubated, then after discarding the solution, washing the coating and treating it subsequently with anti-liver ferritin-.sup.125 Iantibodies and discarding the supernatant, the radioactivity bound to the coating in the tubes is counted in the gamma counter. Web site: http://www.delphion.com/details?pn=US04278652__

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Separation of cells and biological macromolecules by ferritin conjugates Inventor(s): Bose; Arijit (Cambridge, MA), Sonti; Srinivas V. (Narragansett, RI) Assignee(s): Board of Governors for Higher Education, State of Rhode Island and (Providence, RI) Patent Number: 5,248,589 Date filed: January 16, 1992 Abstract: An Fc receptor protein conjugated with Ferritin binds to an exposed Fc region of an antibody to form a cell/Ferritin complex. Magnetic particles are added to the medium and bind to the complex. The magnetic particles when bound to the complex significantly enhance the magnetic field gradient of the complex such that it may be separated magnetically from the medium. Excerpt(s): This invention relates to the separation of biochemical species. For both clinical therapy and biomedical research applications, there is a great need for a rapid and efficient technique for the separation and isolation of specific cell types from a mixture. For example, in the treatment of leukemia, cancerous lymphocytes can be separated from erythrocytes and other cell types in the blood. The healthy blood can then be transfused back into the patient's body. For treatment of childhood bone marrow cancer, diseased cells can be separated in vitro, and the normal cells can be put back into the body, avoiding the laborious (and often futile) process of looking for

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appropriate donors for a transplant. In AIDS patients, helper T cells which harbor the HIV virus within its genome need to be selectively removed, leaving behind B cells, erythrocytes and other healthy cells. The use of magnetic particles for binding and separating target cells is known, see U.S. Pat. No. 4,965,007. In one technique, micron sized latex spheres with magnetic cores are coated with secondary antibodies that are specific to the target cells. The antibody bound target cells then bind to the microspheres and are separated from the mixture by a magnetic field. This method requires two antibodies and relies on three successful bindings--between latex/antibody, antibody/antibody and antibody/ target. For maximum efficiency, the antibodies on the latex should have their Fab regions exposed, a feature that has been particularly difficult to ensure. In addition, a new secondary antibody must be coated on the microspheres each time a new cell is targeted for removal. Furthermore, simultaneous removal of more than a single target from a mixture requires successful coating of multiple secondary antibodies on the microspheres. Web site: http://www.delphion.com/details?pn=US05248589__ •

Serum ferritin as a predictor of the acute respiratory distress syndrome Inventor(s): Repine; John E. (Englewood, CO) Assignee(s): University Technology Corporation (Boulder, CO) Patent Number: 5,679,532 Date filed: December 13, 1995 Abstract: The invention relates to the discovery that serum ferritin concentrations are elevated in patients at risk for the development of Acute Respiratory Distress Syndrome (ARDS) and who subsequently develop ARDS, as compared to at-risk patients who do not subsequently develop ARDS. Thus, the invention includes a method for determining ARDS development potential in an at-risk patient comprising the steps of determining the patient's serum concentration of ferritin and determining ARDS development potential from said serum concentration of ferritin. Excerpt(s): The present invention relates in general to methods and apparatus for performing assays for disease states, and more particularly to methods and apparatus for predicting the likelihood that a patient at risk for the development of acute respiratory distress syndrome will develop acute respiratory distress syndrome. The acute respiratory distress syndrome (ARDS; also known as the adult respiratory distress syndrome) is an inflammatory disorder characterized by the accumulation of neutrophils in the lung and the development of non-cardiogenic pulmonary edema ›Repine, Lancet (1992); 339: 466-469!. ARDS is part of a spectrum of acute lung injury ›Murray et al., Am. Rev. Respir. Dis. (1988); 138: 720-723; Bernard et al., Am. J. Respir. Crit. Care Med. (1994); 149: 818-824!. Once established, ARDS has an approximately 50% mortality, largely because there are still no specific treatments for the syndrome. Patients with major trauma, sepsis or other specific disorders are at risk for ARDS ›Pepe et al., Am. J. Surg. (1982); 144: 124-130; Fowler et al., Ann. Int. Med. (1983); 98: 593-597; Hudson et al., Am. J. Respir. Crit. Care. Med. (1995); 151: 293-301!, but the development of ARDS in any single, at-risk individual remains unpredictable. Web site: http://www.delphion.com/details?pn=US05679532__

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•

Tightly regulated expression system for eucaryotic cells Inventor(s): Thach; Robert E. (St. Louis, MO) Assignee(s): Washington University (St. Louis, MO) Patent Number: 5,342,782 Date filed: February 24, 1992 Abstract: The invention relates to an expression system which permits control of the levels of protein produced, and optionally provides production of the mature form of the protein directly. The expression systems of the invention include the desired gene downstream of a first DNA which comprises the reverse transcript of an inducible translational regulator and a second DNA which is the reverse transcript of an mRNA capable of self-stabilization. This translated sequence is in turn under the control of a transcriptional promoter which may also be inducible. In a preferred embodiment, the inducible translational regulator is the iron responsive element (IRE) region of ferritin mRNA, and the stabilizing element is also a portion of the ferritin sequence. The expression system is useful, especially, for the production of toxic proteins since protein production can be delayed until desired. Excerpt(s): The invention relates to production of recombinant proteins in transformed eucaryotic cells. More specifically, it concerns expression systems for recombinant production which permit regulation of expression so as to obtain this production at times when the cells are able to tolerate enhanced amounts of the recombinant protein. A recognized problem in recombinant protein production is the toxicity of foreign proteins to the recombinant host. Desirably, the protein should be produced in large amounts-as much as about 40% of the total production of protein in the cell. However, foreign proteins are inherently aberrant in the host and therefore are often unhealthy for the cells at high concentration levels, even if they are not toxins in the conventional sense. One approach to mitigating this problem is to delay the production of the desired protein until the cells have achieved a satisfactory level of growth. While the enhanced production at that time may eventually have a morbidity effect on the culture, there are sufficient cells available by the time protein production is induced to supply sufficient yield before morbidity occurs. To effect this delay, conventionally, inducible promoter systems have been employed. In mammalian cells the metallothionein promoter has been most commonly used. "Superinduction" protocols have been devised involving treatment with zinc ion which give a 50-fold induction of the synthesis of human leutropin (Walden, W. E., et al., Gene (1987) 61:317-327) or the encephalomyocarditis (EMC) virus 3B and 3C proteins (Lawson, T. G., et al., J. Virol. (1989) 63:5013-5022). Considerable cell lysis resulted from these enhanced concentrations of protein. As very high levels of protein production were achieved, an increase in overall yield is achievable only by enhancing the effectiveness of induction. This comprises suppressing both transcription and translation of the transcripts so as to minimize cytotoxicity during clonal selection and cell proliferation phases to enhance the probability of isolating cell lines that can be induced to produce large quantities of the desired protein. Web site: http://www.delphion.com/details?pn=US05342782__

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Patent Applications on Ferritin As of December 2000, U.S. patent applications are open to public viewing.9 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 ferritin: •

Ferritin fusion proteins for use in vaccines and other applications Inventor(s): Carter, Daniel C.; (Huntsville, AL), Li, Chester Q.; (Madison, AL) Correspondence: Larson & Taylor, Plc; 1199 North Fairfax Street; Suite 900; Alexandria; VA; 22314; US Patent Application Number: 20040006001 Date filed: May 12, 2003 Abstract: An isolated ferritin fusion protein is provided in which ferritin is fused with a protein or peptide capable of being fused to ferritin without interfering with the polymeric self-assembly of the resulting fusion protein, and the protein may be of the endocapsid form when fused at the C terminus or an exocapsid form when fused at the N terminus. These fusion proteins may self-assemble into a variety of useful higher polymeric forms, e.g., capsid or other polymeric aggregate, and they are advantageous in that they are useful in a variety of applications, including human and veterinary vaccines and therapeutics, blood substitutes, image contrast agents, metal chelating agents, gelling agents, protein purification platforms, and therapeutic receptor-binding proteins. Excerpt(s): The present application claims the benefit of U.S. provisional application 60/379,145, filed May 10, 2002. Ferritin is a highly conserved 24 subunit protein that found in all animals, bacteria, and plants. The major physiological function of ferritin is to control the rate and location of polynuclear Fe(III).sub.2O.sub.3 formation (see, e.g., Theil, E. C. "The ferritin family of iron storage proteins," Adv. Enzymol. Relat. Areas Mol. Biol. 63:421-449 (1990), and Harrison, P. M., Lilley, T. H. "Ferritin in Iron Carriers and Iron Proteins," Loehr T. M., ed. Weinheim: VCH, 1990:353-452; these and all references cited in the present application are incorporated herein by reference). This control is achieved through biomineralization which is performed by transporting hydrated iron ions and protons to and from a mineralized core. Through this mechanism, ferritin accumulates iron at concentrations orders of magnitude greater than the solubility of free iron under physiological conditions. The rate of biomineralization is directly related to the ratio of ferritin H and L subunits (the socalled heavy and light chains) within each capsid and exhibits the general trend of increasing the rate of iron storage with increasing H chain content. These differences in capsid composition are tissue dependent and affect the mechanism of iron oxidation, core formation and iron turnover. For example, ferritin comprised of predominantly L chain is found in the serum, while ferritin from the heart has a high ferritin H content. The ferritin mineralized iron core acts to provide bioavailable iron to a variety of redox enzymes and also serves a detoxification role. Previous work on ferritins, such as disclosed in U.S. Pat. Nos. 5,248,589; 5,358,722; and 5,304,382, all incorporated herein by reference, has focused on the physical aspects of the protein shell and the core such that materials other than ferrihydrate may be located inside the shell. It has also been shown (SP Martsev, AP Vlasov, P Arosio, Protein Engineering vol. 11, 377-381 (1998)) that

9

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

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recombinant human L and H ferritin when explored by differential scanning calorimetry will dissociate into subunit monomers at pH 2.0 to 2.8. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for precisely machining microstructure Inventor(s): Yamashita, Ichiro; (Nara, JP) Correspondence: Harness, Dickey & Pierce, P.L.C.; P.O. Box 828; Bloomfield Hills; MI; 48303; US Patent Application Number: 20020192968 Date filed: June 19, 2002 Abstract: A two-dimensional crystalline film of ferritin 4 holding iron-oxide cores 1 is formed on a silicon substrate 6. The silicon substrate 1 is then etched by using at least the cores 1 as an etching mask. Since the cores 1 have a small diameter of 6 nm, a fine structure can be formed on the substrate, enabling manufacturing of a semiconductor light-emitting element and various semiconductor devices using a quantum effect. Excerpt(s): The present invention relates to a method for precision-processing a fine structure. More particularly, the present invention relates to a method capable of productively forming uniform, ultrafine structures with a size of about several tens of micrometers on the industrial scale. Currently, the electronics industry sees a rapid progress of semiconductor devices. Integration of the elements is improved as the dimensions of the semiconductor devices are reduced. Accordingly, various efforts have been made to fabricate ultrafine devices. Conventionally, fabrication of submicron devices is implemented by downsizing the normal transistors. This downsizing is based on the lithography technology. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Oxidative stress resistance gene Inventor(s): Balazs, Barna; (Budapest, HU), Deak, Maria; (Szeged, HU), Dudits, Denes; (Szeged, HU), Kiraly, Zoltan; (Budapest, HU), Sass, Laszlo; (Szeged, HU), Torok, Karolyne; (Szeged-Tape, HU) Correspondence: Nixon & Vanderhye P.C.; 8th Floor; 1100 N. Glebe RD.; Arlington; VA; 22201; US Patent Application Number: 20010039670 Date filed: April 16, 2001 Abstract: The invention relates to plants, especially transgenic plants, plant parts and plant cells overproducing an iron binding protein (e.g. ferritin) and having an enhanced resistance against a wide range of abiotic and biotic oxidative stress conditions (e.g. against treatment with paraquat or fusaric acid and against viral, bacterial and fungal infections). The invention also comprises nucleic acid sequences encoding an alfalfa ferritin or functional variants thereof and the use of said sequences for rendering plants resistant against oxidative stress conditions.The invention is useful for reducing environmental damages of crops caused by a wide variety of stress conditions.

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Excerpt(s): The present invention relates to plants, especially transgenic plants, plant parts and plant cells overproducing an iron binding protein (e.g. ferritin) and having an enhanced resistance against a wide range of abiotic and biotic oxidative stress conditions (e.g. against treatment with paraquat or fusaric acid and against viral, bacterial and fungal infections). The invention also comprises nucleic acid sequences encoding an alfalfa ferritin or functional variants thereof and the use of said sequences for rendering plants resistant against oxidative stress conditions. The invention is useful for reducing environmental damages of crops caused by a wide variety of stress conditions. With respect to the present specification and claims, we will use the following technical terms in accordance with the given definitions. With regard to the interpretation of the present invention, it shall be understood that the below defined terms are used in accordance with the given definitions even if said definitions might not be in perfect harmony with the usual interpretation of said technical term. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of anti-ferritin monoclonal antibodies in the treatment of some cancers Inventor(s): Kadouche, Jean; (Paris, FR), Levy, Rafael; (Montrouge, FR) Correspondence: Merchant & Gould PC; P.O. Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20020106324 Date filed: September 13, 2001 Abstract: The invention concerns the use, in the preparation of a medicine for treating cancer whereof the cells exhibit overexpression of a product of a gene of the myc-related family, of an anti-ferritin monoclonal antibody or a fragment thereof, said antibody or said fragment identifying an epitope common to acidic and basic human ferritins. Excerpt(s): The present invention relates to the provision of novel means for the diagnosis and therapy of cancers characterized by overexpression of gene products from the myc family. These means essentially include the use of monoclonal antibodies recognising an epitope common to acidic and basic isoferritins. to compare the different characteristics of ferritin extracted from plasma or from different healthy or diseased organs. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with ferritin, 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 “ferritin” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on ferritin.

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You can also use this procedure to view pending patent applications concerning ferritin. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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

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

Comparing serum ferritin values from different population surveys (Vital and health statistics); ISBN: 0840604432; http://www.amazon.com/exec/obidos/ASIN/0840604432/icongroupinterna

•

Transferrin, Ferritin and Iron in the Central and Peripheral Nervous System by J. M. Pasquini; ISBN: 3805575033; http://www.amazon.com/exec/obidos/ASIN/3805575033/icongroupinterna

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

News Services and Press Releases One of the simplest ways of tracking press releases on ferritin is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “ferritin” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to ferritin. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “ferritin” (or synonyms). The following was recently listed in this archive for ferritin: •

Low ferritin level not predictive of renal failure after cardiac surgery Source: Reuters Medical News Date: February 18, 2003

•

Elevated cervical ferritin levels associated with preterm birth Source: Reuters Medical News Date: April 02, 2002

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•

High serum ferritin is linked to increased short-term mortality in dialysis patients Source: Reuters Medical News Date: March 15, 2001

•

Serum ferritin levels not linked to increased CVD mortality in white men Source: Reuters Medical News Date: October 13, 2000

•

Bolus of deferoxamine reduces ferritin levels in patients with iron overload Source: Reuters Medical News Date: May 08, 2000

•

High and low maternal serum ferritin increases risk of fetal growth restriction Source: Reuters Medical News Date: March 23, 2000

•

Serial ferritin measurements predict preterm delivery, low birthweight Source: Reuters Medical News Date: August 06, 1998

•

High Plasma Ferritin Predicts Preterm Delivery And Low Birthweight Source: Reuters Medical News Date: December 09, 1996 The NIH

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

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Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “ferritin” (or synonyms). If you know the name of a company that is relevant to ferritin, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “ferritin” (or synonyms).

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

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APPENDICES

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

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute10: •

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

•

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

•

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

•

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

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

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

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

•

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

10

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

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•

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

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

•

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

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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.nidr.nih.gov/health/

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

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

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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/practitioners/index.cfm

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

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

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

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

•

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

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.11 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:12 •

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

•

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

•

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

•

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

•

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

•

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

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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

•

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

•

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

•

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

11

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). 12 See http://www.nlm.nih.gov/databases/databases.html.

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•

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

•

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

The NLM Gateway13 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.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “ferritin” (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 16210 92 19 34 78 16433

HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 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.17 Simply search by “ferritin” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

13

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

14

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). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17

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

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

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Coffee Break: Tutorials for Biologists18 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.19 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.20 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

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

18 Adapted 19

from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 20 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 B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on ferritin can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to ferritin. 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 ferritin. 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 “ferritin”:

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Anemia http://www.nlm.nih.gov/medlineplus/anemia.html Hemochromatosis http://www.nlm.nih.gov/medlineplus/hemochromatosis.html Laboratory Tests http://www.nlm.nih.gov/medlineplus/laboratorytests.html Liver Diseases http://www.nlm.nih.gov/medlineplus/liverdiseases.html Preventing Disease and Staying Healthy http://www.nlm.nih.gov/medlineplus/preventingdiseaseandstayinghealthy.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. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on ferritin. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •

Liver Function Tests Source: Cedar Grove, NJ: American Liver Foundation. 2 p. Contact: Available from American Liver Foundation. 1425 Pompton Avenue, Cedar Grove, NJ 07009. (800) 223-0179 or (201) 256-2550. Summary: A brief report describes liver function tests used to guide physicians in the diagnosis and management of liver diseases. Included are tests for alanine and aspartate aminotransferases, alkaline phosphatase, bilirubin, albumin, prothrombin time, serum iron and ferritin, ceruloplasmin, alpha-1-antitrypsin, and immunologic test.

•

Guide to Diagnosis: Hemochromatosis Iron Overload Source: Greenville, SC: Iron Disorders Institute. 1999. [2 p.]. Contact: Available from Iron Disorders Institute. P.O. Box 2031, Greenville, SC 29602. (888) 565-IRON. Website: www.irondisorders.org. PRICE: Single copy free. Summary: Hemochromatosis (HHC) is a genetic metabolic disorder in which an individual absorbs and retains too much iron. Increased iron absorption in the gastrointestinal tract may cause lifelong excessive iron absorption and accumulation, and serious health effects, including arthritis, cirrhosis, diabetes, impotence, heart failure, and death can result. This brochure offers readers a guide to the diagnosis of

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HHC. Topics include symptoms, risk factors, candidacy for liver biopsy, tests for body iron status overload, DNA tests, indications for genetic testing, and the importance of working closely with one's physician. Chronic fatigue is generally the first and most common symptom associated with iron overload. Liver biopsy may be recommended if the patient's liver enzymes are elevated and ferritin is about 1,000 ng per milliliter. Liver biopsy is the only way to determine the extent of cirrhosis or fibrosis and formerly was the standard for diagnosing hemochromatosis. Trial phlebotomy (blood removal) is also a way to diagnose HHC. A patient who can tolerate several phlebotomies without developing anemia can be diagnosed with HHC. Genetic typing tests for HHC are available as well. Children do not need to be genetically tested. Once it is determined that parents are carriers or homozygous, offspring should be screened routinely using transferrin saturation percentage and ferritin test levels. The brochure notes that most patients with HHC can be diagnosed and treated by a family practice physician; however, specialists may also be necessary to treat chronic disease that may have developed as a result of iron overload. The brochure concludes with a brief description of the Iron Disorders Institute (IDI), founded to limit pain, suffering, and unnecessary death from common and often misdiagnosed disorders of iron, such as anemia of chronic disease, porphyria cutanea tarda, iron loading anemia, iron deficiency anemia, African siderosis, and HHC. •

Hemochromatosis: Not So Rare Source: Cedar Grove, NJ: American Liver Foundation, Inc. 199x. 2 p. Contact: Available from American Liver Foundation. 1425 Pompton Avenue, Cedar Grove, NJ 07009. (800) 223-0179 or (201) 256-2550. PRICE: $0.50 each; $6 for 25 copies; $12 for 50 copies (as of 1995); discounts available for larger quantities. Summary: Hemochromatosis is a hereditary disease which causes the body to absorb and store too much iron. The wide range of symptoms, varying from person to person, makes diagnosis difficult. Blood tests for serum iron and total iron binding capacity are good screening devices. A follow-up test is the serum ferritin level. If these tests are consistently high, a liver biopsy should be done. Hemochromatosis is treated by removing one to two pints of blood each week until iron stores go down to a normal level. Therapy should then be continued every two to four months for life. Those who are treated early can look forward to a completely normal, active life. When the illness has advanced to the stage of cirrhosis, the situation is more serious. A person with blood relatives with hemochromatosis should be tested with the various blood tests even if there are no symptoms.

•

Role of Iron in Viral Hepatitis Source: idInsight. 2(2): 4. 1999. Contact: Available from Iron Disorders Institute. P.O. Box 2031, Greenville, SC 29602. (864) 241-0111. Fax (864) 244-2104. Website: www.irondisorders.org. Summary: More than 15 years ago, scientists began to notice elevated iron levels in those with chronic viral hepatitis. Some speculate that iron is released from liver cells injured by the presence of hepatitis virus. This brief newsletter article familiarizes patients and physicians with the role of iron in viral hepatitis. One of the researchers noted that patients on dialysis (whose serum ferritin, blood iron levels, were lower) cleared of infection sooner than those with elevated levels of ferritin. The levels of iron may also be correlated to which patients with hepatitis will respond to alpha interferon therapy; in one study, liver iron content in the 50 percent of patients who did not respond to

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treatment were twice as high as levels of iron in responders to interferon. In another study, it was noted that liver enzymes ALT were significantly reduced in response to interferon treatment when administered following a series of phlebotomies (removal of blood) to reduce ferritin. Patients with viral hepatitis are counseled to ask their attending physician to determine body iron status by measuring ferritine and transferrin iron saturation percentage. If elevated, reduction of ferritin levels may be considered for improved response to ongoing treatment. One chart summarizes the most common types of hepatitis, their transmission, risk factors, diagnostic tests, treatment, symptoms, anticipated recovery, and vaccination use. The article concludes with website addresses for readers wishing additional information; a suggested reading list for physicians is also provided. 1 table. 3 references. •

Getting the Most from Your Treatment: What You Need to Know about Hemodialysis Source: New York, NY: National Kidney Foundation. 1998. 31 p. Contact: Available from National Kidney Foundation. 30 East 33rd Street, New York, NY 10016. (800) 622-9010. Website: www.kidney.org. PRICE: Single copy free. Summary: This booklet summarizes the use of hemodialysis to treat kidney diseases. The booklet tells readers why it is important to get the right amount of hemodialysis, how to care for the hemodialysis access, the complication of anemia and how it is treated, why diet restrictions must be followed carefully, how to help prevent bone disease and heart problems, how to cope with kidney disease and its treatment, how to get involved in one's own treatment plan and additional resources that are available. The brochure outlines the roles of each of the various health care team members who may be involved in the care of a person on hemodialysis. One section encourages readers to educate themselves about their disease and its treatment and to be very involved in their own health care. The brochure concludes with a section that summarizes the 13 laboratory tests commonly used to monitor patients with kidney disease: Kt per V and URR, nPNA, albumin (BCG test), hematocrit, hemoglobin, TSAT and serum ferritin, parathyroid hormone (PTH), calcium, phosphorus, potassium, target weight, average daily weight gain, and blood pressure. The brochure is written in nontechnical language and illustrated with simple line drawings. The brochure is one in a series of materials from an educational program of the National Kidney Foundation Dialysis Outcomes Quality Initiative.

•

Dialysis Report Card: Understanding Your Lab Values Source: New York, NY: National Kidney Foundation. 1998. (chart). Contact: Available from National Kidney Foundation. 30 East 33rd Street, New York, NY 10016. (800) 622-9010. Website: www.kidney.org. PRICE: Single copy free. Summary: This chart helps patients on dialysis track important laboratory data and visualize where they stand in relation to established goals. The report card format offers room to record lab values for a 1-year period and is intended to help discussion among patients and the renal health care team about adequacy of treatment. The report card offers space to record 16 values: Kt per V, URR, nPNA, albumin (BCG test), hematocrit, hemoglobin, TSAT, serum ferritin, parathyroid hormone, calcium, phosphorus, potassium, target weight, average daily weight gain, predialysis blood pressure, and postdialysis blood pressure. The card also includes a space for the patient's individual goal numbers in each of these tests. The reverse side of the chart offers a few sentences of explanation for each of the 16 tests. These explanations focus primarily on the daily steps that patients can take to help their own health care be more successful. This report

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card is one of a series of materials from an educational program of the National Kidney Foundation Dialysis Outcomes Quality Initiative. •

American Hemochromatosis Society (AHS): Prevention Through Genetic Testing Source: Delray Beach, FL: American Hemochromatosis Society. 200x. [2 p]. Contact: Available from American Hemochromatosis Society. 777 East Atlantic Avenue, PMB Z-363, Delray Beach, FL 33483-5352. (888) 655-IRON or (561) 266-9037. Fax (561) 266-9038. E-mail: [email protected]. Website: www.americanhs.org. PRICE: Single copy free. Summary: This fact sheet describes the work and activities of the American Hemochromatosis Society (AHS) and the indications for testing for hereditary hemochromatosis (HH), also known as iron overload or iron storage disease. Readers are advised to ask their physician for specific diagnostic tests to be performed, including serum iron, TIBC (total iron binding capacity), and serum ferritin. All family members should be tested to confirm HH in the presence of elevated iron studies or to predict genetic risk of developing HH in the future. The fact sheet provides information for readers who wish to order blood tests or DNA genetic testing directly from a lab without a doctor's order. Treatments should average once or twice weekly bloodlettings, identical to blood donation (therapeutic phlebotomies), as long as the hematocrit is 35 percent or greater immediately prior to each treatment. Treatment frequency can vary in some cases and each case should be handled individually. The fact sheet recommends that patients who have tested positive for the HH gene mutations but who have nonelevated or only slightly elevated iron tests donate blood preventively. The fact sheet outlines the circumstances in which liver biopsy may be appropriate, noting that HH diagnosis is generally accomplished with blood tests and DNA testing. Patients are advised to eat a nutritious natural diet void of processed foods with high iron, to reduce red meat intake, to abstain from alcohol, to avoid all vitamin supplements, to avoid raw seafood, and to not cook in cast iron cookware. Readers are encouraged to become members of the AHS (www.americanhs.org).

•

Nutrition for Children With Chronic Kidney Disease: A Guide for Parents Source: New York, NY: National Kidney Foundation, Inc. 2002. 6 p. Contact: Available from National Kidney Foundation, Inc. Medical Department, 30 East 33rd Street, New York, NY 10016. (800) 622-9010. Fax: (212) 689-9261. E-mail: [email protected]. Website: www.kidney.org. PRICE: Single copy free; Full-text available online at no charge. Summary: This fact sheet helps parents of children with chronic kidney disease understand the role of appropriate diet in helping to keep their children healthy. The guidelines are intended for children who have reduced kidney function caused by chronic kidney disease, have kidney failure and are receiving hemodialysis or peritoneal dialysis, or have received a kidney transplant. Topics include a rationale for good nutrition in children with kidney disease; general guidelines regarding caloric intake, protein, phosphorus, potassium, sodium, fluids, and vitamins and minerals; how to monitor a child's nutrition; how to encourage a child to eat healthy foods; growth and development; the use of supplements; and understanding the child's lab values (diagnostic and monitoring tests), including serum albumin, serum bicarbonate, blood pressure, blood urea nitrogen (BUN), body weight, fluid weight gain, calcium, serum creatinine, glomerular filtration rate (GFR), hemoglobin and hematocrit, phosphorus, potassium, urine protein, and TSAT and serum ferritin. The fact sheet offers a blank form for tracking the child's lab values. 1 table.

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Investigations for IBD Source: St. Albans, England: National Association for Colitis and Crohn's Disease (NACC). 2000. 9 p. Contact: Available from National Association for Colitis and Crohn's Disease (NACC). 4 Beaumont House, Sutton Road, St. Albans, Hertfordshire, AL1 5HH. 01727 844296. Email: [email protected]. Website: www.nacc.org.uk. PRICE: Single copy free to members. Summary: This reference booklet helps people with inflammatory bowel disease (IBD) understand the diagnostic tests that they may need to undergo to confirm diagnosis and monitor progress of their disease and treatment. The booklet has four sections: blood tests, endoscopy, radiography (x rays), and scans. Specific tests discussed include full blood count (FBC), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), ferritin (iron), vitamin B12 and folic acid, liver function tests (LFTs), International normalized ratio (INR), urea and electrolytes (U and E), bone chemistry, magnesium, trace elements, proctoscopy, sigmoidoscopy, flexible sigmoidoscopy, colonoscopy, gastroscopy, abdominal radiography, chest radiography, joint radiography, bone densitometry (DEXA scanning), barium meal, barium follow through, small bowel enema, barium enema, ultrasound, CT (computed tomography) scanning, MRI (magnetic resonance imaging), and nuclear medicine scans. The booklet describes the results that each test can provide and, in the case of endoscopy tests, what the patient can expect during the procedure. The booklet concludes with a list of resource organizations, all based in Britain. 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 ferritin. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

•

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

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

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Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

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

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

•

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

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Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to ferritin. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with ferritin. 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 ferritin. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “ferritin” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “ferritin”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “ferritin” (or synonyms) into the “For these words:”

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box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “ferritin” (or a synonym) into the search box, and click “Submit Query.”

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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.21

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

21

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)22: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

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Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

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California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

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California: Gateway Health Library (Sutter Gould Medical Foundation)

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California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

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Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

22

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

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•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

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Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

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Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

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Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

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Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

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Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

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National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

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National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

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National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

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MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

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Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

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On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

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Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

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Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on ferritin: •

Basic Guidelines for Ferritin Ferritin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003490.htm

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Signs & Symptoms for Ferritin Fainting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003092.htm Heavy menstrual bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003263.htm

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Diagnostics and Tests for Ferritin Blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003398.htm Venipuncture Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003423.htm

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Nutrition for Ferritin Protein Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002467.htm

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Background Topics for Ferritin Adolescent test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002054.htm Bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000045.htm Chronic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002312.htm Infant test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002055.htm Preschooler test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002057.htm Schoolage test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002058.htm Toddler test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002056.htm

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

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MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

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Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

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Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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FERRITIN DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 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] Abortion: 1. The premature expulsion from the uterus of the products of conception - of the embryo, or of a nonviable fetus. The four classic symptoms, usually present in each type of abortion, are uterine contractions, uterine haemorrhage, softening and dilatation of the cervix, and presentation or expulsion of all or part of the products of conception. 2. Premature stoppage of a natural or a pathological process. [EU] 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] Acetaminophen: Analgesic antipyretic derivative of acetanilide. It has weak antiinflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acid Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.2. [NIH] Acidity: The quality of being acid or sour; containing acid (hydrogen ions). [EU] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [NIH]

Acyl: Chemical signal used by bacteria to communicate. [NIH] Acyl Carrier Protein: Consists of a polypeptide chain and 4'-phosphopantetheine linked to a serine residue by a phosphodiester bond. Acyl groups are bound as thiol esters to the pantothenyl group. Acyl carrier protein is involved in every step of fatty acid synthesis by the cytoplasmic system. [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] Adenovirus: A group of viruses that cause respiratory tract and eye infections.

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Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adjuvant Therapy: Treatment given after the primary treatment to increase the chances of a cure. Adjuvant therapy may include chemotherapy, radiation therapy, or hormone therapy. [NIH]

Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Age 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] Ageing: A physiological or morphological change in the life of an organism or its parts, generally irreversible and typically associated with a decline in growth and reproductive vigor. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] 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] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low

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serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [NIH] Alfalfa: A deep-rooted European leguminous plant (Medicago sativa) widely grown for hay and forage. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaline Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.1. [NIH] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]

Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alpha-fetoprotein: AFP. A protein normally produced by a developing fetus. AFP levels are usually undetectable in the blood of healthy nonpregnant adults. An elevated level of AFP suggests the presence of either a primary liver cancer or germ cell tumor. [NIH] Alpha-Thalassemia: A disorder characterized by reduced synthesis of the alpha chains of hemoglobin. The severity of this condition can vary from mild anemia to death, depending on the number of genes deleted. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Aluminum: A metallic element that has the atomic number 13, atomic symbol Al, and atomic weight 26.98. [NIH] Aluminum Hydroxide: Hydrated aluminum. A compound with many biomedical applications: as a gastric antacid, an antiperspirant, in dentifrices, as an emulsifier, as an adjuvant in bacterins and vaccines, in water purification, etc. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH)

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group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Aminolevulinic Acid: A compound produced from succinyl-CoA and glycine as an intermediate in heme synthesis. [NIH] Amino-terminal: The end of a protein or polypeptide chain that contains a free amino group (-NH2). [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amniocentesis: Percutaneous transabdominal puncture of the uterus during pregnancy to obtain amniotic fluid. It is commonly used for fetal karyotype determination in order to diagnose abnormal fetal conditions. [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] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Anaemia: A reduction below normal in the number of erythrocytes per cu. mm., in the quantity of haemoglobin, or in the volume of packed red cells per 100 ml. of blood which occurs when the equilibrium between blood loss (through bleeding or destruction) and blood production is disturbed. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]

Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but

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shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgen-Binding Protein: Carrier proteins produced in the Sertoli cells of the testis, secreted into the seminiferous tubules, and transported via the efferent ducts to the epididymis. They participate in the transport of androgens. Androgen-binding protein has the same amino acid sequence as sex hormone binding-globulin. They differ by their sites of synthesis and post-translational oligosacaccharide modifications. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anemic: Hypoxia due to reduction of the oxygen-carrying capacity of the blood as a result of a decrease in the total hemoglobin or an alteration of the hemoglobin constituents. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Angiopathy: Disease of the blood vessels (arteries, veins, and capillaries) that occurs when someone has diabetes for a long time. There are two types of angiopathy: macroangiopathy and microangiopathy. In macroangiopathy, fat and blood clots build up in the large blood vessels, stick to the vessel walls, and block the flow of blood. In microangiopathy, the walls of the smaller blood vessels become so thick and weak that they bleed, leak protein, and slow the flow of blood through the body. Then the cells, for example, the ones in the center of the eye, do not get enough blood and may be damaged. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anionic: Pertaining to or containing an anion. [EU] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Anomalies: Birth defects; abnormalities. [NIH] Anoxia: Clinical manifestation of respiratory distress consisting of a relatively complete absence of oxygen. [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]

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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-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] 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] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Aponeurosis: Tendinous expansion consisting of a fibrous or membranous sheath which serves as a fascia to enclose or bind a group of muscles. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] Aqueous humor: Clear, watery fluid that flows between and nourishes the lens and the cornea; secreted by the ciliary processes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arsenicals: Inorganic or organic compounds that contain arsenic. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU]

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Arteries: The vessels carrying blood away from the heart. [NIH] Arteriography: A procedure to x-ray arteries. The arteries can be seen because of an injection of a dye that outlines the vessels on an x-ray. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Arthralgia: Pain in the joint. [NIH] Articular: Of or pertaining to a joint. [EU] Ascites: Accumulation or retention of free fluid within the peritoneal cavity. [NIH] Ascitic Fluid: The serous fluid which accumulates in the peritoneal cavity in ascites. [NIH] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aspartate: A synthetic amino acid. [NIH] Aspartate Transaminase: An enzyme of the transferase class that catalyzes the conversion of L-aspartate and 2-ketoglutarate to oxaloacetate and L-glutamate. EC 2.6.1.1. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astringents: Agents, usually topical, that cause the contraction of tissues for the control of bleeding or secretions. [NIH] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Astrocytoma: A tumor that begins in the brain or spinal cord in small, star-shaped cells called astrocytes. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to

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strains of unusual type. [EU] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autologous bone marrow transplantation: A procedure in which bone marrow is removed from a person, stored, and then given back to the person after intensive treatment. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Autophagocytosis: The segregation and degradation of damaged or unwanted cytoplasmic constituents by autophagic vacuoles (cytolysosomes) composed of lysosomes containing cellular components in the process of digestion; it plays an important role in metamorphosis of amphibians, in the removal of bone by osteoclasts, and in the degradation of normal cell components in nutritional deficiency states. [NIH] Axonal: Condition associated with metabolic derangement of the entire neuron and is manifest by degeneration of the distal portion of the nerve fiber. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [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] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Barium: An element of the alkaline earth group of metals. It has an atomic symbol Ba, atomic number 56, and atomic weight 138. All of its acid-soluble salts are poisonous. [NIH] Barium enema: A procedure in which a liquid with barium in it is put into the rectum and colon by way of the anus. Barium is a silver-white metallic compound that helps to show the image of the lower gastrointestinal tract on an x-ray. [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] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus

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and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Beta carotene: A vitamin A precursor. Beta carotene belongs to the family of fat-soluble vitamins called carotenoids. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Beta-Thalassemia: A disorder characterized by reduced synthesis of the beta chains of hemoglobin. There is retardation of hemoglobin A synthesis in the heterozygous form (thalassemia minor), which is asymptomatic, while in the homozygous form (thalassemia major, Cooley's anemia, Mediterranean anemia, erythroblastic anemia), which can result in severe complications and even death, hemoglobin A synthesis is absent. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile 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 Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Biliverdine: 1,3,6,7-Tetramethyl-4,5-dicarboxyethyl-2,8-divinylbilenone. Biosynthesized from hemoglobin as a precursor of bilirubin. Occurs in the bile of amphibia and of birds, but not in normal human bile or serum. [NIH] Binding agent: A substance that makes a loose mixture stick together. For example, binding agents can be used to make solid pills from loose powders. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological 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] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH]

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Bioluminescence: The emission of light by living organisms such as the firefly, certain mollusks, beetles, fish, bacteria, fungi and protozoa. [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] Biomedical Engineering: Application of principles and practices of engineering science to biomedical research and health care. [NIH] Biomolecular: A scientific field at the interface between advanced computing and biotechnology. [NIH] Biophysics: The science of physical phenomena and processes in living organisms. [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] Biotic: Pertaining to living organisms in their ecological rather than their physiological relations. [NIH] Bivalent: Pertaining to a group of 2 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [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 Banks: Centers for collecting, characterizing, and storing human blood. [NIH] Blood Cell Count: A count of the number of leukocytes and erythrocytes per unit volume in a sample of venous blood. A complete blood count (CBC) also includes measurement of the hemoglobin, hematocrit, and erythrocyte indices. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood Substitutes: Substances that can carry oxygen to and carbon dioxide away from the tissues when introduced into the blood stream. They are used to replace hemoglobin in severe hemorrhage and also to perfuse isolated organs. The best known are perfluorocarbon emulsions and various hemoglobin solutions. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [NIH] Blood urea: A waste product in the blood that comes from the breakdown of food protein.

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The kidneys filter blood to remove urea. As kidney function decreases, the BUN level increases. [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-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] 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] Boron: A trace element with the atomic symbol B, atomic number 5, and atomic weight 10.81. Boron-10, an isotope of boron, is used as a neutron absorber in boron neutron capture therapy. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchoalveolar Lavage: Washing out of the lungs with saline or mucolytic agents for diagnostic or therapeutic purposes. It is very useful in the diagnosis of diffuse pulmonary infiltrates in immunosuppressed patients. [NIH] Bronchoalveolar Lavage Fluid: Fluid obtained by washout of the alveolar compartment of the lung. It is used to assess biochemical and inflammatory changes in and effects of therapy on the interstitial lung tissue. [NIH] Buffers: A chemical system that functions to control the levels of specific ions in solution. When the level of hydrogen ion in solution is controlled the system is called a pH buffer.

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[NIH]

Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Caloric intake: Refers to the number of calories (energy content) consumed. [NIH] Cannula: A tube for insertion into a duct or cavity; during insertion its lumen is usually occupied by a trocar. [EU] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capillary Permeability: Property of blood capillary walls that allows for the selective exchange of substances. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas (tight junctions) which may limit large molecule movement. [NIH] Capsid: The outer protein protective shell of a virus, which protects the viral nucleic acid. [NIH]

Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Carcinoid: A type of tumor usually found in the gastrointestinal system (most often in the appendix), and sometimes in the lungs or other sites. Carcinoid tumors are usually benign. [NIH]

Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

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Cardiac: Having to do with the heart. [NIH] Cardiogenic: Originating in the heart; caused by abnormal function of the heart. [EU] Cardiology: The study of the heart, its physiology, and its functions. [NIH] 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] Cardiovirus: A genus of the family Picornaviridae causing encephalitis and myocarditis in rodents. Encephalomyocarditis virus is the type species. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carotenoids: Substance found in yellow and orange fruits and vegetables and in dark green, leafy vegetables. May reduce the risk of developing cancer. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [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] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Causality: The relating of causes to the effects they produce. Causes are termed necessary when they must always precede an effect and sufficient when they initiate or produce an effect. Any of several factors may be associated with the potential disease causation or outcome, including predisposing factors, enabling factors, precipitating factors, reinforcing factors, and risk factors. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Count: A count of the number of cells of a specific kind, usually measured per unit volume of sample. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell

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division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] 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] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Arteries: The arteries supplying the cerebral cortex. [NIH] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [NIH] Cerebral Hemorrhage: Bleeding into a cerebral hemisphere of the brain, including lobar, subcortical white matter, and basal ganglia hemorrhages. Commonly associated conditions include hypertension; intracranial arteriosclerosis; intracranial aneurysm; craniocerebral trauma; intracranial arteriovenous malformations; cerebral amyloid angiopathy; and cerebral infarction. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH]

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Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] 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] Chelation Therapy: Therapy of heavy metal poisoning using agents which sequester the metal from organs or tissues and bind it firmly within the ring structure of a new compound which can be eliminated from the body. [NIH] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemoprevention: The use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the development or recurrence of, cancer. [NIH] Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [NIH] Chemoprotective: A quality of some drugs used in cancer treatment. Chemoprotective agents protect healthy tissue from the toxic effects of anticancer drugs. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] 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] Chloride Channels: Cell membrane glycoproteins selective for chloride ions. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Chloroquine: The prototypical antimalarial agent with a mechanism that is not well

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understood. It has also been used to treat rheumatoid arthritis, systemic lupus erythematosus, and in the systemic therapy of amebic liver abscesses. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Choroid Plexus: A villous structure of tangled masses of blood vessels contained within the third, lateral, and fourth ventricles of the brain. It regulates part of the production and composition of cerebrospinal fluid. [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 granulocytic leukemia: A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myelogenous leukemia or chronic myeloid leukemia. [NIH] Chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Ciliary processes: The extensions or projections of the ciliary body that secrete aqueous humor. [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] 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,

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prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] 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] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colloidal: Of the nature of a colloid. [EU] 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] 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

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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] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU]

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Cone: One of the special retinal receptor elements which are presumed to be primarily concerned with perception of light and color stimuli when the eye is adapted to light. [NIH] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Conjunctivitis: Inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Consensus Sequence: A theoretical representative nucleotide or amino acid sequence in which each nucleotide or amino acid is the one which occurs most frequently at that site in the different sequences which occur in nature. The phrase also refers to an actual sequence which approximates the theoretical consensus. A known conserved sequence set is represented by a consensus sequence. Commonly observed supersecondary protein structures (amino acid motifs) are often formed by conserved sequences. [NIH] Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a consensus sequence. Amino acid motifs are often composed of conserved sequences. [NIH] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Continuum: An area over which the vegetation or animal population is of constantly changing composition so that homogeneous, separate communities cannot be distinguished. [NIH]

Contraception: Use of agents, devices, methods, or procedures which diminish the

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likelihood of or prevent conception. [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] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cotinine: 1-Methyl-5-(3-pyridyl)-2-pyrrolidinone antidepressant. Synonym: Scotine. [NIH]

fumarate.

Stimulant

proposed

as

Coumarins: Synthetic or naturally occurring substances related to coumarin, the deltalactone of coumarinic acid. Coumarin itself occurs in the tonka bean. The various coumarins have a wide range of proposed actions and uses including as anticoagulants, pharmaceutical aids, indicators and reagents, photoreactive substances, and antineoplastic agents. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH]

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Curative: Tending to overcome disease and promote recovery. [EU] Curcumin: A dye obtained from tumeric, the powdered root of Curcuma longa Linn. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes. [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] Cysteinyl: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [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] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoprotection: The process by which chemical compounds provide protection to cells against harmful agents. [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]

Cytostatic: An agent that suppresses cell growth and multiplication. [EU] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Dairy Products: Raw and processed or manufactured milk and milk-derived products. These are usually from cows (bovine) but are also from goats, sheep, reindeer, and water buffalo. [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] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH]

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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] Dehydroepiandrosterone: DHEA. A substance that is being studied as a cancer prevention drug. It belongs to the family of drugs called steroids. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Dentifrices: Any preparations used for cleansing teeth; they usually contain an abrasive, detergent, binder and flavoring agent and may exist in the form of liquid, paste or powder; may also contain medicaments and caries preventives. [NIH] Deoxyribonucleotides: A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. [NIH] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermatosis: Any skin disease, especially one not characterized by inflammation. [EU] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which results in a change in the social, political, and economic structures. [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] Dialysate: A cleansing liquid used in the two major forms of dialysis--hemodialysis and peritoneal dialysis. [NIH] Dialysis Solutions: Solutions prepared for exchange across a semipermeable membrane of solutes below a molecular size determined by the cutoff threshold of the membrane material. [NIH]

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Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [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] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [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] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is

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receiving. [EU] Double-blinded: A clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. [NIH] 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] 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 Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eclampsia: Onset of convulsions or coma in a previously diagnosed pre-eclamptic patient. [NIH]

Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrolysis: Destruction by passage of a galvanic electric current, as in disintegration of a chemical compound in solution. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU]

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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]

Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryo Transfer: Removal of a mammalian embryo from one environment and replacement in the same or a new environment. The embryo is usually in the pre-nidation phase, i.e., a blastocyst. The process includes embryo or blastocyst transplantation or transfer after in vitro fertilization and transfer of the inner cell mass of the blastocyst. It is not used for transfer of differentiated embryonic tissue, e.g., germ layer cells. [NIH] Emulsions: Colloids of two immiscible liquids where either phase may be either fatty or aqueous; lipid-in-water emulsions are usually liquid, like milk or lotion and water-in-lipid emulsions tend to be creams. [NIH] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]

Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of this condition. [NIH] Encephalitis, Viral: Inflammation of brain parenchymal tissue as a result of viral infection. Encephalitis may occur as primary or secondary manifestation of Togaviridae infections; Herpesviridae infections; Adenoviridae infections; Flaviviridae infections; Bunyaviridae infections; Picornaviridae infections; Paramyxoviridae infections; Orthomyxoviridae infections; Retroviridae infections; and Arenaviridae infections. [NIH] Encephalomyocarditis Virus: The type species of cardiovirus causing encephalomyelitis and myocarditis in rodents, pigs, and monkeys. Infection in man has been reported with CNS involvement but without myocarditis. [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] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH]

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Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endoscopy: Endoscopic examination, therapy or surgery performed on interior parts of the body. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enema: The injection of a liquid through the anus into the large bowel. [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] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [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] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU]

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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] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]

Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythroleukemia: Cancer of the blood-forming tissues in which large numbers of immature, abnormal red blood cells are found in the blood and bone marrow. [NIH] Erythropoiesis: The production of erythrocytes. [EU] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estrogen: One of the two female sex hormones. [NIH] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [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] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and

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in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extrapyramidal: Outside of the pyramidal tracts. [EU] Extravascular: Situated or occurring outside a vessel or the vessels. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Family Practice: A medical specialty concerned with the provision of continuing, comprehensive primary health care for the entire family. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty Acid Desaturases: Enzymes that catalyze the conversion of saturated fatty acid CoA complexes to unsaturated fatty acid CoA complexes in the presence of any acceptor. They include EC 1.3.1.8, EC 1.3.99.3 and EC 1.14.99.5. [NIH] Fatty Liver: The buildup of fat in liver cells. The most common cause is alcoholism. Other causes include obesity, diabetes, and pregnancy. Also called steatosis. [NIH] Febrile: Pertaining to or characterized by fever. [EU] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Fertilization in Vitro: Fertilization of an egg outside the body when the egg is normally fertilized in the body. [NIH] Fetoprotein: Transabdominal aspiration of fluid from the amniotic sac with a view to detecting increases of alpha-fetoprotein in maternal blood during pregnancy, as this is an important indicator of open neural tube defects in the fetus. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filariasis: Infections with nematodes of the superfamily Filarioidea. The presence of living worms in the body is mainly asymptomatic but the death of adult worms leads to granulomatous inflammation and permanent fibrosis. Organisms of the genus Elaeophora infect wild elk and domestic sheep causing ischaemic necrosis of the brain, blindness, and dermatosis of the face. [NIH]

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Fish Products: Food products manufactured from fish (e.g., fish flour, fish meal). [NIH] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flatus: Gas passed through the rectum. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Antibody Technique: Test for tissue antigen using either a direct method by conjugation of antibody with fluorescent dye or an indirect method by formation of antigenantibody complex which is then labeled with fluorescein-conjugated anti-immunoglobulin antibody. The tissue is then examined by fluorescence microscopy. [NIH] Fluoroimmunoassay: The use of fluorescence spectrometry to obtain quantitative results for the fluorescent antibody technique. One advantage over the other methods (e.g., radioimmunoassay) is its extreme sensitivity, with a detection limit on the order of tenths of microgram/liter. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fourth Ventricle: An irregularly shaped cavity in the rhombencephalon, between the medulla oblongata, the pons, and the isthmus in front, and the cerebellum behind. It is continuous with the central canal of the cord below and with the cerebral aqueduct above, and through its lateral and median apertures it communicates with the subarachnoid space. [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]

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Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fusaric Acid: A picolinic acid derivative isolated from various Fusarium species. It has been proposed for a variety of therapeutic applications but is primarily used as a research tool. Its mechanisms of action are poorly understood. It probably inhibits dopamine betahydroxylase, the enzyme that converts dopamine to norepinephrine. It may also have other actions, including the inhibition of cell proliferation and DNA synthesis. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [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] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gasoline: Volative flammable fuel (liquid hydrocarbons) derived from crude petroleum by processes such as distillation reforming, polymerization, etc. [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Juices: Liquids produced in the stomach to help break down food and kill bacteria. [NIH]

Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastroscopy: Endoscopic examination, therapy, or surgery of the interior of the stomach. [NIH]

Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Frequency: The proportion of one particular allele in the total of all alleles for one genetic locus in a breeding population. [NIH]

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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] 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 Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [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] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glioblastoma: A malignant form of astrocytoma histologically characterized by pleomorphism of cells, nuclear atypia, microhemorrhage, and necrosis. They may arise in any region of the central nervous system, with a predilection for the cerebral hemispheres, basal ganglia, and commissural pathways. Clinical presentation most frequently occurs in the fifth or sixth decade of life with focal neurologic signs or seizures. [NIH] Glioblastoma multiforme: A type of brain tumor that forms from glial (supportive) tissue of the brain. It grows very quickly and has cells that look very different from normal cells. Also called grade IV astrocytoma. [NIH] Globus Pallidus: The representation of the phylogenetically oldest part of the corpus striatum called the paleostriatum. It forms the smaller, more medial part of the lentiform nucleus. [NIH]

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Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] 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] Glucose-6-Phosphatase: An enzyme that catalyzes the conversion of D-glucose 6-phosphate and water to D-glucose and orthophosphate. EC 3.1.3.9. [NIH] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glucuronides: Glycosides of glucuronic acid formed by the reaction of uridine diphosphate glucuronic acid with certain endogenous and exogenous substances. Their formation is important for the detoxification of drugs, steroid excretion and bilirubin metabolism to a more water-soluble compound that can be eliminated in the urine and bile. [NIH] Glucuronosyltransferase: A family of enzymes accepting a wide range of substrates, including phenols, alcohols, amines, and fatty acids. They function as drug-metabolizing enzymes that catalyze the conjugation of UDPglucuronic acid to a variety of endogenous and exogenous compounds. EC 2.4.1.17. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycols: A generic grouping for dihydric alcohols with the hydroxy groups (-OH) located

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on different carbon atoms. They are viscous liquids with high boiling points for their molecular weights. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Goblet Cells: Cells of the epithelial lining that produce and secrete mucins. [NIH] Goiter: Enlargement of the thyroid gland. [NIH] Gonads: The gamete-producing glands, ovary or testis. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [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] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] 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] Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Gravidity: Pregnancy; the condition of being pregnant, without regard to the outcome. [EU] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Haematological: Relating to haematology, that is that branch of medical science which treats of the morphology of the blood and blood-forming tissues. [EU] Haematology: The science of the blood, its nature, functions, and diseases. [NIH] Haematoma: A localized collection of blood, usually clotted, in an organ, space, or tissue, due to a break in the wall of a blood vessel. [EU] Haemodialysis: The removal of certain elements from the blood by virtue of the difference in the rates of their diffusion through a semipermeable membrane, e.g., by means of a haemodialyzer. [EU] Haemorrhage: The escape of blood from the vessels; bleeding. Small haemorrhages are classified according to size as petechiae (very small), purpura (up to 1 cm), and ecchymoses (larger). The massive accumulation of blood within a tissue is called a haematoma. [EU] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH]

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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] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heart Transplantation: The transference of a heart from one human or animal to another. [NIH]

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] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemerythrin: A non-heme iron protein consisting of eight apparently identical subunits each containing 2 iron atoms. It binds one molecule of oxygen per pair of iron atoms and functions as a respiratory protein. [NIH] Hemin: Chloro(7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18dipropanoato(4-)-N(21),N(22),N(23),N(24)) ferrate(2-) dihydrogen. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemodialysis Solutions: Solutions prepared for hemodialysis. The composition of the predialysis solution may be varied in order to determine the effect of solvated metabolites on anoxia, malnutrition, acid-base balance, etc. Of principal interest are the effect of the choice of buffers (e.g., acetate or carbonate), the addition of cations (Na+, K+, Ca2+), and addition of carbohydrates (glucose). [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]

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Hemoglobin C: A commonly occurring abnormal hemoglobin in which lysine replaces a glutamic acid residue at the sixth position of the beta chains. It results in reduced plasticity of erythrocytes. [NIH] Hemoglobin H: An abnormal hemoglobin composed of four beta chains. It is caused by the reduced synthesis of the alpha chain. This abnormality results in alpha-thalassemia. [NIH] Hemoglobin M: A group of abnormal hemoglobins in which amino acid substitutions take place in either the alpha or beta chains but near the heme iron. This results in facilitated oxidation of the hemoglobin to yield excess methemoglobin which leads to cyanosis. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemosiderin: Molecule which can bind large numbers of iron atoms. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatitis A: Hepatitis caused by hepatovirus. It can be transmitted through fecal contamination of food or water. [NIH] 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] Hepatocyte: A liver cell. [NIH] Hepatoma: A liver tumor. [NIH] Hepatotoxic: Toxic to liver cells. [EU] Hepatovirus: A genus of Picornaviridae causing infectious hepatitis naturally in humans and experimentally in other primates. It is transmitted through fecal contamination of food or water. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] 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]

Heterotrophic: Pertaining to organisms that are consumers and dependent on other organisms for their source of energy (food). [NIH] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic

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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] 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] Homozygote: An individual in which both alleles at a given locus are identical. [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] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxides: Inorganic compounds that contain the OH- group. [NIH] Hydroxyl Radical: The univalent radical OH that is present in hydroxides, alcohols, phenols, glycols. [NIH] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of

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ribonucleoside diphosphate reductase. [NIH] Hyperaemia: An excess of blood in a part; engorgement. [EU] Hyperoxia: An abnormal increase in the amount of oxygen in the tissues and organs. [NIH] Hyperpigmentation: Excessive pigmentation of the skin, usually as a result of increased melanization of the epidermis rather than as a result of an increased number of melanocytes. Etiology is varied and the condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] 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] Hypoxanthine: A purine and a reaction intermediate in the metabolism of adenosine and in the formation of nucleic acids by the salvage pathway. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] 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] Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience

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with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppression: Deliberate prevention or diminution of the host's immune response. It may be nonspecific as in the administration of immunosuppressive agents (drugs or radiation) or by lymphocyte depletion or may be specific as in desensitization or the simultaneous administration of antigen and immunosuppressive drugs. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] In 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] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

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Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [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] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [NIH] 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] 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] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are

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distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] 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] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intracranial Aneurysm: A saclike dilatation of the walls of a blood vessel, usually an artery. [NIH]

Intracranial Arteriosclerosis: Vascular diseases characterized by thickening, hardening, and remodeling of the walls of intracranial arteries. There are three subtypes: (1) atherosclerosis, marked by fatty depositions in the innermost layer of the arterial walls, (2) Monckeberg's sclerosis, which features calcium deposition in the media and (3) arteriolosclerosis, which refers to sclerosis of small caliber arteries. Clinically, this process may be associated with transient ischemic attack, brain infarction, intracranial embolism and thrombosis, or intracranial aneurysm. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intraocular: Within the eye. [EU] Intraocular pressure: Pressure of the fluid inside the eye; normal IOP varies among individuals. [NIH] Intrathecal: Describes the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. Drugs can be injected into the fluid or a sample of the fluid can be removed for testing. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Introns: Non-coding, intervening sequences of DNA that are transcribed, but are removed from within the primary gene transcript and rapidly degraded during maturation of messenger RNA. Most genes in the nuclei of eukaryotes contain introns, as do mitochondrial and chloroplast genes. [NIH] Inulin: A starch found in the tubers and roots of many plants. Since it is hydrolyzable to fructose, it is classified as a fructosan. It has been used in physiologic investigation for determination of the rate of glomerular function. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

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Invertebrates: Animals that have no spinal column. [NIH] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is called an ion pump. Secondary active transport utilizes the voltage and ion gradients produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Islet: Cell producing insulin in pancreas. [NIH] Isozymes: The multiple forms of a single enzyme. [NIH] Kallidin: A decapeptide bradykinin homolog produced by the action of tissue and glandular kallikreins on low-molecular-weight kininogen. It is a smooth-muscle stimulant and hypotensive agent that functions through vasodilatation. [NIH] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] 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

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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] Kidney Cortex: The outer zone of the kidney, beneath the capsule, consisting of kidney glomerulus; kidney tubules, distal; and kidney tubules, proximal. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kidney stone: A stone that develops from crystals that form in urine and build up on the inner surfaces of the kidney, in the renal pelvis, or in the ureters. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lactate Dehydrogenase: A tetrameric enzyme that, along with the coenzyme NAD+, catalyzes the interconversion of lactate and pyruvate. In vertebrates, genes for three different subunits (LDH-A, LDH-B and LDH-C) exist. [NIH] Lactation: The period of the secretion of milk. [EU] Lag: The time elapsing between application of a stimulus and the resulting reaction. [NIH] Lamivudine: A reverse transcriptase inhibitor and zalcitabine analog in which a sulfur atom replaces the 3' carbon of the pentose ring. It is used to treat HIV disease. [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] 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] Leprosy: A chronic granulomatous infection caused by Mycobacterium leprae. The granulomatous lesions are manifested in the skin, the mucous membranes, and the

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peripheral nerves. Two polar or principal types are lepromatous and tuberculoid. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Libido: The psychic drive or energy associated with sexual instinct in the broad sense (pleasure and love-object seeking). It may also connote the psychic energy associated with instincts in general that motivate behavior. [NIH] Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Linear Models: Statistical models in which the value of a parameter for a given value of a factor is assumed to be equal to a + bx, where a and b are constants. The models predict a linear regression. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver 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] 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]

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Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Locomotor: Of or pertaining to locomotion; pertaining to or affecting the locomotive apparatus of the body. [EU] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [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] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Luminescence: The property of giving off light without emitting a corresponding degree of heat. It includes the luminescence of inorganic matter or the bioluminescence of human matter, invertebrates and other living organisms. For the luminescence of bacteria, bacterial luminescence is available. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphocyte Depletion: Immunosuppression by reduction of circulating lymphocytes or by T-cell depletion of bone marrow. The former may be accomplished in vivo by thoracic duct drainage or administration of antilymphocyte serum. The latter is performed ex vivo on bone marrow before its transplantation. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokines: Soluble protein factors generated by activated lymphocytes that affect other cells, primarily those involved in cellular immunity. [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]

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Lysosome: A sac-like compartment inside a cell that has enzymes that can break down cellular components that need to be destroyed. [NIH] Macroglia: A type of neuroglia composed of astrocytes. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macrophage Activation: The process of altering the morphology and functional activity of macrophages so that they become avidly phagocytic. It is initiated by lymphokines, such as the macrophage activation factor (MAF) and the macrophage migration-inhibitory factor (MMIF), immune complexes, C3b, and various peptides, polysaccharides, and immunologic adjuvants. [NIH] Macula: A stain, spot, or thickening. Often used alone to refer to the macula retinae. [EU] Macula Lutea: An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the superior pole of the eye and slightly below the level of the optic disk. [NIH] Macular Degeneration: Degenerative changes in the macula lutea of the retina. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] 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 ascites: A condition in which fluid containing cancer cells collects in the abdomen. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely

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expressed in behaviour. [EU] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH]

Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] 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] Mengovirus: A strain of encephalomyocarditis virus, a species of cardiovirus, isolated from rodents and lagomorphs and occasionally causing febrile illness in man. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Menopause: Permanent cessation of menstruation. [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed

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therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metallothionein: A low-molecular-weight (approx. 10 kD) protein occurring in the cytoplasm of kidney cortex and liver. It is rich in cysteinyl residues and contains no aromatic amino acids. Metallothionein shows high affinity for bivalent heavy metals. [NIH] Metamorphosis: The ontogeny of insects, i. e. the series of changes undergone from egg, through larva and pupa, or through nymph, to adult. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] 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] Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling. [NIH] Microgram: A unit of mass (weight) of the metric system, being one-millionth of a gram (106 gm.) or one one-thousandth of a milligram (10-3 mg.). [EU] 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] Microsomal: Of or pertaining to microsomes : vesicular fragments of endoplasmic reticulum formed after disruption and centrifugation of cells. [EU] Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]

labeled

with

Middle Cerebral Artery: The largest and most complex of the cerebral arteries. Branches of the middle cerebral artery supply the insular region, motor and premotor areas, and large regions of the association cortex. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Mineralization: The action of mineralizing; the state of being mineralized. [EU]

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Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] 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] Mononuclear: A cell with one nucleus. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Mucinous: Containing or resembling mucin, the main compound in mucus. [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU]

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Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]

Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] 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] Myelodysplastic syndrome: Disease in which the bone marrow does not function normally. Also called preleukemia or smoldering leukemia. [NIH] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myelosuppression: A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. Myelosuppression is a side effect of some cancer treatments. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] 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] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH]

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Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Neostriatum: The phylogenetically newer part of the corpus striatum consisting of the caudate nucleus and putamen. It is often called simply the striatum. [NIH] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [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] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neuroendocrine tumor: A tumor derived from cells that release a hormone in response to a signal from the nervous system. Some examples of neuroendocrine tumors are carcinoid tumors, islet cell tumors, medullary thyroid carcinoma, and pheochromocytoma. These tumors secrete hormones in excess, causing a variety of symptoms. [NIH] 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] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]

Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH]

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Neutrophil Infiltration: The diffusion or accumulation of neutrophils in tissues or cells in response to a wide variety of substances released at the sites of inflammatory reactions. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Medicine: A specialty field of radiology concerned with diagnostic, therapeutic, and investigative use of radioactive compounds in a pharmaceutical form. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleocapsid: A protein-nucleic acid complex which forms part or all of a virion. It consists of a capsid plus enclosed nucleic acid. Depending on the virus, the nucleocapsid may correspond to a naked core or be surrounded by a membranous envelope. [NIH] Nucleocapsid Proteins: Viral proteins found in either the nucleocapsid or the viral core (viral core proteins). [NIH] Nucleolus: A small dense body (sub organelle) within the nucleus of eukaryotic cells, visible by phase contrast and interference microscopy in live cells throughout interphase. Contains RNA and protein and is the site of synthesis of ribosomal RNA. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Observational study: An epidemiologic study that does not involve any intervention, experimental or otherwise. Such a study may be one in which nature is allowed to take its course, with changes in one characteristic being studied in relation to changes in other characteristics. Analytical epidemiologic methods, such as case-control and cohort study designs, are properly called observational epidemiology because the investigator is observing without intervention other than to record, classify, count, and statistically analyze results. [NIH] Occupational Exposure: The exposure to potentially harmful chemical, physical, or biological agents that occurs as a result of one's occupation. [NIH]

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Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] 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] Ophthalmology: A surgical specialty concerned with the structure and function of the eye and the medical and surgical treatment of its defects and diseases. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]

Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] 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] Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxaloacetate: An anionic form of oxaloacetic acid. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which

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electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative 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] Oxides: Binary compounds of oxygen containing the anion O(2-). The anion combines with metals to form alkaline oxides and non-metals to form acidic oxides. [NIH] Oximetry: The determination of oxygen-hemoglobin saturation of blood either by withdrawing a sample and passing it through a classical photoelectric oximeter or by electrodes attached to some translucent part of the body like finger, earlobe, or skin fold. It includes non-invasive oxygen monitoring by pulse oximetry. [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU]

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Parathyroid Glands: Two small paired endocrine glands in the region of the thyroid gland. They secrete parathyroid hormone and are concerned with the metabolism of calcium and phosphorus. [NIH] Parathyroid hormone: A substance made by the parathyroid gland that helps the body store and use calcium. Also called parathormone, parathyrin, or PTH. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parity: The number of offspring a female has borne. It is contrasted with gravidity, which refers to the number of pregnancies, regardless of outcome. [NIH] Particle: A tiny mass of material. [EU] Parturition: The act or process of given birth to a child. [EU] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Patient Selection: Criteria and standards used for the determination of the appropriateness of the inclusion of patients with specific conditions in proposed treatment plans and the criteria used for the inclusion of subjects in various clinical trials and other research protocols. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [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] 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] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nerves: The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The

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peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneal Dialysis: Dialysis fluid being introduced into and removed from the peritoneal cavity as either a continuous or an intermittent procedure. [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] Perivascular: Situated around a vessel. [EU] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Petechiae: Pinpoint, unraised, round red spots under the skin caused by bleeding. [NIH] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] 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] Phlebotomy: The letting of blood from a vein. Although it is one of the techniques used in drawing blood to be used in diagnostic procedures, in modern medicine, it is used commonly in the treatment of erythrocytosis, hemochromocytosis, polycythemia vera, and porphyria cutanea tarda. Its historical counterpart is bloodletting. (From Cecil Textbook of Medicine, 19th ed & Wintrobe's Clinical Hematology, 9th ed) Venipuncture is not only for the letting of blood from a vein but also for the injecting of a drug into the vein for diagnostic analysis. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and

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teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photodynamic therapy: Treatment with drugs that become active when exposed to light. These drugs kill cancer cells. [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] Physician Assistants: Persons academically trained, licensed, or credentialed to provide medical care under the supervision of a physician. The concept does not include nurses, but does include orthopedic assistants, surgeon's assistants, and assistants to other specialists. [NIH]

Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pigmentation: Coloration or discoloration of a part by a pigment. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] 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] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of

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molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]

Plexus: A network or tangle; a general term for a network of lymphatic vessels, nerves, or veins. [EU] Pneumoconiosis: Condition characterized by permanent deposition of substantial amounts of particulate matter in the lungs, usually of occupational or environmental origin, and by the tissue reaction to its presence. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH]

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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] Porphyrins: A group of compounds containing the porphin structure, four pyrrole rings connected by methine bridges in a cyclic configuration to which a variety of side chains are attached. The nature of the side chain is indicated by a prefix, as uroporphyrin, hematoporphyrin, etc. The porphyrins, in combination with iron, form the heme component in biologically significant compounds such as hemoglobin and myoglobin. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [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] Precancerous: A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant. [NIH] Precipitating Factors: Factors associated with the definitive onset of a disease, illness, accident, behavioral response, or course of action. Usually one factor is more important or more obviously recognizable than others, if several are involved, and one may often be regarded as "necessary". Examples include exposure to specific disease; amount or level of an infectious organism, drug, or noxious agent, etc. [NIH] Precipitation: The act or process of precipitating. [EU] Preclinical: Before a disease becomes clinically recognizable. [EU]

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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] Preeclampsia: A toxaemia of late pregnancy characterized by hypertension, edema, and proteinuria, when convulsions and coma are associated, it is called eclampsia. [EU] Pregnancy Outcome: Results of conception and ensuing pregnancy, including live birth, stillbirth, spontaneous abortion, induced abortion. The outcome may follow natural or artificial insemination or any of the various reproduction techniques, such as embryo transfer or fertilization in vitro. [NIH] Preleukemia: Conditions in which the abnormalities in the peripheral blood or bone marrow represent the early manifestations of acute leukemia, but in which the changes are not of sufficient magnitude or specificity to permit a diagnosis of acute leukemia by the usual clinical criteria. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prenatal Care: Care provided the pregnant woman in order to prevent complications, and decrease the incidence of maternal and prenatal mortality. [NIH] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Prickle: Several layers of the epidermis where the individual cells are connected by cell bridges. [NIH] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Procollagen: A biosynthetic precursor of collagen containing additional amino acid sequences at the amino-terminal ends of the three polypeptide chains. Protocollagen, a precursor of procollagen consists of procollagen peptide chains in which proline and lysine have not yet been hydroxylated. [NIH] Proctoscopy: Endoscopic examination, therapy or surgery of the rectum. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] 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] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should

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fertilization occur. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] 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] Prophylaxis: An attempt to prevent disease. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Protein Subunits: Single chains of amino acids that are the units of a multimeric protein. They can be identical or non-identical subunits. [NIH] Protein Synthesis Inhibitors: Compounds which inhibit the synthesis of proteins. They are usually antibiotics or toxins. Mechanism of the action of inhibition includes the interruption of peptide-chain elongation, the blocking the the A site of ribosomes, the misreading of the genetic code or the prevention of the attachment of oligosaccharide side chains to glycoproteins. [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]

Prothrombin Time: Measurement of clotting time of plasma recalcified in the presence of excess tissue thromboplastin. Factors measured are fibrinogen, prothrombin, and factors V, VII, and X. It is used for monitoring anticoagulant therapy with coumarins. [NIH]

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Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Protozoan: 1. Any individual of the protozoa; protozoon. 2. Of or pertaining to the protozoa; protozoal. [EU] Pseudogenes: Genes bearing close resemblance to known genes at different loci, but rendered non-functional by additions or deletions in structure that prevent normal transcription or translation. When lacking introns and containing a poly-A segment near the downstream end (as a result of reverse copying from processed nuclear RNA into doublestranded DNA), they are called processed genes. [NIH] Pseudomonas: A genus of gram-negative, aerobic, rod-shaped bacteria widely distributed in nature. Some species are pathogenic for humans, animals, and plants. [NIH] Pseudomonas putida: A species of gram-negative, aerobic bacteria isolated from soil and water as well as clinical specimens. Occasionally it is an opportunistic pathogen. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

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] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Pupil: The aperture in the iris through which light passes. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic

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acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Putamen: The largest and most lateral of the basal ganglia lying between the lateral medullary lamina of the globus pallidus and the external capsule. It is part of the neostriatum and forms part of the lentiform nucleus along with the globus pallidus. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Quinones: Hydrocarbon rings which contain two ketone moieties in any position. They can be substituted in any position except at the ketone groups. [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] Radioactivity: The quality of emitting or the emission of corpuscular or electromagnetic radiations consequent to nuclear disintegration, a natural property of all chemical elements of atomic number above 83, and possible of induction in all other known elements. [EU] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radioimmunoassay: Classic quantitative assay for detection of antigen-antibody reactions using a radioactively labeled substance (radioligand) either directly or indirectly to measure the binding of the unlabeled substance to a specific antibody or other receptor system. Nonimmunogenic substances (e.g., haptens) can be measured if coupled to larger carrier proteins (e.g., bovine gamma-globulin or human serum albumin) capable of inducing antibody formation. [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] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays,

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gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombinant Proteins: Proteins prepared by recombinant DNA technology. [NIH] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]

Renal failure: Progressive renal insufficiency and uremia, due to irreversible and

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progressive renal glomerular tubular or interstitial disease. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Reproduction Techniques: Methods pertaining to the generation of new individuals. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH] Response Elements: Nucleotide sequences, usually upstream, which are recognized by specific regulatory transcription factors, thereby causing gene response to various regulatory agents. These elements may be found in both promotor and enhancer regions. [NIH]

Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinoids: Derivatives of vitamin A. Used clinically in the treatment of severe cystic acne, psoriasis, and other disorders of keratinization. Their possible use in the prophylaxis and treatment of cancer is being actively explored. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve

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impulses to the brain. [NIH] Ribavirin: 1-beta-D-Ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. A nucleoside antimetabolite antiviral agent that blocks nucleic acid synthesis and is used against both RNA and DNA viruses. [NIH] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [NIH] 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] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rickets: A condition caused by deficiency of vitamin D, especially in infancy and childhood, with disturbance of normal ossification. The disease is marked by bending and distortion of the bones under muscular action, by the formation of nodular enlargements on the ends and sides of the bones, by delayed closure of the fontanelles, pain in the muscles, and sweating of the head. Vitamin D and sunlight together with an adequate diet are curative, provided that the parathyroid glands are functioning properly. [EU] Rickettsiae: One of a group of obligate intracellular parasitic microorganisms, once regarded as intermediate in their properties between bacteria and viruses but now classified as bacteria in the order Rickettsiales, which includes 17 genera and 3 families: Rickettsiace. [NIH]

Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risk patient: Patient who is at risk, because of his/her behaviour or because of the type of person he/she is. [EU] Rod: A reception for vision, located in the retina. [NIH] Saline: A solution of salt and water. [NIH] Saturated fat: A type of fat found in greatest amounts in foods from animals, such as fatty cuts of meat, poultry with the skin, whole-milk dairy products, lard, and in some vegetable oils, including coconut, palm kernel, and palm oils. Saturated fat raises blood cholesterol more than anything else eaten. On a Step I Diet, no more than 8 to 10 percent of total calories should come from saturated fat, and in the Step II Diet, less than 7 percent of the day's total calories should come from saturated fat. [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] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU]

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Screening: Checking for disease when there are no symptoms. [NIH] Seafood: Marine fish and shellfish used as food or suitable for food. (Webster, 3d ed) shellfish and fish products are more specific types of seafood. [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] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Sella Turcica: A bony prominence situated on the upper surface of the body of the sphenoid bone. It houses the pituitary gland. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sepsis: The presence of bacteria in the bloodstream. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Sequester: A portion of dead bone which has become detached from the healthy bone tissue, as occurs in necrosis. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Hormone-Binding Globulin: A glycoprotein migrating as a beta-globulin. Its molecular weight, 52,000 or 95,000-115,000, indicates that it exists as a dimer. The protein binds testosterone, dihydrotestosterone, and estradiol in the plasma. Sex hormone-binding protein has the same amino acid sequence as androgen-binding protein. They differ by their sites of synthesis and post-translational oligosacaccharide modifications. [NIH]

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Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Siderosis: The deposition of iron in a tissue. In the eye, the iron may be deposited in the stroma adjacent to the Descemet's membrane. [NIH] Sigmoid: 1. Shaped like the letter S or the letter C. 2. The sigmoid colon. [EU] Sigmoidoscopy: Endoscopic examination, therapy or surgery of the sigmoid flexure. [NIH] Silicon: A trace element that constitutes about 27.6% of the earth's crust in the form of silicon dioxide. It does not occur free in nature. Silicon has the atomic symbol Si, atomic number 14, and atomic weight 28.09. [NIH] Silicon Dioxide: Silica. Transparent, tasteless crystals found in nature as agate, amethyst, chalcedony, cristobalite, flint, sand, quartz, and tridymite. The compound is insoluble in water or acids except hydrofluoric acid. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small Bowel Enema: X-rays of the small intestine taken as barium liquid passes through the organ. Also called small bowel follow-through. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smoldering leukemia: Disease in which the bone marrow does not function normally. Also called preleukemia or myelodysplastic syndrome. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] 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

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distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrophotometry: The art or process of comparing photometrically the relative intensities of the light in different parts of the spectrum. [NIH] Spectroscopic: The recognition of elements through their emission spectra. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spike: The activation of synapses causes changes in the permeability of the dendritic membrane leading to changes in the membrane potential. This difference of the potential travels along the axon of the neuron and is called spike. [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] Splenectomy: An operation to remove the spleen. [NIH] Spontaneous Abortion: The non-induced birth of an embryo or of fetus prior to the stage of viability at about 20 weeks of gestation. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stabilization: The creation of a stable state. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Steady state: Dynamic equilibrium. [EU] Steatosis: Fatty degeneration. [EU] 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] Sterile: Unable to produce children. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other

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excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] 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] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subiculum: A region of the hippocampus that projects to other areas of the brain. [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] 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] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Surface Plasmon Resonance: A biosensing technique in which biomolecules capable of binding to specific analytes or ligands are first immobilized on one side of a metallic film. Light is then focused on the opposite side of the film to excite the surface plasmons, that is, the oscillations of free electrons propagating along the film's surface. The refractive index of light reflecting off this surface is measured. When the immobilized biomolecules are bound by their ligands, an alteration in surface plasmons on the opposite side of the film is created which is directly proportional to the change in bound, or adsorbed, mass. Binding is measured by changes in the refractive index. The technique is used to study biomolecular interactions, such as antigen-antibody binding. [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]

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Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] Synchrotron: An accelerator in which the particles are guided by an increasing magnetic field while they are accelerated several times in an approximately circular path by electric fields produced by a high-frequency generator. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systemic therapy: Treatment that uses substances that travel through the bloodstream, reaching and affecting cells all over the body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Systolic blood pressure: The maximum pressure in the artery produced as the heart contracts and blood begins to flow. [NIH] Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [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] Tendon: A discrete band of connective tissue mainly composed of parallel bundles of collagenous fibers by which muscles are attached, or two muscles bellies joined. [NIH] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetany: 1. Hyperexcitability of nerves and muscles due to decrease in concentration of extracellular ionized calcium, which may be associated with such conditions as parathyroid hypofunction, vitamin D deficiency, and alkalosis or result from ingestion of alkaline salts; it is characterized by carpopedal spasm, muscular twitching and cramps, laryngospasm with inspiratory stridor, hyperreflexia and choreiform movements. 2. Tetanus. [EU] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include

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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] Theophylline: Alkaloid obtained from Thea sinensis (tea) and others. It stimulates the heart and central nervous system, dilates bronchi and blood vessels, and causes diuresis. The drug is used mainly in bronchial asthma and for myocardial stimulation. Among its more prominent cellular effects are inhibition of cyclic nucleotide phosphodiesterases and antagonism of adenosine receptors. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thromboplastin: Constituent composed of protein and phospholipid that is widely distributed in many tissues. It serves as a cofactor with factor VIIa to activate factor X in the extrinsic pathway of blood coagulation. [NIH] Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a

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specific function. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxaemia: 1. The condition resulting from the spread of bacterial products (toxins) by the bloodstream. 2. A condition resulting from metabolic disturbances, e.g. toxaemia of pregnancy. [EU] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic 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] 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 analogous to bacterial transformation. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] 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

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protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [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] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumorigenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH]

Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] 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] 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] Ultrasonography: The visualization of deep structures of the body by recording the reflections of echoes of pulses of ultrasonic waves directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1.6 to 10 megahertz. [NIH] Univalent: Pertaining to an unpaired chromosome during the zygotene stage of prophase to first metaphase in meiosis. [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and

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constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Uridine Diphosphate: A uracil nucleotide containing a pyrophosphate group esterified to C5 of the sugar moiety. [NIH] Uridine Diphosphate Glucuronic Acid: A nucleoside diphosphate sugar which serves as a source of glucuronic acid for polysaccharide biosynthesis. It may also be epimerized to UDP iduronic acid, which donates iduronic acid to polysaccharides. In animals, UDP glucuronic acid is used for formation of many glucosiduronides with various aglycones. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinate: To release urine from the bladder to the outside. [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] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccines: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa, or rickettsiae), antigenic proteins derived from them, or synthetic constructs, administered for the prevention, amelioration, or treatment of infectious and other diseases. [NIH]

Vacuole: A fluid-filled cavity within the cytoplasm of a cell. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] 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

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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] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Villous: Of a surface, covered with villi. [NIH] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Core Proteins: Proteins found mainly in icosahedral DNA and RNA viruses. They consist of proteins directly associated with the nucleic acid inside the nucleocapsid. [NIH] 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] Virion: The infective system of a virus, composed of the viral genome, a protein core, and a protein coat called a capsid, which may be naked or enclosed in a lipoprotein envelope called the peplos. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Vitamin D: The vitamin that mediates intestinal calcium absorption, bone calcium metabolism, and probably muscle activity. It usually acts as a hormone precursor, requiring 2 stages of metabolism before reaching actual hormonal form. It is isolated from fish liver oils and used in the treatment and prevention of rickets. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] 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]

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Vivo: Outside of or removed from the body of a living organism. [NIH] Void: To urinate, empty the bladder. [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] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xanthine: An urinary calculus. [NIH] Xanthine Oxidase: An iron-molybdenum flavoprotein containing FAD that oxidizes hypoxanthine, some other purines and pterins, and aldehydes. Deficiency of the enzyme, an autosomal recessive trait, causes xanthinuria. EC 1.1.3.22. [NIH] Xenobiotics: Chemical substances that are foreign to the biological system. They include naturally occurring compounds, drugs, environmental agents, carcinogens, insecticides, etc. [NIH]

Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Yellow Fever: An acute infectious disease primarily of the tropics, caused by a virus and transmitted to man by mosquitoes of the genera Aedes and Haemagogus. [NIH] Zalcitabine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication at low concentrations, acting as a chainterminator of viral DNA by binding to reverse transcriptase. Its principal toxic side effect is axonal degeneration resulting in peripheral neuropathy. [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]

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INDEX A Abdominal, 9, 88, 166, 177, 229, 231, 249 Abdominal Pain, 177, 249 Aberrant, 51, 141, 177 Abortion, 177, 235 Acceptor, 177, 204, 219, 229, 248 Acetaminophen, 132, 177 Acetylcholine, 177, 226, 227 Acid Phosphatase, 25, 58, 177 Acidity, 177, 231 Acute leukemia, 72, 177, 235 Acyl, 48, 177 Acyl Carrier Protein, 48, 177 Adaptability, 177, 190 Adenine, 177, 237 Adenocarcinoma, 177, 211 Adenosine, 177, 188, 213, 232, 247 Adenovirus, 50, 177 Adjuvant, 28, 122, 178, 179, 206 Adjuvant Therapy, 122, 178 Adrenal Cortex, 178, 196, 203, 235 Adrenal Medulla, 18, 178, 189, 203, 227 Adrenergic, 178, 199, 203, 246 Adverse Effect, 178, 243 Aerobic, 32, 51, 119, 178, 224, 237 Affinity, 24, 26, 34, 102, 178, 183, 219, 223, 243 Age of Onset, 178, 249 Ageing, 87, 178 Agonist, 178, 199 Airway, 46, 99, 115, 178 Alanine, 56, 70, 108, 162, 178 Albumin, 11, 162, 164, 178, 232 Aldehydes, 179, 252 Alfalfa, 143, 144, 179 Algorithms, 179, 186 Alimentary, 4, 6, 179, 230 Alkaline, 11, 162, 179, 180, 184, 188, 229, 246 Alkaline Phosphatase, 11, 162, 179 Alkylating Agents, 179, 249 Alleles, 179, 206, 212 Allergen, 179, 198, 242 Alopecia, 77, 78, 179 Alpha Particles, 179, 238 Alpha-1, 162, 179 Alpha-fetoprotein, 109, 179, 204 Alpha-Thalassemia, 179, 211

Alternative medicine, 150, 179 Aluminum, 114, 132, 179 Aluminum Hydroxide, 132, 179 Ameliorating, 41, 179 Amino Acid Sequence, 180, 181, 195, 207, 235, 242 Aminolevulinic Acid, 101, 124, 180 Amino-terminal, 180, 235 Ammonia, 180, 249 Amniocentesis, 81, 180 Amnion, 180 Amniotic Fluid, 81, 180 Amyloid, 47, 53, 180, 190 Anaemia, 83, 110, 120, 180, 222 Anaesthesia, 84, 180, 214 Anal, 180, 202, 205 Analgesic, 177, 180 Analog, 132, 180, 218 Analogous, 57, 180, 248 Analytes, 180, 245 Anaphylatoxins, 180, 194 Anatomical, 181, 191, 195, 214, 223 Androgen-Binding Protein, 181, 242 Anemic, 5, 83, 106, 181 Anesthesia, 178, 181 Anesthetics, 181, 203 Angiopathy, 181, 190 Animal model, 5, 13, 16, 181 Anionic, 42, 129, 181, 228 Anions, 178, 181, 217, 242, 245 Anomalies, 47, 181 Anoxia, 57, 181, 210 Antibacterial, 181, 244 Antibiotic, 181, 197, 200, 244 Antibodies, 23, 70, 97, 134, 137, 139, 140, 181, 210, 212, 213, 220, 224, 232 Antibody, 11, 19, 33, 139, 140, 144, 178, 181, 182, 193, 203, 205, 210, 212, 213, 214, 217, 222, 224, 238, 239, 242, 244, 245, 252 Anticoagulant, 182, 236 Antigen, 67, 75, 98, 178, 181, 182, 194, 205, 212, 213, 214, 222, 223, 238, 242, 245 Antigen-Antibody Complex, 182, 194, 205 Anti-infective, 182, 212, 217 Anti-inflammatory, 16, 177, 182 Antimetabolite, 182, 241

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Ferritin

Antineoplastic, 179, 182, 196, 200, 206, 212, 251 Antioxidant, 11, 17, 22, 28, 30, 32, 35, 48, 51, 70, 182, 183, 229 Antipyretic, 177, 182 Antiviral, 182, 206, 215, 241 Anus, 180, 182, 184, 187, 193, 202 Apolipoproteins, 5, 182, 219 Aponeurosis, 182, 206 Apoptosis, 24, 36, 46, 70, 105, 182, 189, 197 Applicability, 19, 182 Aqueous, 33, 182, 192, 197, 201, 212, 218, 219 Aqueous humor, 33, 182, 192 Arginine, 180, 182, 227 Arsenicals, 101, 182 Arterial, 182, 183, 192, 213, 216, 236, 246 Arteries, 181, 182, 183, 186, 187, 190, 196, 216, 220, 223, 225, 237 Arteriography, 92, 183 Arterioles, 183, 187, 188, 225 Arteriovenous, 183, 190 Artery, 136, 182, 183, 196, 201, 216, 223, 237, 246 Arthralgia, 3, 183 Articular, 183, 228 Ascites, 183 Ascitic Fluid, 109, 183 Ascorbic Acid, 11, 23, 80, 82, 101, 122, 183, 212 Aspartate, 9, 108, 162, 183 Aspartate Transaminase, 108, 183 Assay, 14, 31, 40, 47, 69, 79, 80, 104, 121, 135, 136, 137, 139, 183, 213, 238 Astringents, 183, 223 Astrocytes, 22, 183, 221, 223 Astrocytoma, 183, 207 Asymptomatic, 183, 185, 204 Ataxia, 51, 99, 183, 246 Atrophy, 183, 226 Attenuated, 183, 250 Atypical, 108, 114, 183 Autologous, 124, 184 Autologous bone marrow transplantation, 124, 184 Autonomic, 177, 184, 227, 230, 231, 245 Autonomic Nervous System, 184, 231, 245 Autophagocytosis, 99, 115, 184 Axonal, 57, 184, 252 Axons, 57, 184, 198, 228, 230 B Bactericidal, 184, 203

Bacteriophage, 184, 248 Barium, 166, 184, 243 Barium enema, 166, 184 Basal Ganglia, 75, 97, 183, 184, 190, 206, 207, 238 Basal Ganglia Diseases, 183, 184 Basement Membrane, 184, 204 Basophils, 184, 209, 219 Benign, 185, 188, 206, 225, 238 Beta carotene, 136, 185 Beta-pleated, 180, 185 Beta-Thalassemia, 55, 81, 95, 185 Bilateral, 59, 72, 185 Bile, 31, 49, 185, 206, 208, 211, 219, 244 Bile Acids, 185, 244 Bile Acids and Salts, 185 Bile Pigments, 31, 49, 185 Biliary, 72, 185, 211 Bilirubin, 11, 17, 29, 32, 50, 72, 162, 178, 185, 208 Biliverdine, 185 Binding agent, 64, 185 Binding Sites, 6, 21, 61, 75, 185 Bioavailability, 61, 74, 82, 185 Bioavailable, 38, 134, 142, 185 Biological therapy, 185, 209 Biological Transport, 185, 199 Bioluminescence, 186, 220 Biomarkers, 14, 40, 48, 186 Biomedical Engineering, 33, 48, 186 Biomolecular, 48, 186, 245 Biophysics, 48, 49, 95, 101, 107, 119, 120, 121, 125, 186 Biopsy, 4, 6, 9, 15, 47, 55, 163, 165, 186 Biosynthesis, 51, 87, 186, 242, 250 Biotechnology, 62, 68, 81, 85, 150, 157, 186 Biotic, 143, 144, 186 Bivalent, 186, 223 Bladder, 186, 194, 236, 250, 252 Blastocyst, 186, 194, 201, 232 Blood Banks, 40, 186 Blood Cell Count, 186, 210 Blood Coagulation, 186, 188, 247 Blood Glucose, 5, 78, 186, 210, 215 Blood pressure, 5, 78, 164, 165, 175, 186, 189, 213, 224, 237, 243 Blood Substitutes, 142, 186 Blood transfusion, 7, 11, 110, 135, 186 Blood urea, 165, 186, 218 Blood-Brain Barrier, 18, 187 Body Fluids, 186, 187, 200, 243, 249

255

Bone Marrow, 7, 55, 70, 86, 103, 139, 177, 184, 187, 192, 203, 207, 213, 220, 225, 235, 243 Bone Marrow Transplantation, 86, 187 Bone scan, 187, 241 Boron, 187, 197 Bowel, 4, 180, 187, 202, 215, 216, 231, 243, 245, 249 Bowel Movement, 187, 245 Brachytherapy, 187, 216, 217, 238, 252 Bradykinin, 84, 187, 217, 227, 232 Breeding, 41, 187, 206 Bronchi, 187, 203, 247, 248 Bronchial, 46, 187, 212, 247 Bronchoalveolar Lavage, 110, 187 Bronchoalveolar Lavage Fluid, 110, 187 Buffers, 187, 210 C Caffeine, 188, 238 Calcium, 5, 117, 164, 165, 188, 193, 216, 230, 236, 246, 251 Caloric intake, 165, 188 Cannula, 84, 188 Capillary, 84, 109, 187, 188, 208, 251 Capillary Permeability, 187, 188 Capsid, 142, 188, 227, 251 Capsules, 188, 206, 208 Carbohydrate, 188, 208, 233 Carbon Dioxide, 186, 188, 205, 206, 232, 240, 250 Carcinogenesis, 32, 188, 191 Carcinogenic, 134, 179, 188, 215, 228, 236, 244, 249 Carcinogens, 51, 135, 136, 188, 229, 252 Carcinoid, 188, 226 Carcinoma, 56, 70, 90, 188, 226 Cardiac, 10, 15, 42, 47, 149, 188, 189, 203, 225, 244 Cardiogenic, 140, 189 Cardiology, 15, 71, 189 Cardiomyopathy, 10, 15, 189 Cardiovascular, 5, 7, 33, 40, 83, 104, 189 Cardiovascular disease, 33, 40, 189 Cardiovirus, 189, 201, 222 Carotene, 11, 106, 185, 189, 240 Carotenoids, 185, 189 Caspase, 23, 37, 189 Catabolism, 114, 189 Cataract, 16, 58, 72, 80, 100, 189 Catecholamine, 18, 54, 189, 199 Cathode, 189, 201 Cations, 38, 189, 210, 217

Caudal, 189, 199, 213, 234 Causal, 189, 202 Causality, 40, 189 Cell Count, 13, 189 Cell Cycle, 24, 189 Cell Death, 23, 31, 44, 50, 182, 190, 225 Cell Division, 184, 190, 209, 224, 232, 242 Cell membrane, 59, 185, 190, 191, 217, 231 Cell proliferation, 80, 141, 190, 206 Cell Respiration, 190, 224, 240 Cell Survival, 24, 190, 209 Cellular metabolism, 59, 136, 190 Cellulose, 190, 232 Central Nervous System, 41, 177, 178, 184, 188, 190, 206, 207, 208, 223, 228, 247 Centrifugation, 190, 210, 223 Cerebellar, 183, 190, 239 Cerebral, 17, 49, 71, 183, 184, 187, 190, 191, 196, 203, 205, 207, 221, 223, 237, 246 Cerebral Arteries, 190, 223 Cerebral Cortex, 183, 190 Cerebral hemispheres, 184, 190, 191, 207, 246 Cerebral Hemorrhage, 49, 190 Cerebrospinal, 72, 75, 190, 192 Cerebrospinal fluid, 72, 75, 190, 192 Cerebrovascular, 28, 184, 189, 191, 247 Cerebrum, 190, 191, 246 Cervical, 149, 191 Cervix, 177, 191 Character, 25, 191, 198 Chelating Agents, 122, 142, 191 Chelation, 15, 26, 45, 55, 66, 116, 121, 122, 126, 191 Chelation Therapy, 15, 55, 191 Chemokines, 17, 191 Chemoprevention, 135, 191 Chemopreventive, 22, 25, 85, 124, 191 Chemoprotective, 134, 191 Chemotactic Factors, 191, 194 Chemotherapy, 18, 38, 62, 124, 178, 191 Chin, 191, 222 Chloride Channels, 24, 191 Chlorophyll, 191 Chloroquine, 38, 191 Cholesterol, 11, 93, 185, 192, 196, 219, 220, 241, 244 Cholesterol Esters, 192, 219 Choroid, 17, 192, 240 Choroid Plexus, 17, 192 Chromatin, 182, 192, 202 Chromosomal, 62, 192

256

Ferritin

Chromosome, 33, 64, 192, 195, 209, 217, 219, 242, 249 Chronic Disease, 4, 40, 163, 192 Chronic granulocytic leukemia, 192 Chronic myelogenous leukemia, 102, 192 Chronic renal, 7, 23, 81, 192 Chylomicrons, 192, 219 Ciliary, 36, 182, 192 Ciliary processes, 182, 192 Cirrhosis, 3, 8, 10, 11, 30, 56, 57, 162, 163, 192, 210 CIS, 22, 51, 53, 54, 60, 62, 192, 240 Clathrin, 99, 192, 193 Clinical Medicine, 80, 81, 85, 192, 235 Clinical trial, 12, 29, 35, 157, 192, 196, 199, 200, 225, 230, 237, 239 Clone, 60, 65, 193 Cloning, 38, 62, 75, 186, 193 Coated Vesicles, 192, 193 Coenzyme, 183, 193, 218 Cofactor, 193, 236, 247 Cohort Studies, 193, 202 Colitis, 166, 193 Collagen, 180, 184, 193, 204, 206, 233, 235, 236 Colloidal, 178, 193, 201, 242 Colon, 27, 90, 95, 184, 193, 215, 218, 243, 249 Colonoscopy, 166, 193 Colorectal, 39, 193 Colorectal Cancer, 39, 193 Complement, 16, 180, 193, 194, 207, 217, 221, 232, 242 Complementary and alternative medicine, 119, 127, 194 Complementary medicine, 119, 194 Complementation, 78, 194 Compliance, 13, 34, 126, 194 Computational Biology, 157, 194 Computed tomography, 72, 110, 166, 194, 241 Computerized axial tomography, 194, 241 Computerized tomography, 9, 194 Conception, 41, 177, 194, 196, 204, 235 Concomitant, 53, 194 Cone, 57, 195 Confounding, 77, 195 Congestive heart failure, 56, 195 Conjugated, 19, 135, 185, 195, 197, 205 Conjugation, 67, 195, 205, 208 Conjunctiva, 195 Conjunctivitis, 13, 195

Connective Tissue, 183, 187, 193, 195, 204, 206, 220, 230, 240, 246 Consciousness, 180, 195, 199 Consensus Sequence, 195 Conserved Sequence, 63, 195 Constriction, 195, 217, 250 Constriction, Pathologic, 195, 250 Contamination, 123, 195, 211 Continuum, 134, 195 Contraception, 92, 195 Contraindications, ii, 196 Control group, 31, 196, 235, 239 Convulsions, 196, 200, 235 Coordination, 191, 196 Cornea, 20, 182, 196, 241, 245 Corneum, 196, 203 Coronary, 5, 15, 92, 93, 102, 114, 136, 189, 196, 223, 225 Coronary Arteriosclerosis, 196, 225 Coronary heart disease, 5, 93, 114, 189, 196 Coronary Thrombosis, 196, 223, 225 Corpus, 196, 207, 220, 226, 235, 251 Corpus Luteum, 196, 220, 235 Cortex, 196, 202, 223, 239 Cortisol, 104, 178, 196 Cotinine, 48, 196 Coumarins, 196, 236 Creatinine, 165, 196, 218 Cross-Sectional Studies, 196, 202 Cultured cells, 28, 196 Curative, 197, 241, 247 Curcumin, 22, 197 Cyclic, 188, 197, 209, 227, 234, 247 Cysteine, 22, 55, 107, 191, 197, 245 Cysteinyl, 197, 223 Cystine, 197 Cytochrome, 37, 197, 229 Cytokine, 31, 53, 78, 197 Cytoplasm, 61, 182, 185, 190, 197, 202, 209, 223, 241, 250 Cytoprotection, 51, 197 Cytoskeletal Proteins, 192, 197 Cytostatic, 38, 197 Cytotoxic, 28, 39, 138, 197, 214, 239 Cytotoxicity, 141, 197 D Dairy Products, 197, 241 Daunorubicin, 197, 200 De novo, 87, 197 Deamination, 197, 249 Decidua, 198, 232

257

Deferoxamine, 15, 150, 198 Degenerative, 136, 198, 211, 221, 228 Dehydroepiandrosterone, 104, 198 Deletion, 30, 49, 182, 198 Dendrites, 57, 198, 226 Dendritic, 198, 222, 244 Density, 17, 27, 34, 57, 77, 94, 190, 198, 219, 228 Dentate Gyrus, 198, 211 Dentifrices, 179, 198 Deoxyribonucleotides, 58, 198, 207, 241 Deprivation, 38, 50, 198 Dermatosis, 198, 204 Desensitization, 198, 214 Detoxification, 31, 35, 43, 46, 51, 123, 135, 142, 198, 208 Deuterium, 198, 212 Developing Countries, 13, 198 Diabetes Mellitus, 10, 198, 208, 210 Diagnostic procedure, 131, 150, 198, 231 Dialysate, 35, 198, 199 Dialysis Solutions, 35, 198 Dialyzer, 199, 210 Diastolic, 199, 213 Diencephalon, 199, 213, 246 Diffusion, 97, 185, 188, 199, 209, 215, 217, 227 Digestion, 74, 179, 184, 185, 187, 199, 216, 219, 230, 245 Dihydrotestosterone, 199, 239, 242 Dilation, 187, 199 Dimethyl, 39, 199 Diploid, 194, 199, 232 Direct, iii, 18, 20, 23, 29, 35, 54, 65, 137, 192, 199, 205, 239, 246 Discrete, 16, 199, 246 Disinfectant, 199, 203 Dissociation, 35, 76, 178, 199 Dissociative Disorders, 199 Distal, 32, 184, 199, 218 Dopamine, 41, 52, 54, 199, 206, 226 Dorsum, 199, 206 Dose-dependent, 57, 199 Double-blind, 35, 52, 199, 200 Double-blinded, 35, 200 Doxorubicin, 82, 200 Drive, ii, vi, 3, 4, 9, 10, 45, 50, 58, 61, 113, 200, 217, 219 Drug Interactions, 200 Drug Resistance, 38, 200 Drug Tolerance, 200, 248 Duct, 188, 200, 203, 220

Duodenum, 50, 185, 200, 245 Dura mater, 200, 222, 229 Dyes, 180, 185, 200 Dystrophy, 56, 200 E Eclampsia, 200, 235 Edema, 44, 200, 235 Effector, 39, 49, 177, 193, 200 Effector cell, 39, 200 Efficacy, 13, 18, 23, 35, 200 Elective, 124, 200 Electrolysis, 181, 189, 200 Electrolyte, 200, 218, 234, 243 Electrons, 182, 189, 201, 217, 229, 238, 239, 245 Electrophoresis, 80, 201 Electrophysiological, 41, 201 Elementary Particles, 201, 226, 237 Embolus, 201, 214 Embryo, 177, 180, 186, 201, 214, 235, 244 Embryo Transfer, 201, 235 Emulsions, 186, 201 Encapsulated, 39, 132, 201 Encephalitis, 106, 189, 201 Encephalitis, Viral, 201 Encephalomyocarditis Virus, 201, 222 Endemic, 38, 201, 221, 244 Endocrine System, 201, 226 Endocytosis, 23, 99, 129, 201 Endogenous, 23, 24, 32, 48, 199, 202, 208, 229, 248 Endoscopy, 166, 202 Endothelial cell, 87, 187, 202, 247 Endothelium, 32, 34, 98, 202, 227, 233 Endothelium, Lymphatic, 202 Endothelium, Vascular, 202 Endothelium-derived, 202, 227 Endotoxins, 194, 202 End-stage renal, 8, 34, 110, 192, 202 Enema, 202 Enhancer, 32, 51, 54, 63, 202, 240 Enterocytes, 56, 202 Entorhinal Cortex, 202, 211 Environmental Health, 17, 156, 158, 202 Enzymatic, 44, 60, 135, 180, 188, 189, 194, 202, 211, 240 Eosinophils, 202, 209, 219 Epidemiologic Studies, 40, 202 Epidemiological, 31, 202 Epidermal, 202, 218, 222 Epidermis, 122, 196, 202, 203, 213, 217, 218, 235, 238

258

Ferritin

Epigastric, 203, 229 Epinephrine, 18, 178, 199, 203, 226, 227, 249 Epithelial, 13, 20, 32, 46, 50, 59, 65, 90, 96, 100, 124, 133, 177, 185, 198, 203, 209 Epithelial Cells, 13, 32, 46, 50, 59, 65, 90, 96, 124, 133, 203 Epithelium, 27, 50, 61, 99, 115, 184, 202, 203, 217 Epitope, 144, 203 Erythrocytes, 22, 26, 38, 44, 93, 139, 180, 181, 186, 187, 203, 211, 239, 242 Erythroleukemia, 65, 203 Erythropoiesis, 4, 6, 106, 110, 203 Erythropoietin, 4, 6, 7, 8, 9, 12, 23, 34, 83, 106, 110, 120, 122, 125, 203 Estradiol, 104, 203, 242 Estrogen, 203, 235 Ethanol, 114, 203 Ethnic Groups, 9, 11, 203 Eukaryotic Cells, 197, 203, 227, 228, 249 Excrete, 203, 218 Exhaustion, 203, 221 Exocrine, 203, 229 Exogenous, 22, 32, 46, 48, 202, 203, 208, 249 External-beam radiation, 203, 217, 238, 252 Extracellular, 16, 22, 31, 34, 36, 37, 79, 180, 183, 195, 201, 203, 204, 243, 246 Extracellular Matrix, 34, 195, 203, 204 Extracellular Space, 203, 204 Extrapyramidal, 199, 204 Extravascular, 22, 204 Eye Infections, 13, 177, 204 F Family Planning, 157, 204 Family Practice, 109, 163, 204 Fat, 9, 14, 69, 181, 185, 187, 189, 196, 201, 204, 219, 240, 241, 243 Fatigue, 3, 8, 10, 163, 204, 210 Fatty Acid Desaturases, 58, 204 Fatty Liver, 9, 91, 204 Febrile, 204, 221, 222 Feces, 204, 245 Fertilization in Vitro, 204, 235 Fetoprotein, 204 Fetus, 177, 179, 203, 204, 232, 235, 244, 250 Fibrinogen, 204, 232, 233, 236, 247 Fibroblasts, 65, 66, 76, 108, 204, 216 Fibrosis, 9, 42, 46, 56, 163, 204 Filariasis, 106, 204

Fish Products, 205, 242 Fixation, 205, 242 Flatus, 205, 206 Fluorescence, 27, 205 Fluorescent Antibody Technique, 205 Fluoroimmunoassay, 76, 205 Folate, 13, 27, 205 Fold, 15, 25, 26, 34, 53, 54, 56, 57, 134, 141, 205, 229 Folic Acid, 12, 110, 166, 205 Forearm, 186, 205 Fourth Ventricle, 192, 205 Free Radicals, 22, 28, 30, 36, 50, 51, 60, 137, 182, 199, 205 Fungi, 134, 186, 195, 204, 206, 209, 223, 250, 252 Fusaric Acid, 143, 144, 206 G Gallbladder, 177, 185, 206 Gamma-interferon, 206, 215 Ganglia, 36, 177, 184, 206, 226, 231, 245 Ganglion, 36, 57, 206, 228 Gas, 16, 132, 180, 188, 199, 205, 206, 212, 227, 240, 250 Gas exchange, 206, 240, 250 Gasoline, 17, 206 Gastric, 63, 66, 179, 206, 212, 230 Gastric Juices, 206, 230 Gastrin, 206, 212 Gastrointestinal, 3, 7, 11, 34, 162, 184, 187, 188, 203, 206, 221, 249 Gastrointestinal tract, 3, 11, 162, 184, 203, 206, 249 Gastroscopy, 166, 206 Gelatin, 206, 208, 247 Gene Expression, 16, 17, 27, 32, 38, 50, 54, 62, 65, 206, 207 Gene Frequency, 9, 206 Gene Therapy, 13, 42, 178, 207 Generator, 207, 246 Genetic Code, 207, 227, 236 Genetic Engineering, 186, 193, 207 Genetic Markers, 14, 207 Genetic testing, 4, 163, 165, 207 Genetic transcription, 207, 236, 248 Genetics, 16, 24, 72, 78, 86, 195, 207 Genotype, 16, 33, 40, 207, 231 Germ Cells, 207, 228, 243, 246 Gestation, 13, 48, 207, 232, 244 Gestational, 86, 87, 88, 96, 114, 207 Gland, 178, 207, 220, 229, 230, 232, 236, 242, 244, 247

259

Glioblastoma, 75, 100, 207 Glioblastoma multiforme, 100, 207 Globus Pallidus, 184, 207, 238 Glomerular, 89, 165, 208, 216, 218, 240 Glomerular Filtration Rate, 165, 208, 218 Glomerulus, 208, 218 Glucose, 5, 71, 96, 114, 121, 183, 186, 190, 198, 208, 210, 215 Glucose Intolerance, 71, 198, 208 Glucose tolerance, 96, 114, 208 Glucose Tolerance Test, 208 Glucose-6-Phosphatase, 121, 208 Glucuronic Acid, 208, 250 Glucuronides, 42, 208 Glucuronosyltransferase, 29, 208 Glutamate, 49, 183, 208 Glutamic Acid, 205, 208, 211, 226, 236 Glutathione Peroxidase, 28, 30, 208, 242 Glycine, 129, 180, 185, 208, 226, 242 Glycols, 208, 212 Glycoprotein, 13, 29, 203, 204, 209, 224, 242, 247, 249 Glycosidic, 42, 209 Goblet Cells, 202, 209 Goiter, 107, 209 Gonads, 209, 213 Governing Board, 209, 234 Grade, 207, 209 Gram-negative, 209, 237 Granule, 198, 209, 241 Granulocytes, 209, 219, 252 Grasses, 205, 209 Gravidity, 209, 230 Growth factors, 37, 209, 223 Guanine, 89, 209, 237 Guanylate Cyclase, 209, 227 H Habitual, 191, 209 Haematological, 76, 110, 115, 209 Haematology, 70, 84, 87, 88, 103, 108, 110, 121, 209 Haematoma, 209 Haemodialysis, 71, 209 Haemorrhage, 72, 177, 209 Haploid, 209, 232 Haplotypes, 29, 210 Haptens, 178, 210, 238 Heart attack, 189, 210 Heart failure, 3, 137, 162, 210 Heart Transplantation, 42, 210 Hematocrit, 7, 8, 9, 164, 165, 186, 210

Hematology, 41, 59, 79, 82, 92, 94, 103, 126, 210, 231 Hematopoietic Stem Cells, 60, 210 Hemerythrin, 58, 210 Hemin, 23, 63, 65, 210 Hemodialysis, 6, 9, 34, 69, 73, 80, 105, 122, 125, 164, 165, 198, 199, 210, 218 Hemodialysis Solutions, 35, 210 Hemoglobin A, 70, 88, 106, 165, 185, 191, 210, 234 Hemoglobin C, 6, 7, 126, 181, 211 Hemoglobin H, 49, 211 Hemoglobin M, 211 Hemoglobinopathies, 60, 207, 211 Hemolytic, 211, 247 Hemorrhage, 22, 31, 44, 50, 186, 211, 238, 245 Hemosiderin, 43, 79, 94, 97, 211 Hepatic, 6, 8, 10, 11, 39, 42, 54, 56, 88, 116, 120, 136, 179, 208, 211, 234 Hepatitis, 6, 11, 30, 53, 56, 88, 91, 103, 116, 163, 211, 251 Hepatitis A, 164, 211 Hepatobiliary, 28, 211 Hepatocellular, 30, 101, 102, 109, 211 Hepatocellular carcinoma, 30, 102, 109, 211 Hepatocyte, 9, 211 Hepatoma, 68, 86, 91, 211 Hepatotoxic, 11, 211 Hepatovirus, 211 Hereditary, 3, 9, 11, 29, 40, 43, 46, 53, 56, 80, 83, 85, 99, 163, 165, 211, 226, 247 Heredity, 206, 207, 211 Heterogeneity, 28, 31, 138, 178, 211 Heterotrophic, 206, 211 Hippocampus, 125, 198, 211, 245 Histamine, 180, 211, 212 Histidine, 58, 212 Homeostasis, 14, 17, 21, 25, 29, 33, 45, 46, 51, 54, 56, 60, 65, 85, 212 Homodimer, 70, 212 Homogeneous, 135, 195, 212 Homologous, 179, 186, 207, 212, 242 Homozygote, 98, 212 Hormonal, 92, 183, 212, 251 Hormone therapy, 178, 212 Hybrid, 69, 132, 193, 212 Hybridomas, 212, 216 Hydrogen Peroxide, 35, 43, 49, 54, 208, 212, 219, 245 Hydrolysis, 35, 58, 212, 217, 233, 236

260

Ferritin

Hydrophobic, 212, 219 Hydroxides, 212 Hydroxyl Radical, 20, 51, 54, 121, 212 Hydroxylation, 44, 212 Hydroxyproline, 180, 193, 212 Hydroxyurea, 29, 212 Hyperaemia, 195, 213 Hyperoxia, 32, 213 Hyperpigmentation, 4, 10, 213 Hypersensitivity, 179, 198, 213, 240, 242 Hypertension, 18, 90, 189, 190, 213, 235 Hyperthermia, 28, 213 Hypertrophy, 16, 213 Hypogonadism, 10, 213 Hypothalamus, 123, 184, 199, 213, 232 Hypoxanthine, 213, 252 Hypoxia, 16, 54, 81, 181, 213, 247 Hypoxic, 17, 213 I Idiopathic, 72, 213 Imaging procedures, 213, 248 Immune response, 49, 59, 178, 182, 210, 213, 214, 221, 242, 250, 251 Immune system, 34, 185, 200, 213, 214, 220, 221, 231, 252 Immunization, 213, 242 Immunoassay, 93, 96, 135, 213 Immunodeficiency, 138, 213 Immunoglobulin, 67, 181, 205, 213, 224 Immunohistochemistry, 84, 213 Immunologic, 59, 162, 191, 213, 221, 239 Immunology, 51, 59, 89, 98, 115, 178, 214 Immunosuppression, 138, 214, 220 Immunosuppressive, 67, 101, 138, 214 Immunosuppressive Agents, 214 Impairment, 13, 183, 204, 214 Implant radiation, 214, 216, 217, 238, 252 Implantation, 194, 214 Impotence, 11, 137, 162, 214 Incision, 214, 216 Incubated, 139, 214 Incubation, 97, 139, 214 Induction, 22, 25, 30, 31, 32, 45, 51, 62, 65, 91, 115, 124, 135, 141, 214, 235, 238 Infancy, 13, 41, 100, 109, 214, 241 Infarction, 17, 78, 190, 214, 216 Infection, 4, 10, 13, 30, 34, 60, 87, 88, 91, 103, 105, 106, 138, 163, 185, 191, 192, 201, 204, 213, 214, 218, 220, 240, 245, 252 Infiltration, 32, 215 Inflammatory bowel disease, 4, 166, 215 Informed Consent, 29, 215

Infusion, 4, 7, 35, 52, 215, 248 Ingestion, 23, 30, 208, 215, 233, 246 Inhalation, 215, 233 Initiation, 7, 215, 236, 248 Inorganic, 86, 120, 122, 132, 182, 212, 215, 220, 225 Inotropic, 199, 215 Insecticides, 215, 252 Insight, 21, 22, 44, 52, 58, 215 Insulin, 69, 71, 73, 91, 208, 215, 217, 249 Insulin-dependent diabetes mellitus, 215 Intercellular Adhesion Molecule-1, 14, 215 Interferon, 6, 56, 66, 103, 107, 116, 163, 206, 215 Interferon-alpha, 215 Interleukin-1, 53, 100, 215 Interleukin-2, 216 Interleukin-6, 14, 216 Intermittent, 216, 231, 234 Internal radiation, 216, 217, 238, 252 Interstitial, 187, 204, 216, 217, 240, 252 Intestinal, 27, 56, 100, 133, 189, 202, 208, 216, 251 Intestine, 185, 187, 193, 216, 218 Intracellular Membranes, 26, 216 Intracranial Aneurysm, 190, 216 Intracranial Arteriosclerosis, 190, 216 Intramuscular, 116, 216, 230 Intraocular, 33, 216 Intraocular pressure, 33, 216 Intrathecal, 32, 216 Intravenous, 7, 10, 34, 52, 105, 122, 125, 215, 216, 230 Intrinsic, 19, 133, 178, 184, 216 Introns, 216, 237 Inulin, 208, 216 Invasive, 43, 46, 99, 136, 216, 221, 229 Invertebrates, 134, 217, 220 Iodine, 107, 139, 217 Ion Channels, 183, 217 Ion Transport, 42, 217 Ions, 26, 43, 132, 142, 177, 187, 191, 199, 200, 212, 217, 236 Iris, 196, 217, 237 Irradiation, 59, 217, 252 Ischemia, 30, 50, 183, 217 Islet, 217, 226 Isozymes, 50, 217 K Kallidin, 187, 217 Karyotype, 180, 217 Kb, 156, 217

261

Keratin, 217, 218 Keratinocytes, 76, 218 Kidney Cortex, 218, 223 Kidney Disease, 4, 7, 8, 80, 156, 164, 165, 218 Kidney Failure, 165, 202, 218 Kidney Failure, Acute, 218 Kidney Failure, Chronic, 218 Kidney stone, 218, 250 Kinetic, 27, 43, 58, 218 L Labile, 60, 95, 100, 193, 218 Lactate Dehydrogenase, 11, 218 Lactation, 218, 235 Lag, 35, 218 Lamivudine, 105, 218 Large Intestine, 193, 216, 218, 239, 243 Lens, 16, 58, 88, 90, 182, 189, 218, 251 Leprosy, 90, 218 Lesion, 219 Lethal, 18, 184, 219 Leucocyte, 179, 219 Leukemia, 19, 68, 86, 139, 192, 200, 207, 219, 235 Leukocytes, 64, 102, 184, 186, 187, 191, 202, 209, 215, 219, 249 Libido, 3, 219 Life cycle, 206, 219 Ligament, 219, 236 Ligands, 219, 245 Linear Models, 40, 219 Linkage, 207, 219 Lipid, 49, 60, 82, 91, 93, 122, 182, 188, 201, 215, 219, 229 Lipid Peroxidation, 49, 91, 122, 219, 229 Lipophilic, 39, 219 Lipoprotein, 94, 209, 219, 220, 251 Liposome, 39, 219 Liver cancer, 10, 179, 219 Liver scan, 219, 241 Localization, 20, 55, 62, 67, 213, 219 Localized, 33, 46, 201, 205, 209, 214, 219, 232 Locomotion, 220, 232 Locomotor, 32, 220 Longitudinal Studies, 15, 33, 196, 220 Loop, 21, 51, 67, 94, 220 Low-density lipoprotein, 219, 220 Lumbar, 36, 220 Luminescence, 82, 220 Lupus, 220, 246 Lutein Cells, 220, 235

Lymph, 191, 202, 220 Lymph node, 191, 220 Lymphatic, 106, 202, 214, 220, 233, 243, 244, 247 Lymphatic system, 220, 243, 244, 247 Lymphocyte, 64, 95, 182, 214, 220, 221, 222 Lymphocyte Depletion, 214, 220 Lymphoid, 80, 86, 181, 219, 220 Lymphokines, 220, 221 Lymphoma, 86, 102, 220 Lysine, 211, 220, 235 Lysosome, 45, 221 M Macroglia, 221, 223 Macrophage, 32, 38, 65, 68, 83, 88, 216, 221 Macrophage Activation, 88, 221 Macula, 221 Macula Lutea, 221 Macular Degeneration, 125, 221 Magnetic Resonance Imaging, 9, 79, 121, 123, 136, 166, 221, 241 Major Histocompatibility Complex, 210, 221 Malaria, 38, 115, 221 Malaria, Falciparum, 221 Malaria, Vivax, 221 Malignancy, 106, 221 Malignant, 60, 109, 138, 177, 182, 207, 219, 221, 225, 238 Malignant ascites, 109, 221 Malnutrition, 179, 183, 210, 221 Manifest, 41, 184, 221 Meat, 165, 222, 241 Mediate, 31, 199, 222 Mediator, 60, 216, 222 Medical Staff, 200, 222 MEDLINE, 157, 222 Medullary, 222, 226, 238 Megaloblastic, 205, 222 Melanocytes, 213, 222 Melanoma, 71, 222 Membrane, 13, 24, 26, 46, 58, 180, 183, 190, 192, 193, 194, 195, 198, 199, 201, 203, 209, 217, 222, 225, 228, 231, 233, 234, 240, 243, 244, 249, 251 Memory, 11, 41, 222 Mengovirus, 107, 222 Meninges, 190, 200, 222 Meningitis, 72, 79, 222 Menopause, 222, 234 Menstruation, 8, 92, 198, 222

262

Ferritin

Mental, iv, 12, 76, 156, 158, 190, 191, 199, 204, 222, 237, 250 Mental Health, iv, 12, 156, 158, 222, 237 Mental Processes, 199, 222, 237 Mentors, 59, 61, 222 Mercury, 20, 222 Metabolic disorder, 162, 223 Metabolite, 199, 223 Metallothionein, 141, 223 Metamorphosis, 184, 223 Methionine, 199, 223, 245 MI, 39, 74, 176, 223 Microbe, 223, 248 Microbiology, 51, 81, 98, 106, 183, 223 Microglia, 31, 84, 183, 223 Microgram, 205, 223 Microorganism, 193, 223, 230, 251 Microsomal, 121, 223 Microspheres, 140, 223 Middle Cerebral Artery, 44, 223 Migration, 215, 221, 223 Milliliter, 7, 163, 223 Mineralization, 26, 43, 49, 96, 223 Mitochondria, 36, 224, 228 Mitochondrial Swelling, 224, 225 Mitosis, 182, 224 Mitotic, 224, 251 Mobility, 19, 31, 224 Mobilization, 64, 70, 107, 116, 124, 224 Modeling, 58, 224 Modification, 19, 180, 207, 224, 238, 252 Modulator, 33, 224 Monitor, 42, 43, 71, 164, 165, 166, 196, 224, 227 Monoclonal, 97, 137, 138, 144, 212, 217, 224, 238, 252 Monoclonal antibodies, 137, 138, 144, 224 Monocyte, 68, 224 Mononuclear, 31, 66, 85, 224, 249 Morphological, 34, 178, 201, 222, 224 Morphology, 189, 209, 210, 221, 224 Mucinous, 206, 224 Mucins, 202, 209, 224 Mucolytic, 187, 224 Mucosa, 202, 220, 225, 235 Mucositis, 225, 247 Mucus, 224, 225, 249 Multicenter study, 55, 225 Muscular Dystrophies, 200, 225 Mutagenesis, 21, 30, 36, 38, 225 Mutagenic, 20, 179, 225 Mutagens, 225

Myelodysplastic syndrome, 103, 225, 243 Myelogenous, 225 Myelosuppression, 65, 225 Myocardial infarction, 11, 39, 81, 85, 87, 196, 223, 225 Myocardial Ischemia, 16, 225 Myocardium, 223, 225 Myotonic Dystrophy, 100, 225 N NCI, 1, 155, 192, 225 Necrosis, 14, 182, 204, 207, 214, 223, 225, 242 Neonatal, 81, 94, 106, 111, 225 Neoplasia, 60, 225, 226 Neoplasm, 225, 226, 249 Neoplastic, 70, 212, 220, 226 Neostriatum, 226, 238 Nephropathy, 218, 226 Nerve, 36, 178, 181, 183, 184, 191, 198, 206, 222, 226, 228, 240, 244, 249 Nerve Growth Factor, 36, 226 Nervous System, 184, 190, 222, 226, 230, 245, 246 Neural, 74, 78, 92, 126, 180, 204, 223, 226 Neuroblastoma, 18, 69, 226 Neurodegenerative Diseases, 17, 74, 184, 226 Neuroendocrine, 18, 226 Neuroendocrine tumor, 18, 226 Neurologic, 44, 207, 226 Neuronal, 17, 23, 36, 49, 54, 78, 81, 114, 226, 230 Neurons, 22, 36, 49, 54, 198, 206, 226, 245, 246 Neurotoxicity, 17, 97, 226 Neurotransmitter, 177, 180, 187, 199, 208, 212, 217, 226, 227 Neutrons, 179, 217, 226, 238 Neutrophil, 17, 98, 215, 226, 227 Neutrophil Infiltration, 17, 227 Nitric Oxide, 4, 28, 38, 65, 81, 227 Nitrogen, 65, 107, 116, 165, 205, 218, 227 Norepinephrine, 178, 199, 206, 226, 227 Nuclear, 20, 45, 54, 61, 63, 65, 79, 166, 184, 195, 201, 203, 206, 207, 225, 227, 237, 238 Nuclear Medicine, 166, 227 Nuclei, 57, 61, 115, 121, 179, 195, 201, 207, 216, 221, 224, 226, 227, 228, 237 Nucleic acid, 135, 143, 144, 188, 207, 213, 225, 227, 238, 241, 251, 252 Nucleocapsid, 134, 227, 251 Nucleocapsid Proteins, 134, 227

263

Nucleolus, 227, 241 Nucleus, 21, 61, 182, 184, 192, 197, 198, 201, 202, 203, 207, 224, 226, 227, 237, 238, 245, 246 O Observational study, 9, 227 Occupational Exposure, 17, 227 Ocular, 13, 20, 228 Oliguria, 218, 228 Oncogenic, 26, 228 Opacity, 189, 198, 228 Operon, 228, 236, 240 Ophthalmology, 16, 205, 228 Opsin, 228, 240 Optic Chiasm, 213, 228 Optic Nerve, 228, 229, 240, 241 Organ Transplantation, 43, 228 Organelles, 190, 192, 197, 222, 228, 233 Osmotic, 178, 224, 228, 242 Osteoarthritis, 4, 228 Osteoclasts, 184, 228 Ovary, 196, 203, 209, 228 Overexpress, 23, 49, 228 Ovum, 196, 198, 207, 219, 228, 235, 252 Oxaloacetate, 183, 228 Oxidants, 25, 28, 32, 36, 38, 85, 228 Oxidation-Reduction, 229 Oxidative Phosphorylation, 36, 229 Oxides, 47, 100, 229 Oximetry, 36, 229 Oxygenase, 16, 22, 31, 32, 49, 66, 69, 70, 87, 229 Oxygenation, 15, 229 P Pachymeningitis, 222, 229 Palliative, 229, 247 Pancreas, 29, 177, 186, 210, 215, 217, 229, 249 Parasite, 38, 229 Parasitic, 38, 229, 241 Parathyroid, 164, 229, 230, 241, 246 Parathyroid Glands, 229, 230, 241 Parathyroid hormone, 164, 230 Parenteral, 8, 34, 91, 230 Parity, 92, 230 Particle, 219, 230, 248 Parturition, 230, 235 Pathogen, 66, 214, 230, 237 Pathogenesis, 12, 14, 22, 32, 230 Pathologic, 16, 47, 55, 182, 186, 196, 213, 230 Pathologic Processes, 182, 230

Pathologies, 27, 114, 230 Patient Education, 162, 170, 172, 176, 230 Patient Selection, 4, 230 Pelvic, 230, 236 Pelvis, 218, 220, 230, 250 Pepsin, 230 Peptic, 133, 230 Peptide, 47, 53, 57, 59, 142, 180, 217, 230, 233, 235, 236 Perception, 195, 230 Perfusion, 213, 230 Peripheral blood, 31, 138, 215, 230, 235 Peripheral Nerves, 219, 230 Peripheral Nervous System, 147, 226, 230 Peritoneal, 165, 183, 198, 231 Peritoneal Cavity, 183, 231 Peritoneal Dialysis, 165, 198, 231 Peritoneum, 231 Perivascular, 223, 231 Peroxide, 36, 54, 231 Petechiae, 209, 231 Petroleum, 206, 231 PH, 57, 65, 68, 74, 120, 231 Phagocyte, 229, 231 Phagocytosis, 223, 231 Pharmacologic, 181, 231, 248 Phenotype, 25, 29, 33, 42, 194, 231 Phlebotomy, 10, 11, 89, 163, 231 Phospholipids, 204, 219, 231 Phosphorus, 164, 165, 188, 230, 231, 232 Phosphorylated, 37, 193, 232 Phosphorylation, 37, 232 Photodynamic therapy, 28, 232 Photosensitivity, 232, 234 Physician Assistants, 11, 232 Physiologic, 18, 45, 178, 186, 216, 222, 232, 239 Physiology, 13, 51, 59, 75, 96, 109, 120, 189, 201, 210, 232 Pigment, 185, 222, 232 Pigmentation, 8, 213, 232 Pilot study, 47, 232 Pituitary Gland, 123, 232, 242 Placenta, 101, 137, 203, 232, 235 Plants, 26, 64, 107, 134, 142, 143, 144, 187, 188, 191, 208, 216, 224, 227, 232, 237, 248, 249 Plasma cells, 181, 232 Plasma protein, 178, 202, 232, 236, 242 Plasmin, 232, 233 Plasminogen, 29, 232, 233 Plasminogen Activators, 232, 233

264

Ferritin

Plasticity, 211, 233 Plastids, 63, 228, 233 Platelet Aggregation, 180, 227, 233 Platelets, 225, 227, 233, 247 Platinum, 220, 233 Plexus, 17, 233 Pneumoconiosis, 91, 110, 233 Pneumonia, 196, 233 Point Mutation, 92, 233 Poisoning, 34, 191, 223, 233 Polymerase, 233, 236, 240 Polymers, 94, 233, 236 Polymorphism, 87, 233 Polypeptide, 92, 99, 105, 134, 177, 180, 193, 195, 204, 232, 233, 235, 247, 252 Polyposis, 193, 233 Polysaccharide, 182, 190, 233, 250 Porphyria, 163, 231, 234 Porphyria Cutanea Tarda, 163, 231, 234 Porphyria, Hepatic, 234 Porphyrins, 234 Posterior, 180, 183, 192, 199, 217, 229, 234, 241 Postmenopausal, 5, 82, 92, 234 Postnatal, 234, 244 Post-translational, 181, 234, 242 Potassium, 164, 165, 234 Potentiates, 215, 234 Practice Guidelines, 158, 234 Precancerous, 191, 234 Precipitating Factors, 189, 234 Precipitation, 94, 132, 234 Preclinical, 15, 234 Precursor, 53, 58, 185, 199, 200, 202, 227, 232, 235, 236, 249, 251 Preeclampsia, 98, 235 Pregnancy Outcome, 13, 48, 115, 235 Preleukemia, 225, 235, 243 Prenatal, 13, 201, 235 Prenatal Care, 13, 235 Prevalence, 9, 15, 29, 40, 64, 71, 89, 91, 235 Prickle, 218, 235 Primary endpoint, 57, 235 Probe, 63, 235 Procollagen, 57, 235 Proctoscopy, 166, 235 Progesterone, 104, 235, 244 Progression, 24, 30, 50, 59, 138, 181, 235 Progressive, 8, 56, 135, 192, 200, 218, 225, 226, 228, 235, 239, 249 Projection, 43, 227, 228, 235, 239 Prolactin, 104, 235

Proline, 193, 212, 235, 236 Promoter, 26, 30, 32, 69, 141, 236 Promotor, 42, 236, 240 Prone, 54, 236 Prophylaxis, 236, 240, 250 Prospective study, 9, 48, 236 Prostate, 28, 106, 186, 236, 249 Protease, 45, 236 Protein C, 43, 137, 139, 178, 180, 182, 184, 193, 210, 217, 219, 236, 249, 251 Protein S, 22, 26, 54, 74, 82, 107, 132, 138, 141, 142, 186, 195, 207, 236, 241 Protein Subunits, 26, 132, 236 Protein Synthesis Inhibitors, 82, 236 Proteinuria, 235, 236 Proteolytic, 179, 194, 204, 232, 233, 236 Prothrombin, 11, 29, 162, 236, 247 Prothrombin Time, 162, 236 Protocol, 7, 29, 237 Protons, 42, 142, 179, 212, 237, 238 Protozoa, 186, 195, 223, 237, 250 Protozoan, 221, 237 Pseudogenes, 86, 237 Pseudomonas, 120, 237 Pseudomonas putida, 120, 237 Psychic, 219, 222, 237, 242 Psychology, 199, 237 Psychomotor, 76, 237 Public Health, 12, 13, 14, 20, 30, 40, 56, 158, 237 Public Policy, 157, 237 Publishing, 3, 62, 237 Pulmonary, 16, 140, 186, 187, 218, 237, 250 Pulmonary Artery, 186, 237, 251 Pulmonary Edema, 140, 218, 237 Pulmonary hypertension, 16, 237 Pulse, 43, 224, 229, 237 Pupil, 196, 199, 237 Purines, 27, 237, 242, 252 Purpura, 209, 238 Putamen, 23, 184, 226, 238 Pyrimidines, 238, 242 Q Quality of Life, 7, 10, 52, 56, 238 Quaternary, 134, 238 Quinones, 54, 238 R Radiation, 18, 24, 28, 108, 124, 178, 201, 203, 205, 213, 214, 216, 217, 238, 241, 252 Radiation therapy, 178, 203, 216, 217, 238, 252

265

Radioactive, 61, 103, 187, 212, 214, 216, 217, 219, 224, 227, 228, 238, 241, 249, 252 Radioactivity, 133, 139, 238 Radiography, 166, 238 Radioimmunoassay, 205, 238 Radioisotope, 238, 248 Radiolabeled, 14, 133, 217, 238, 252 Radiological, 9, 29, 42, 238 Radiology, 18, 28, 46, 97, 227, 238 Radiotherapy, 187, 217, 238, 252 Random Allocation, 239 Randomization, 13, 239 Randomized, 5, 13, 31, 35, 52, 56, 200, 239 Reactive Oxygen Species, 5, 23, 25, 32, 43, 124, 239 Recombinant, 6, 7, 12, 23, 35, 36, 38, 43, 65, 74, 85, 104, 122, 141, 143, 239, 250 Recombinant Proteins, 141, 239 Recombination, 195, 207, 239 Rectum, 182, 184, 187, 193, 205, 206, 215, 218, 235, 236, 239 Recurrence, 191, 239 Red blood cells, 7, 9, 203, 211, 225, 229, 234, 239 Red Nucleus, 183, 239 Reductase, 29, 48, 58, 239 Refer, 1, 193, 205, 206, 219, 220, 221, 226, 239, 248 Refraction, 239, 244 Refractory, 20, 43, 103, 239 Regimen, 200, 239 Reliability, 133, 239 Renal failure, 12, 90, 149, 211, 239 Repressor, 63, 68, 228, 240 Reproduction Techniques, 235, 240 Respiration, 188, 224, 240 Respiratory distress syndrome, 32, 73, 140, 240 Respiratory failure, 32, 240 Response Elements, 21, 240 Retina, 57, 192, 218, 221, 228, 240, 241, 251 Retinal, 57, 195, 228, 240 Retinoids, 240 Retinol, 106, 240 Retrospective, 8, 240 Retroviral vector, 207, 240 Rheumatism, 83, 240 Rheumatoid, 83, 192, 229, 240 Rheumatoid arthritis, 83, 192, 240 Rhodopsin, 228, 240 Ribavirin, 6, 103, 241 Riboflavin, 13, 241

Ribonucleoside Diphosphate Reductase, 213, 241 Ribosome, 53, 241, 249 Rickets, 241, 251 Rickettsiae, 241, 250 Risk factor, 5, 11, 29, 40, 74, 88, 104, 163, 164, 189, 202, 236, 241 Risk patient, 140, 241 Rod, 237, 241 S Saline, 187, 241 Saturated fat, 69, 204, 241 Scans, 72, 166, 241 Sclera, 192, 195, 241 Screening, 4, 9, 11, 30, 46, 82, 105, 163, 192, 242 Seafood, 165, 242 Secretion, 212, 215, 218, 223, 224, 225, 242 Sediment, 242 Sedimentation, 166, 190, 242 Segregation, 184, 239, 242 Seizures, 207, 242 Selenium, 30, 111, 242 Sella Turcica, 199, 232, 242 Semen, 236, 242 Sensitization, 98, 242 Sepsis, 84, 140, 242 Sequencing, 36, 242 Sequester, 21, 43, 134, 191, 242 Serine, 27, 87, 177, 242 Serologic, 213, 242 Serous, 183, 202, 242 Serum, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 23, 29, 31, 33, 35, 40, 46, 48, 52, 56, 64, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 103, 104, 105, 106, 107, 108, 109, 110, 111, 114, 115, 116, 121, 123, 124, 125, 126, 135, 138, 139, 140, 142, 147, 150, 162, 163, 164, 165, 178, 180, 185, 193, 218, 220, 238, 242, 249 Serum Albumin, 165, 238, 242 Sex Hormone-Binding Globulin, 104, 242 Shock, 28, 115, 243, 249 Side effect, 7, 8, 178, 185, 225, 243, 248, 252 Siderosis, 163, 243 Sigmoid, 243 Sigmoidoscopy, 166, 243 Silicon, 143, 243 Silicon Dioxide, 243 Skull, 243, 246

266

Ferritin

Small Bowel Enema, 166, 243 Small intestine, 192, 200, 212, 216, 243 Smoldering leukemia, 225, 243 Smooth muscle, 16, 180, 188, 212, 243 Social Environment, 238, 243 Sodium, 6, 42, 165, 243 Soft tissue, 187, 243 Solid tumor, 200, 243 Solvent, 203, 228, 243 Soma, 57, 243 Specialist, 167, 199, 243 Specificity, 38, 70, 178, 235, 244 Spectrophotometry, 103, 244 Spectroscopic, 43, 44, 49, 58, 244 Spectrum, 60, 140, 197, 223, 244 Sperm, 192, 244 Spike, 57, 244 Spinal cord, 31, 101, 183, 190, 192, 200, 206, 216, 222, 226, 229, 230, 244, 245 Spinous, 203, 218, 244 Spleen, 46, 70, 137, 220, 244 Splenectomy, 39, 244 Spontaneous Abortion, 235, 244 Sporadic, 226, 234, 244 Stabilization, 141, 244 Staging, 241, 244 Steady state, 37, 244 Steatosis, 9, 204, 244 Stem Cells, 60, 136, 203, 244 Sterile, 229, 244 Steroid, 185, 196, 208, 244 Stillbirth, 235, 244 Stimulus, 200, 217, 218, 244, 247 Stomach, 177, 206, 208, 212, 230, 231, 243, 244, 245 Stool, 23, 193, 218, 245 Strand, 51, 233, 245 Stroke, 29, 30, 44, 49, 71, 78, 94, 105, 156, 189, 245 Stroma, 217, 243, 245 Subacute, 214, 245 Subarachnoid, 50, 72, 205, 245 Subclinical, 214, 242, 245 Subcutaneous, 15, 200, 230, 245 Subiculum, 211, 245 Subspecies, 243, 245 Substrate, 26, 135, 143, 245 Sulfur, 38, 218, 223, 245 Superoxide, 28, 43, 64, 67, 122, 245 Superoxide Dismutase, 28, 122, 245 Supplementation, 5, 6, 7, 8, 34, 41, 115, 120, 121, 122, 123, 124, 125, 126, 245

Surface Plasmon Resonance, 115, 245 Sympathetic Nervous System, 18, 184, 245, 246 Sympathomimetic, 199, 203, 227, 246 Symphysis, 191, 236, 246 Synapse, 57, 178, 246, 249 Synchrotron, 47, 246 Synergistic, 235, 246 Systemic, 11, 17, 32, 50, 78, 102, 107, 186, 192, 203, 214, 217, 238, 246, 252 Systemic disease, 11, 246 Systemic lupus erythematosus, 102, 107, 192, 246 Systemic therapy, 192, 246 Systolic, 11, 15, 213, 246 Systolic blood pressure, 11, 246 T Telencephalon, 184, 190, 246 Temporal, 39, 211, 221, 246 Tendon, 206, 246 Testis, 90, 181, 203, 209, 246 Testosterone, 239, 242, 246 Tetany, 229, 246 Thalamic, 183, 246 Thalamic Diseases, 183, 246 Thalassemia, 15, 28, 46, 55, 59, 77, 94, 123, 185, 247 Theophylline, 238, 247 Therapeutics, 4, 6, 125, 142, 247 Thermal, 199, 226, 247 Thorax, 220, 247 Threonine, 119, 242, 247 Threshold, 46, 198, 213, 247 Thrombin, 44, 204, 233, 236, 247 Thrombolytic, 233, 247 Thrombomodulin, 236, 247 Thromboplastin, 236, 247 Thrombosis, 29, 216, 236, 245, 247 Thrombus, 196, 214, 225, 233, 247 Thymidine, 87, 247 Thymus, 213, 220, 247 Thyroid, 107, 209, 217, 226, 229, 230, 247, 249 Thyroid Gland, 209, 229, 230, 247 Thyroxine, 21, 178, 247 Tolerance, 177, 208, 248 Tomography, 18, 248 Topical, 183, 203, 212, 248 Torsion, 214, 248 Toxaemia, 235, 248 Toxicity, 15, 22, 28, 34, 44, 49, 50, 51, 55, 124, 141, 200, 223, 248

267

Toxicology, 50, 101, 114, 119, 123, 124, 158, 248 Toxin, 30, 34, 55, 61, 248 Trace element, 115, 166, 187, 243, 248 Tracer, 18, 89, 248 Trachea, 187, 247, 248 Transcriptase, 218, 248, 252 Transcription Factors, 51, 240, 248 Transduction, 32, 60, 248 Transfection, 38, 42, 70, 186, 207, 248 Transferases, 22, 248 Transfusion, 15, 43, 55, 78, 94, 115, 123, 125, 248 Translation, 21, 30, 37, 38, 53, 64, 65, 68, 141, 180, 237, 248 Translational, 21, 38, 53, 60, 62, 63, 64, 65, 66, 68, 103, 141, 249 Translocation, 61, 115, 249 Transmitter, 177, 183, 199, 217, 222, 227, 249 Transplantation, 71, 87, 192, 201, 213, 218, 220, 221, 249 Trauma, 140, 184, 190, 225, 247, 249 Tropism, 13, 249 Tuberculosis, 82, 220, 249 Tumor marker, 75, 97, 186, 249 Tumor Necrosis Factor, 14, 25, 65, 249 Tumorigenic, 90, 249 Tumour, 206, 249 Type 2 diabetes, 5, 14, 73, 104, 249 Tyrosine, 199, 249 U Ubiquitin, 24, 249 Ulcerative colitis, 4, 215, 249 Ultrasonography, 9, 249 Univalent, 212, 229, 249 Uracil, 27, 238, 249, 250 Urea, 10, 166, 187, 249, 250 Uremia, 218, 239, 250 Urethra, 236, 250 Uric, 5, 93, 238, 250 Uridine Diphosphate, 208, 250 Uridine Diphosphate Glucuronic Acid, 208, 250 Urinary, 107, 228, 250, 252 Urinate, 250, 252 Urine, 13, 165, 186, 196, 208, 218, 228, 236, 241, 250 Uroporphyrinogen Decarboxylase, 234, 250 Uterus, 177, 180, 191, 196, 198, 222, 235, 250

V Vaccination, 164, 250 Vaccines, 142, 179, 250, 251 Vacuole, 25, 250 Vagina, 191, 222, 250 Vascular, 17, 32, 73, 87, 192, 202, 214, 216, 227, 232, 233, 247, 250 Vasoconstriction, 16, 203, 250 Vasodilator, 187, 199, 212, 250 Vector, 37, 42, 248, 250 Vein, 183, 216, 227, 231, 250 Venous, 84, 183, 186, 236, 250 Venous blood, 84, 186, 250 Ventricle, 211, 213, 237, 246, 250, 251 Ventricular, 16, 251 Venules, 187, 188, 202, 251 Vertebrae, 244, 251 Vesicular, 25, 223, 251 Veterinary Medicine, 157, 251 Villous, 192, 251 Vinblastine, 121, 251 Vinca Alkaloids, 251 Viral, 11, 26, 31, 53, 60, 105, 143, 144, 163, 188, 201, 227, 228, 248, 249, 251, 252 Viral Core Proteins, 227, 251 Viral Hepatitis, 11, 105, 163, 251 Viral vector, 60, 251 Virion, 227, 251 Virulence, 14, 183, 248, 251 Vitamin D, 27, 241, 251 Vitreous, 218, 240, 251 Vitreous Body, 240, 251 Vitro, 17, 22, 24, 26, 32, 37, 38, 39, 47, 54, 63, 65, 67, 74, 80, 85, 86, 120, 124, 133, 139, 201, 207, 214, 251 Vivo, 13, 16, 17, 18, 22, 24, 25, 26, 32, 38, 39, 43, 54, 60, 65, 100, 120, 122, 136, 137, 207, 214, 220, 229, 252 Void, 165, 252 W White blood cell, 19, 181, 192, 214, 219, 220, 221, 224, 225, 226, 232, 252 Windpipe, 247, 252 Wound Healing, 32, 252 X Xanthine, 67, 252 Xanthine Oxidase, 67, 252 Xenobiotics, 25, 85, 124, 134, 252 Xenograft, 181, 252 X-ray, 21, 26, 36, 47, 58, 63, 183, 184, 189, 194, 205, 217, 227, 238, 241, 243, 252 X-ray therapy, 217, 252

268

Ferritin

Y Yeasts, 206, 231, 252 Yellow Fever, 60, 252

Z Zalcitabine, 218, 252 Zygote, 194, 195, 252 Zymogen, 236, 252