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

HEMOGLOBIN A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES J AMES N. ...

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HEMOGLOBIN A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

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., 1960Hemoglobin: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83977-8 1. Hemoglobin-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 hemoglobin. 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 HEMOGLOBIN ........................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Hemoglobin ................................................................................. 48 E-Journals: PubMed Central ..................................................................................................... 104 The National Library of Medicine: PubMed .............................................................................. 114 CHAPTER 2. NUTRITION AND HEMOGLOBIN................................................................................ 141 Overview.................................................................................................................................... 141 Finding Nutrition Studies on Hemoglobin................................................................................ 141 Federal Resources on Nutrition ................................................................................................. 143 Additional Web Resources ......................................................................................................... 143 CHAPTER 3. ALTERNATIVE MEDICINE AND HEMOGLOBIN ......................................................... 145 Overview.................................................................................................................................... 145 National Center for Complementary and Alternative Medicine................................................ 145 Additional Web Resources ......................................................................................................... 149 General References ..................................................................................................................... 150 CHAPTER 4. DISSERTATIONS ON HEMOGLOBIN ........................................................................... 151 Overview.................................................................................................................................... 151 Dissertations on Hemoglobin..................................................................................................... 151 Keeping Current ........................................................................................................................ 155 CHAPTER 5. CLINICAL TRIALS AND HEMOGLOBIN ...................................................................... 157 Overview.................................................................................................................................... 157 Recent Trials on Hemoglobin..................................................................................................... 157 Keeping Current on Clinical Trials ........................................................................................... 161 CHAPTER 6. PATENTS ON HEMOGLOBIN ...................................................................................... 163 Overview.................................................................................................................................... 163 Patents on Hemoglobin .............................................................................................................. 163 Patent Applications on Hemoglobin .......................................................................................... 195 Keeping Current ........................................................................................................................ 231 CHAPTER 7. BOOKS ON HEMOGLOBIN .......................................................................................... 233 Overview.................................................................................................................................... 233 Book Summaries: Federal Agencies............................................................................................ 233 Book Summaries: Online Booksellers......................................................................................... 239 The National Library of Medicine Book Index ........................................................................... 243 Chapters on Hemoglobin............................................................................................................ 244 CHAPTER 8. MULTIMEDIA ON HEMOGLOBIN ............................................................................... 261 Overview.................................................................................................................................... 261 Video Recordings ....................................................................................................................... 261 Bibliography: Multimedia on Hemoglobin................................................................................. 263 CHAPTER 9. PERIODICALS AND NEWS ON HEMOGLOBIN ............................................................ 265 Overview.................................................................................................................................... 265 News Services and Press Releases.............................................................................................. 265 Newsletter Articles .................................................................................................................... 267 Academic Periodicals covering Hemoglobin .............................................................................. 267 CHAPTER 10. RESEARCHING MEDICATIONS ................................................................................. 269 Overview.................................................................................................................................... 269 U.S. Pharmacopeia..................................................................................................................... 269 Commercial Databases ............................................................................................................... 270 Researching Orphan Drugs ....................................................................................................... 270 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 275

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Overview.................................................................................................................................... 275 NIH Guidelines.......................................................................................................................... 275 NIH Databases........................................................................................................................... 277 Other Commercial Databases..................................................................................................... 280 The Genome Project and Hemoglobin........................................................................................ 280 APPENDIX B. PATIENT RESOURCES ............................................................................................... 285 Overview.................................................................................................................................... 285 Patient Guideline Sources.......................................................................................................... 285 Finding Associations.................................................................................................................. 288 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 291 Overview.................................................................................................................................... 291 Preparation................................................................................................................................. 291 Finding a Local Medical Library................................................................................................ 291 Medical Libraries in the U.S. and Canada ................................................................................. 291 ONLINE GLOSSARIES................................................................................................................ 297 Online Dictionary Directories ................................................................................................... 300 HEMOGLOBIN DICTIONARY.................................................................................................. 303 INDEX .............................................................................................................................................. 399

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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 hemoglobin is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about hemoglobin, 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 hemoglobin, 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 hemoglobin. 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 hemoglobin, 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 hemoglobin. 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 HEMOGLOBIN Overview In this chapter, we will show you how to locate peer-reviewed references and studies on hemoglobin.

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

Secretion of GIP in Responders to Acarbose in Obese Type 2 (NIDDM) Patients Source: Journal of Diabetes and its Complications. 15(5): 245-249. September-October 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Acarbose (an oral hypoglycemic agent) has been shown to reduce postprandial (after a meal) hyperglycemia (high blood glucose) and to improve lipid (fats) parameters in people with diabetes via its inhibitory effects on intestinal alpha glucosidases. Response to acarbose may therefore be dependent upon gastric or pancreatic hormone function. To test this hypothesis, the authors of this study treated 27 Japanese patients with type 2 diabetes who were mildly obese with low dose acarbose

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(150 milligrams per day) for 3 months. The authors then performed a responder analysis to determine specific hormone responses that may be associated with a good response to acarbose. At the end of the treatment period, a total of 15 evaluable patients was grouped as responders (n = 6) and nonresponders (n = 9), based on an effective decrease in postprandial glucose levels (greater than 30 milligrams per day) and glycosylated hemoglobin (HbA1c, a measure of blood glucose levels over time) levels. There were no differences between the two groups in demographic variables or mean postprandial glucose levels at baseline. There was a small but significant increase in postprandial cholecystokinin (CCK) in responders, and fasting gastric inhibitory peptide (GIP) levels were significantly increased in responders and in all patients after treatment. Serum leptin levels were reduced by treatment in these mildly obese responders and this was associated with a significant decrease in body weight. These results suggest that treatment with low dose acarbose may reduce hyperglycemia in mild type 2 Japanese patients and may improve metabolic control by regulating hormones involved in glycemic control and digestive absorption. Acarbose may provide a safe adjunct to help treat insulin resistance in type 2 patients. 1 figure. 2 tables. 19 references. •

Hormone Replacement Therapy and Its Relationship to Lipid and Glucose Metabolism in Diabetic and Nondiabetic Postmenopausal Wome Source: Diabetes Care. 25(10): 1675-1680. October 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Among postmenopausal women, those with diabetes experience more cardiovascular diseases than those without diabetes. In this study, the authors examined the relationship of hormone replacement therapy (HRT) with indicators of lipid and glucose metabolism using a national sample of postmenopausal women with and without diabetes. The authors used data from the Third National Health and Nutrition Examination Survey, conducted from 1988 to 1994. A total of 2,786 postmenopausal women aged 40 to 74 years participated in an oral glucose tolerance test (OGTT), had blood drawn for lipid (fats) assessment, and responded to HRT questions. The results showed that postmenopausal women with diabetes had increased dyslipidemia compared with nondiabetic women. Among diabetic women, current users of HRT had significant different lipid and glucose control levels than never users of HRT for the following variables: total cholesterol, non-HDL, apoA, fibrinogen, glucose, insulin, and glycosylated hemoglobin. The authors conclude that women with diabetes and nondiabetic postmenopausal women currently taking HRT had better lipoprotein profile than never or previous users of HRT. Women with diabetes currently taking HRT had better glycemic control than never or previous users of HRT. 3 tables. 29 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

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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 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. •

Oral Antihyperglycemic Therapy for Type 2 Diabetes: Scientific Review Source: JAMA. Journal of the American Medical Association. 287(3): 360-372. January 16, 2002. Summary: Care of patients with type 2 diabetes has been revolutionized throughout the past several years; first, by the realization of the importance of tight glycemic (blood glucose) control in forestalling complications, and second, by the availability of several unique classes of oral antidiabetes agents. Figuring out which agent to use in certain clinical situations is a new problem facing the primary care physician. This article reports on a systematic review of available data from the literature regarding the effectiveness of oral antidiabetes agents, both as monotherapy (alone) and in combination (more than one drug given at a time). Studies (n = 63) were included in the analysis if they had a study period of at least 3 months; if each group contained at least 10 subjects at the study's conclusion; and if hemoglobin A1c (a measure of blood glucose levels over time) was reported. When multiple dosages of a drug were tested, the results of the highest approved dosage were used. Five distinct oral drug classes are now available for the treatment of type 2 diabetes. Compared with placebo treatment, most of these agents lower hemoglobin A1c levels approximately 1 to 2 percent. Equivalent effectiveness is usually demonstrated when different agents are compared with one another in the same study population. When they are used in combination, there are additional glycemic benefits. Long term vascular risk reduction has been demonstrated only with sulfonylureas and metformin. The mechanisms of action of the various oral antidiabetes agents are different and as a result they appear to have distinct metabolic effects. These are reflected in their adverse effect profiles and their effect on cardiovascular risk, which may influence drug choice. 1 figure. 4 tables. 154 references.

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Limitations of Conventional Methods of Self-Monitoring of Blood Glucose Source: Diabetes Care. 24(11): 1858-1862. November 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Children with type 1 diabetes are usually asked to perform self monitoring of blood glucose (SMBG) before meals and at bedtime, and it is assumed that if results are in target range, along with HbA1c (glycosylated hemoglobin, a measure of blood glucose over time) measurements, then overall glycemic (blood glucose) control is

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adequate. However, the brief glimpses in the 24 hour glucose profile provided by SMBG may miss marked glycemic excursions. This article describes the MiniMed Continuous Glucose Monitoring System (CGMS) which has provided a new method to obtain continuous glucose profiles and opportunities to examine limitations of conventional monitoring. The MiniMed CGMS uses a glucose oxidase-based sensor to measure extracellular fluid glucose in subcutaneous tissue, which is calibrated against corresponding blood glucose levels. A total of 56 children with type 1 diabetes (age 2 to 18 years) wore the CGMS for 3 days. Patients entered four fingerstick blood samples into the monitor for calibration and kept records of food intake, exercise, and hypoglycemic (low blood glucose levels) symptoms. Data were downloaded, and glycemic patterns were identified. Despite satisfactory HbA1c levels and premeal glucose levels near the target range, the CGMS revealed profound postprandial hyperglycemia (high levels of blood glucose). Almost 90 percent of the peak postprandial glucose levels after every meal were above target (more than 180 milligrams per deciliter), and nearly 50 percent were greater than 300 milligrams per deciliter. Additionally, the CGMS revealed frequent and prolonged asymptomatic hypoglycemia in almost 70 percent of the children (often nocturnal). Repeated use of the CGMS may provide a means to optimize basal and bolus insulin replacement in patients with type 1 diabetes. 3 figures. 1 table. 13 references. •

Nonlinear Effect of Hyperglycemia and Current Cigarette Smoking are Major Determinants of the Onset of Microalbuminuria in Type 1 Diabetes Source: Diabetes. 50(12): 2842-2849. December 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Cigarette smoking and poor glycemic control are risk factors for diabetic nephropathy (kidney disease) in patients with type 1 diabetes. However, the specifics of the relation of these risk factors to the onset of this complication have not been elucidated. This article reports on a study that followed for 4 years 943 Joslin Clinic patients aged 15 to 44 years with type 1 diabetes who had normoalbuminuria (normal levels of protein in the urine) during the 2 year baseline period. Microalbuminuria developed in 109 of the 943 individuals, giving an incidence rate of 3.3 per 100 person years. The risk of onset of microalbuminuria was predicted somewhat more precisely by the measurements during the first and second years preceding onset than by all the measurements during the longer (4 year) interval, suggesting weakening of the impact of past hyperglycemia over time. Point estimates of the incidence rate (per 100 person years) according to smoking status were 7.9 for current smokers, 1.8 for past smokers, and 2.2 for those who had never smoked. In multivariate modeling, the independent effects of HbA1c level and cigarette smoking remained highly significant, but their magnitudes were reduced. The authors also investigated the relationship between HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time) and onset of microalbuminuria. The authors conclude that patients with type 1 diabetes who smoke and have an HbA1c level greater than 8 percent have the highest risk of onset of microalbuminuria. 2 figures. 3 tables. 37 references.

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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.

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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. •

Continuous Subcutaneous Insulin Infusion at 25 Years: Evidence Base for the Expanding use of Insulin Pump Therapy in Type 1 Diabetes Source: Diabetes Care. 25(3): 593-598. March 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Continuous subcutaneous insulin infusion (CSII) is used in selected type 1 diabetes subjects to achieve strict blood glucose control. This article reviews the evidence base that justifies the present increase in the use of CSII, including effectiveness compared with modern intensified insulin injection regimens and concern about possible complications. Review of controlled trials shows that, in most patients, mean blood glucose concentrations and glycated hemoglobin percentages are either slightly lower or similar on CSII versus multiple insulin injections. However, hypoglycemia (low blood glucose) is markedly less frequent than during intensive injection therapy. Ketoacidosis occurs at the same rate. Nocturnal glycemic control is improved with insulin pumps, and automatic basal rate changes help to minimize a prebreakfast blood glucose increase (the dawn phenomenon) often seen with injection therapy. Patients with brittle diabetes characterized by recurrent ketoacidosis are often not improved by CSII, although there may be exceptions. The authors argue that explicit clinical indications for CSII are helpful; they suggest the principal indications for health service or health insurance-funded CSII should include frequent, unpredictable hypoglycemia or a marked dawn phenomenon, which persist after attempts to improve control with intensive insulin injection regimens. In any circumstances, candidates for CSII must be motivated, willing and able to undertake pump therapy, and adequately psychologically stable. Some diabetic patients with well defined clinical problems are likely to benefit substantially from CSII and should not be denied a trial of the treatment. 72 references.

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Delayed Gastric Emptying and Gastric Autoimmunity in Type 1 Diabetes Source: Diabetes Care. 25(5): 912-917. May 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Delayed gastric (stomach) emptying (gastroparesis) and or other gastrointestinal symptoms occur in 30 to 50 percent of people with diabetes. Known contributing factors for this problem are autonomic neuropathy (nerve disease) and acute hyperglycemia (high blood glucose), but the role of gastric autoimmunity has never been investigated, even though 15 to 20 percent of people with type 1 diabetes exhibit parietal cell antibodies (PCAs). This article reports on a study of gastric motility in diabetes in relation to PCA status, autonomic nerve function, HbA1c (glycosylated hemoglobin a measure of blood glucose over time), thyroid stimulating hormone (TSH), Helicobacter pylori (HP), acid production, and gastric histology. The study included 42 patients with type 1 diabetes: 29 men, 13 women; 15 PCA positive; mean age 40 years plus or minus 15 years; mean HbA1c 7.8 percent plus or minus 0.9 percent. Solid gastric emptying was delayed in 40 percent and liquid emptying in 36 percent of patients. Gastric motility did not correlate with symptoms. PCA status, gastric morphology (shape), and acid secretion were similar in those with and without gastroparesis. HbA1c level was the only risk factor for delayed solid emptying in a logistic regression model. The authors found that approximately 50 percent of the type 1 diabetes patients studied had delayed gastric emptying that did not correlate with symptoms. Gastric autoimmunity did not contribute to diabetic gastroparesis. Metabolic control was worse in patients with delayed solid emptying. 3 tables. 47 references.

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Predictors of Acute Complications in Children with Type 1 Diabetes Source: JAMA. Journal of the American Medical Association. 287(19): 2511-2518. May 15, 2002. Summary: Diabetic ketoacidosis (severe high blood glucose levels) and severe hypoglycemia (low blood glucose levels) are acute complications of type 1 diabetes that are related, respectively, to insufficient or excessive insulin treatment. However, little is known about additional modifiable risk factors for these complications. This article reports on a study undertaken to examine the incidence of ketoacidosis and severe hypoglycemia in children with diabetes and to determine the factors that predict these complications. A cohort of 1,243 children from infancy to age 19 years with type 1 diabetes were included. The incidence of ketoacidosis was 8 per 100 person years and increased with age in girls. In analysis, the risk of ketoacidosis in younger children increased with higher hemoglobin A1c (HbA1c, a test for blood glucose levels over time) and higher reported insulin dose. In older children, the risk of ketoacidosis increased with higher HbA1c, higher reported insulin does, underinsurance, and presence of psychiatric disorders. The incidence of severe hypoglycemia was 19 per 100 person years and decreased with age in girls. In younger children, the risk of severe hypoglycemia increased with diabetes duration, and underinsurance. In older children, the risk of severe hypoglycemia increased with duration, underinsurance, lower HbA1c, and presence of psychiatric disorders. Eighty percent of episodes occurred among the 20 percent of children who had recurrent events. The authors conclude that age and sex specific incidence patterns suggest that ketoacidosis is a challenge in adolescent girls while severe hypoglycemia continues to affect disproportionally the youngest patients and boys of all ages. The pattern of modifiable risk factors indicates that underinsured children and those with psychiatric disorders or at the extremes of the HbA1c

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distribution should be targeted for specific interventions. 4 figures. 4 tables. 38 references. •

Anemia: A Risk Factor for Diabetic Retinopathy? Source: Practical Diabetology. 20(4): 32-34. December 2001. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (212) 989-0200 or (773) 777-6801. Summary: Diabetic retinopathy (eye disease associated with diabetes) continues to be a major problem in the United States. This article reviews the risk factors for diabetic retinopathy and then presents a case report that supports the idea that anemia needs to be added to the list of risk factors. Retinal hypoxia (reduced amounts of oxygen being delivered to the retina) has long been associated with the development of diabetic retinopathy; anemia is one of the conditions that can contribute to retinal hypoxia. The authors discuss the clinical features, mechanism of injury from anemia, and relationship between retinopathy and hemoglobin level. The authors conclude by suggesting laboratory evaluation for anemia in patients with diabetes who may have an increased risk of developing anemia. This group includes pregnant women, women with menorrhagia (loss of large amounts of blood with their menstruation), postoperative patients, patients with renal (kidney) failure, patients with neoplastic processes (including cancer), patients with gastrointestinal bleeding, and patients with poor blood glucose control. Normalization of hemoglobin levels may stabilize progressive retinopathy. 9 references.

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HbA1c Levels are Genetically Determined Even in Type 1 Diabetes Source: Diabetes. 50(12): 2858-2863. December 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Glycosylated hemoglobin (HbA1c, a measure of blood glucose values over time) reflects glucose levels in the months preceding the test. In people with diabetes, HbA1c levels predict the risk of microvascular complications. This article reports on a study undertaken to determine whether genetic factors could influence HbA1c levels in normal subjects and patients with type 1 diabetes. The authors performed a classical twin study of HbA1c in healthy nondiabetic female twins and 42 monozygotic (MZ, identical) and 47 dizygotic (DZ, fraternal) pairs. Interclass correlations were higher in MZ compared with DZ twin pairs, suggesting a substantial genetic effect; this was confirmed by quantitative genetic model fitting. Additive genetic effects (heritability) explained 62 percent of population variance in HbA1c; the remainder was attributable to the influence of unique environment. Multivariate modeling showed that genetic factors also have a substantial influence on fasting glucose levels (51 percent). However, HbA1c heritability could not be explained by genes in common with fasting glucose. In the patients with type 1 diabetes, HbA1c levels were correlated in 33 MZ twins concordant (both either had the disease or did not have the disease) for diabetes, but also in 45 MZ twins discordant (one had diabetes, one did not) for the disease. These significant correlations for HbA1c in both concordant and discordant pairs indicate a diabetes independent familial effect. Thus, HbA1c levels are largely genetically determined and independent of the genes influencing fasting glucose levels. Even in type 1 diabetes, familial (i.e., diabetes independent) factors influence protein glycation, implying that familial factors may explain, in part, the risk for microvascular complications, as indicated by high HbA1c levels. 3 figures. 5 tables. 28 references.

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Association of Health Literacy with Diabetes Outcomes Source: JAMA. Journal of the American Medical Association. 288(4): 475-482. July 24-31, 2002. Summary: Health literacy is a measure of patients' ability to read, comprehend, and act on medical instructions. Poor health literacy is common among racial and ethnic minorities, elderly persons, and patients with chronic conditions, particularly in public sector settings. This article reports on a study undertaken to examine the association between health literacy and diabetes outcomes among patients with type 2 diabetes. The study included 408 English and Spanish speaking patients who were older than 30 years and had type 2 diabetes. After adjusting for patients' sociodemographic characteristics, depressive symptoms, social support, treatment regimen, and years with diabetes, for each 1 point decrement in the Test of Functional Health Literacy in Adults (TOFHLA), the glycosylated hemoglobin (HbA1c, a measure of blood glucose levels over time) increased by 0.02. Patients with inadequate health literacy were less likely than patients with adequate health literacy to achieve tight glycemic control and were more likely to have poor glycemic control and to report having retinopathy (eye disease). The authors conclude that inadequate health literacy may contribute to the disproportionate burden of diabetes-related problems among disadvantaged populations. 1 figure. 3 tables. 54 references.

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Long-Term Cisapride Treatment Improves Diabetic Gastroparesis But Not Glycaemic Control Source: Alimentary Pharmacology and Therapeutics. 16(7):1341-1346. July 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 diabetic gastroparesis (delayed emptying of the stomach's contents), delayed food delivery to the intestine may become a major obstacle to postprandial (after a meal) glycemic control. This article reports on a study undertaken to investigate whether cisapride accelerates gastric (stomach) emptying in the long term or improves diabetes control in patients with diabetic gastroparesis. The study included 85 patients with longstanding insulin dependent diabetes mellitus, dyspepsia, and diabetic neuropathy who were tested for impaired gastric emptying of solids. Nineteen of these patients with severe diabetic gastroparesis were randomly treated with 10 milligrams cisapride three times a day (n = 9) or placebo (n = 10) for 12 months. Thereafter, the breath test, dyspeptic symptoms and glycosylated hemoglobin (a measure of blood glucose control over time) values were reassessed. Half emptying times in nine patients with diabetic gastroparesis were significantly shortened by cisapride. Half emptying times in the 10 patients taking placebo did not change. Cisapride significantly reduced dyspepsia. HbA1c (glycosylated hemoglobin) values after 12 months of treatment were not different. The authors conclude that prokinetic treatment with cisapride accelerates gastric emptying of solids and improves dyspeptic symptoms in diabetic gastroparesis. Glycemic control, however, is not affected by cisapride. 2 figures. 2 tables. 22 references.

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Administration of Neutral Protamine Hagedorn Insulin at Bedtime Versus with Dinner in Type 1 Diabetes Mellitus To Avoid Nocturnal Hypoglycemia and Improve Control Source: Annals of Internal Medicine. 136(7): 547-549. April 2, 2002.

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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: Intensive insulin treatment of type 1 diabetes mellitus increases the risk for nocturnal hypoglycemia (low levels of blood glucose overnight). This article reports on a study undertaken to demonstrate that splitting the evening insulin regimen reduces the risk for nocturnal hypoglycemia in the intensive treatment of people with type 1 diabetes mellitus (n = 22). Each patient was randomly assigned to one of the two insulin regimens for 4 months and then switched to the other regimen for another 4 months. The treatment regimens were: mixed treatment, i.e., a mixture of human regular and neutral protamine Hagedorn (NPH) insulin administered before dinner; and split treatment, i.e., human regular insulin administered at dinner and NPH insulin administered at bedtime. During the split regimen treatment period, patients had fewer episodes of nocturnal hypoglycemia, a lower fasting blood glucose level, less variable fasting blood glucose levels, and lower hemoglobin A1c values (a measure of blood glucose over time) than during the mixed regimen. 5 figures. 2 tables. 45 references. •

Interferon Alfa-2b Alone or in Combination with Ribavirin for the Treatment of Relapse of Chronic Hepatitis C Source: New England Journal of Medicine. 339(21): 1493-1499. November 19, 1998. Summary: Interferon alfa is the only effective treatment for patients with chronic hepatitis C. Forty percent of patients have an initial response to this therapy, but most subsequently relapse. This article reports on a study in which the authors compared the effect of interferon alone with that of interferon plus oral ribavirin for relapses of chronic hepatitis C. The study included 345 patients who relapsed after interferon treatment with chronic hepatitis C. A total of 173 patients were randomly assigned to received standard dose recombinant interferon alfa2b concurrently with ribavirin (1,000 to 1,200 mg orally per day, depending on body weight) for 6 months, and 172 patients were assigned to receive interferon and placebo. At the completion of treatment, serum levels of hepatitis C virus (HCV) RNA were undetectable in 141 of the 173 patients (82 percent) who were treated with interferon and ribavirin and in 80 of the 172 patients (47 percent) who were treated with interferon alone. Serum HCV RNA levels remained undetectable 24 weeks after the end of treatment in 84 patients (49 percent) in the combination therapy group, but in only 8 patients (5 percent) in the interferon group. Viral genotypes other than type 1 were associated with sustained responses only in the combination therapy group. Combined therapy caused a predictable fall in hemoglobin concentrations but otherwise has a safety profile similar to that of interferon alone. The authors conclude that in patients with chronic hepatitis C who relapse after treatment with interferon, therapy with interferon and oral ribavirin results in higher rates of sustained virologic, biochemical, and histologic response than treatment with interferon alone. 4 tables. 45 references. (AA-M).

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Postprandial Glucose Control Important? Is it Practical in Primary Care Settings? Source: Clinical Diabetes. 20(2): 71-76. 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Large interventional studies have shown that achieving and maintaining near-normal glycemic (blood sugar) levels reduces the risk for microvascular and macrovascular complications in type 2 diabetes. The impact of postprandial (after a

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meal) glucose on glycemic control has become a topic of much discussion among clinicians. This article examines the literature related to the role of postprandial glucose in type 2 diabetes, both as a contributor to overall glycemia and as an independent risk factor for diabetes complications. The authors also discuss the practicality of managing postprandial hyperglycemia (high blood glucose levels) in primary care settings. The authors conclude by addressing the argument that the new glycemic goals are inappropriate because they are unsafe or too difficult to achieve. The authors stress that the focus should be on achieving the best possible glycemic control for each patient because any reduction in A1C (glycosylated hemoglobin, a measure of blood glucose levels over time) significantly reduces the risk for diabetes complications. Helping patients achieve their best possible level of glycemic control requires the use of appropriate therapy, appropriate monitoring, and comprehensive instruction in diabetes self-management. 1 figure. 2 tables. 40 references. •

Combination of Interferon-Alpha and Ribavirin Therapy for Recurrent Hepatitis C Virus Infection After Liver Transplantation Source: Transplantation Proceedings. 32(4): 714-716. June 2000. Contact: Available from Appleton and Lange. P.O. Box 86, Congers, NY 10920-0086. (203) 406-4623. Summary: Liver transplantation (LT) used as treatment for hepatitis C virus (HCV) infection is almost universally associated with a recurrence of infection. More than 60 percent of patients show clinical and histological signs of hepatitis within 1 year of transplantation, and in several studies a rapid development of fibrosis and cirrhosis was reported. This study was undertaken to examine the efficacy, safety, and tolerability of the combination of interferon (IFN) and ribavirin for recurrent HCV infection after LT. Five patients (3 men and 2 women, age range 43 to 63 years) were included in the study; the median time between LT and initiation of treatment was 20 months (range, 10 to 24 months). Only one patient completed the 6 months of combination therapy. He had a normal serum ALT level at the end of the course, but remained serum positive for HCV, and 3 months after completing therapy, his serum ALT increased again. In the other four patients, therapy was discontinued after 1 to 3 months. All four had severe symptomatic hemolysis (breakdown of red blood cells); two patients required blood transfusions. Decreasing the ribavirin dose did not yield an increase in serum hemoglobin level, and ribavirin had to be withdrawn in all 4 patients. No episodes of rejection were recorded. All patients retained stable graft function 3 to 5 years after transplantation. The authors conclude that, despite the small sample size, the study suggests that the combination therapy with IFN and ribavirin after LT for recurrent HCV infection is associated with a high rate of severe side effects necessitating withdrawal of therapy. 1 table. 9 references.

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American Diabetes Association Position Statement: Evidence-based Nutrition Principles and Recommendations for the Treatment and Prevention of Diabetes and Related Complications Source: Journal of the American Dietetic Association. 102(1): 109-118. January 2002. Contact: Available from American Dietetic Association. 216 West Jackson Boulevard, Suite 800, Chicago, IL 60606-6995. (800) 877-4746. Summary: Medical nutrition therapy (MNT) is an integral component of diabetes management and of diabetes self-management education. This position statement from the American Diabetes Association (ADA) provides evidence based principles and

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recommendations for diabetes MNT. The goal of evidence-based recommendations is to improve diabetes care by increasing the awareness of clinicians and persons with diabetes about beneficial nutrition therapies. It is still important to take into account individual circumstances, preferences, cultural and ethnic preferences, and patient involvement in the decision making process. The article outlines six goals of MNT for diabetes, then offers specific guidelines for type 1 and type 2 diabetes, gestational diabetes, and specific situations, including the presence of kidney disease, children and adolescents, and acute illness. A final section reviews diabetes prevention. The article concludes by reiterating that MNT for people with diabetes should be individualized, with consideration given to the individual's usual food and eating habits, metabolic profile, treatment goals, and desired outcomes. Monitoring of metabolic parameters, including glucose, HbA1c (glycosylated hemoglobin, a measure of blood glucose over time), lipids (fats), blood pressure, body weight, and renal function, when appropriate, as well as quality of life is essential to asses the need for changes in therapy and ensure successful outcomes. Ongoing nutrition self management education and care needs to be available for individuals with diabetes. 7 references. •

Effect of Metformin in Pediatric Patients with Type 2 Diabetes: A Randomized Controlled Trial Source: Diabetes Care. 25(1): 89-94. January 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Metformin is the most commonly prescribed oral antidiabetic agent in the United States for adults with type 2 diabetes. The incidence of type 2 diabetes in children has increased dramatically over the past 10 years, and yet, metformin has never been formally studied in children with type 2 diabetes. This study evaluated the safety and efficacy of metformin at doses up to 1,000 milligrams twice daily in 82 subjects aged 10 to 16 years for up to 16 weeks in a randomized double blind placebo controlled trial from September 1998 to November 1999. Metformin significantly improved glycemic control. Mean HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time) values, adjusted for baseline levels, were also significantly lower for metformin compared with placebo. Improvement in fasting plasma glucose (FPG) was seen in both sexes and in all race subgroups. Metformin did not have a negative impact on body weight or lipid profile. Adverse events were similar to those reported in adults treated with metformin. The authors conclude that metformin was shown to be safe and effective for treatment of type 2 diabetes in pediatric patients. 1 figure. 2 tables. 15 references.

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Tests of Glycemia in Diabetes Source: Diabetes Care. 25(Supplement 1): S97-S99. January 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Monitoring of glycemic (blood glucose) status, as performed by patients and health care providers, is considered a cornerstone of diabetes care. Results of monitoring are used to assess the effectiveness of therapy and to guide adjustments in medical nutrition therapy (MNT), exercise, and medications to achieve the best possible blood glucose control. This article presents the American Diabetes Association position statement on the tests used most widely in monitoring the glycemic status of people with diabetes. The guidelines address both patient and physician or laboratory-based

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testing; the guidelines do not cover tests for diabetes screening and diagnosis. The guidelines discuss blood glucose testing, comparisons between patient and laboratory testing, urine glucose testing (for ketones), glycated protein testing (glycosylated hemoglobin or HbA1c), and glycated serum protein testing. 3 references. •

Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus Source: Diabetes Care. 25(4): 436-472. April 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Multiple laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. This article reports the findings of an expert committee that drafted evidence-based recommendations for the use of laboratory analysis in patients with diabetes. An external panel of experts reviewed a draft of the guidelines, which were modified in response to the reviewers' suggestions. A revised draft was posted on the Internet and was presented at the American Association for Clinical Chemistry Annual Meeting in July 2000. The recommendations were modified again in response to oral and written comments. The guidelines were also reviewed by the Professional Practice Committee of the American Diabetes Association. Measurement of plasma glucose remains the sole diagnostic criterion for diabetes. Monitoring of glycemic control is performed by the patients, who measure their own plasma or blood glucose with meters, and by laboratory analysis of glycated hemoglobin (a measure of blood glucose levels over time). The potential roles of noninvasive glucose monitoring, genetic testing, autoantibodies, microalbumin, proinsulin, C-peptide, and other analytes are addressed. Several analytes are of minimal clinical value at the present time, and measurement of them is not recommended. 7 tables. 267 references.

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2002 Diabetes Nutrition Recommendations: Grading the Evidence Source: Diabetes Educator. 28(5): 756, 758-759, 762-764, 766. September-October 2002. Contact: Available from American Association of Diabetes Educators. 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: Nutrition therapy plays a critical role in the successful management of diabetes. This article offers a practical approach to diabetes nutrition recommendations. The author helps readers discern whether nutrition recommendations are based on strong supporting scientific evidence or if they are based on expert consensus. Topics include goals and outcomes for medical nutrition therapy (MNT); nutrition recommendations in the areas of carbohydrate, protein, fats, micronutrients, and alcohol; special considerations for type 1 diabetes and for type 2 diabetes; and prevention of diabetes. The author concludes that monitoring of blood glucose, HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time), lipids, and blood pressure is essential in patients with diabetes to assess the success of lifestyle strategies, including MNT, and to determine if changes in medications are necessary. Patients also require ongoing education and support as they make and maintain lifestyle changes. 33 references.

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Impact of Program to Improve Adherence to Diabetes Guidelines by Primary Care Physicians Source: Diabetes Care. 25(11): 1946-1951. November 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Previous studies have shown that primary care physician (PCP) adherence to diabetes guidelines is suboptimal. This article reports on a study undertaken to determine the state of diabetes care given by independently practicing PCPs in a rural county in Indiana. The authors considered whether a multifaceted intervention targeting PCPs, patients, and the health care system would improve adherence to diabetes guidelines. Before any intervention, rates of adherence to guidelines were low: 15 percent for foot exams, 20 percent for HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time) measurement, 23 percent for eye exam referrals, 33 percent for urine protein screening, 44 percent for lipid profiles, 73 percent for home glucose monitoring, and 78 percent for blood pressure measurements. One year after development of local consensus guidelines and feedback of baseline performance, significant improvements were seen in blood pressure measurements, foot exams, HbA1c measurements, and PCP eye exams; a trend toward improvement was seen in referral to eye specialists. After a second year of multiple interventions, only blood pressure measurements and foot exams remained significantly improved; all other areas returned to rates indistinguishable from baseline. The authors conclude that in busy primary care practices lacking organizational support and computerized tracking systems, sustained improvements in diabetes care are difficult to attain using traditional physician-targeted approaches. 1 table. 35 references.

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Update on Managing Hepatitis C: Diagnosis, Treatment, Prevention: How to Recognize At-Risk Patients Early, While Therapy Can Still Be Effective Source: Journal of Critical Illness. 14(8): 444-451. August 1999. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Greenwich, CT 06831-0010. (203) 661-0600. Summary: Recent advances in the management of chronic hepatitis C have greatly improved long term results. This article offers an update on the diagnosis, treatment, and prevention of hepatitis C. Combination therapy with interferon alfa and ribavirin has afforded sustained viral eradication in up to 41 percent of patients treated. The authors caution that the absence of symptoms and mild to modest elevations in alanine aminotransferase levels can be misleading; liver biopsy is required to ascertain disease severity. The decision to treat should be based on the severity of liver damage, the patient's age and comorbid conditions, and the presence of contraindications to therapy. In patients with HCV infection, factors that increase risk for the development of cirrhosis include male gender, alcohol use, and infection after age 40. Alcohol use is one of the most important factors in accelerating progression of the disease. Patients with HCV infection should abstain from alcohol totally, regardless of the severity of disease on liver biopsy. Flulike symptoms and bone marrow suppression are the side effects most frequently associated with interferon. Ribavirin is associated with hemolytic anemia; hemoglobin levels should be monitored weekly or every other week, particularly during the first 2 months of treatment, in patients on ribavirin. One sidebar offers a list of three resource organizations for patients with hepatitis C. 7 figures. 2 tables. 16 references.

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Interpersonal Predictors of HbA1c in Patients with Type 1 Diabetes Source: Diabetes Care. 25(4): 731-736. April 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Research suggests that increased collaboration and satisfaction in the patientprovider relationship is associated with better outcomes in patients with diabetes. In adults, an interpersonal style characterized by low trust of others and excessive selfreliance is known as 'dismissing attachment style.' The authors of this article hypothesized that patients with diabetes who have dismissing attachment style, due to a decreased ability to collaborate with providers and others, would have significantly higher HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time) levels than patients with secure attachment style. The article reports on a study of 276 adult tertiary care patients with type 1 diabetes for whom the authors obtained mean HbA1c levels over the prior year and assessed patient attachment style, demographics, and clinical characteristics. The authors found the 62 percent of the patients with dismissing attachment style had mean HbA1c levels greater than 8 percent, compared with 34 percent of patients with secure attachment style. After adjusting for demographics, diabetes severity, medical comorbidity, and depression, dismissing attachment style remained significantly associated with HbA1c levels greater than 8 percent, compared with secure attachment style. The authors conclude that this has relevance from a population based perspective because approximately 25 percent of the general population has a dismissing attachment style. Attachment style is easily measured using self report instruments and may inform clinicians how to work with patients who are less engaged in the health care relationship. 2 figures. 2 tables. 36 references.

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Nutritional Care of Ambulatory Residents in Special Care Units for Alzheimer's Patients Source: Journal of Nutrition for the Elderly. 12(4): 5-19. 1993. Summary: Researchers evaluated data about nutrition from medical records of 100 ambulatory Alzheimer's residents in 10 special care units (SCUs) for Alzheimer's patients in long-term care facilities. The Minimum Data Set obtained data on the diagnosis of Alzheimer's disease (AD) or other dementias, illness duration, admission date, age, sex, other relevant medical problems, mood and behavior patterns, oral and nutritional status, dental status, medication use, skin conditions, health status, physical function, structural problems, food intake, clinical signs and symptoms of nutrient deficiencies or excesses, individual nutrition care plans, and biochemical indicators of nutritional status (namely serum albumin, hemoglobin, hematocrit, and cholesterol levels). Eight facilities estimated calorie and fluid needs, and four facilities estimated protein needs of their residents. Over 40 percent of the residents were underweight, and 20 percent reported significant weight loss. Several patients had hemoglobin, hematocrit, and albumin levels that were lower and cholesterol levels that were higher than levels associated with high death rates among older institutionalized people. Many factors placed patients at high risk for malnutrition. Staff at each facility monitored the nutritional status of AD patients to a variable extent. 20 references.

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Quality of Care for Patients Diagnosed with Diabetes at Screening Source: Diabetes Care. 26(2): 367-371. February 2003.

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Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Screening for diabetes has the potential to be an effective intervention, especially if patients have intensive treatment of their newly diagnosed diabetes and comorbid hypertension (high blood pressure). This article reports on a study undertaken to determine the process and quality of diabetes care for patients diagnosed with diabetes by systematic screening. A total of 1,253 patients of a Veterans Affairs Medical Center aged 45 to 64 years who did not report having diabetes were screened for diabetes with an HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time) test. All subjects with an HbA1c level greater than 6.0 percent were invited for follow up blood pressure and fasting plasma glucose (FPG) measurements. A case of unrecognized diabetes was defined as HbA1c greater than 7.0 percent. For each of the 56 patients for whom a new diagnosis of diabetes was determined, the authors notified the patient's primary care provider of the diagnosis. One year after diagnosis, the authors performed follow up and review of the patient's medical records. Among patients diagnosed with diabetes at screening, 34 of 53 (64 percent) had evidence of diet or medical treatment for their diabetes, 42 of 53 (79 percent) had HbA1c measured within the year after diagnosis, 32 of 53 (60 percent) had cholesterol measured, 25 of 53 (47 percent) received foot examinations, 29 of 53 (55 percent) had eye examinations performed by an eye specialist, and 16 of 53 (30 percent) had any measure of urine protein. The mean blood pressure decline over the year after diagnosis for patients with diabetes was 2.3 mmHg; this decline was similar to that found for 183 patients in the study without diabetes. The authors conclude that patients with diabetes diagnosed at screening achieve less tight blood pressure control than similar patients without diabetes. Primary care providers do not appear to manage diabetes diagnosed at screening as intensively as long-standing diabetes and do not improve the management of hypertension given the new diagnosis of diabetes. 3 tables. 18 references. •

Compliance with Home Blood Glucose Monitoring Among Patients with Diabetes Mellitus Source: Practical Diabetology. 20(4): 16-19. December 2001. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (212) 989-0200 or (773) 777-6801. Summary: Self monitoring of blood glucose (SMBG) is the standard of care for management of people with diabetes mellitus. This article explores the issue of compliance with SMBG among patients with diabetes mellitus. The aims of SMB are to reduce levels of glycosylated hemoglobin (HbA1c, a measure of blood glucose over time) and to improve overall glycemic control; to reduce the occurrence of severe hypoglycemia; and to empower patients to make adjustments in their treatment regimen according to variations in their diet, exercise, and general health status. For health care workers to provide accurate and practical advice to patients regarding SMBG, they need to be familiar with the current guidelines for home blood glucose monitoring, anticipated compliance rates and reasons for lack of compliance, evidence demonstrating that SMBG is beneficial in achieving the aims listed above, costs to patients associated with SMBG, and possible adverse effects. The authors conclude by cautioning that if the diabetes research community is unable to provide evidence that SMBG improves clinically relevant outcomes in Type 2 diabetes, patients may ultimately face difficulty receiving reimbursement for the cost of testing supplies. Patients should also be given an appropriate plan of action for modifying their treatment regimen based on the results of self monitoring. 1 figure. 12 references.

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Adding a Daily Dosage of Diabetes Wisdom to Your Prescription Source: Diabetes Spectrum. 14(3): 163-167. August, 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: The amount of patient information needed to manage diabetes on a daily basis is often overwhelming. This article explains how providing daily diabetes management tips in a calendar format allows patients to digest self-management techniques one day at a time without causing information overload. The author describes how her facility developed this unique information and education resource for Medicare recipients. The author first distributed the daily, spiral bound diabetes calendar logbook in 1997, after conducting focus groups and gathering feedback from Medicare recipients. From 1998 to 2001, 964 patients with diabetes received the calendars yearly. The initial survey conducted among calendar recipients after the first year of use revealed that 83 percent found the calendar helpful; 70 percent like the reminders, advice, and encouragement; 83 percent learned about the importance of the HbA1c (glycosylated hemoglobin, a measure of hyperglycemia over time) test; and 92 percent better understood the importance of a foot exam. Patients attributed the benefits of the calendar to its permanence, content, and inspirational messages. The author concludes that this daily calendar format may be more beneficial to patients than traditional educational materials designed for one time use. The article also describes some of the barriers to delivering optimal self-management training materials, and reviews the ongoing process of developing this tool. 2 figures. 34 references.

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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. 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.

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Jelly Beans to Kidney Beans: What Diabetes Educators Should Know About the Glycemic Index Source: Diabetes Educator. 27(4): 505-508. July-August 2001. Contact: Available from American Association of Diabetes Educators. 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: The glycemic index (GI) has been proposed as a nutrition approach for improving blood glucose control in individuals with diabetes. The GI is a scientifically based method of ranking foods from 0 to 100 according to their potential for raising blood glucose. This article reviews the use of the GI and helps diabetes educators learn how to incorporate the GI in their work with patients. Although research results are mixed, clinical studies in individuals with diabetes have shown that low GI diets improve glucose control by decreasing HbA1c (glycosylated hemoglobin), fructosamine, postprandial (after a meal) blood glucose excursions, the incidence of hypoglycemia (low blood glucose levels), and blood lipids (fats). By learning more about the glycemic index, diabetes educators can help their clients better understand the relationship between food choices and blood glucose, thus achieving improved glycemic control. Pure glucose, which produces the greatest rise in glucose levels, is assigned a GI of 100. Every other food is ranked on a scale from 0 to 00 according to its actual effect on blood glucose levels when eaten as an equal amount of carbohydrate. The author emphasizes that GI information should be used in the context of the healthy eating guidelines for overall good diabetes nutrition. Just because a food has a low GI does not mean people with diabetes can eat unlimited portions of it without affecting their blood glucose levels, weight, and blood lipids (portion size is still very important). The article includes practical strategies for putting the GI into practice. 2 tables. 12 references.

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Impact of Planned Care and a Diabetes Electronic Management System on Community-Based Diabetes Care: The Mayo Health System Diabetes Translation Project Source: Diabetes Care. 25(11): 1952-1957. November 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: The Mayo Health System Diabetes Translation Project sought to assess models of community-based diabetes care and use of a diabetes electronic management system (DEMS). Planned care is a redesigned model of chronic disease care that involves guideline implementation, support of self-management, and use of clinical information systems. This article reports on a study of adult patients with diabetes attending three primary care practice sites in Wisconsin and Minnesota. The authors assessed quality of diabetes care using standard indicators for 200 patients randomly selected from each site at baseline and at 24 months of implementation. Planned care was associated with improvements in measurement of HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time), HDL cholesterol, and microalbuminuria (microscopic protein in the urine), as well as the provision of tobacco advice, among other performance measures. DEMS use was associated with improvements in all indicators, including microalbuminuria, retinal examination, foot examinations, and selfmanagement support. Although planned care was associated with improvements in metabolic control, the authors observed no additional metabolic benefit when providers used DEMS. 4 tables. 21 references.

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Use of a No-Concentrated-Sweets Diet in the Management of Type 2 Diabetes in Nursing Homes Source: Journal of the American Dietetic Association. 101(12): 1463-1466. December 2001. Contact: Available from American Dietetic Association. 216 West Jackson Boulevard, Suite 800, Chicago, IL 60606-6995. (800) 877-4746. Summary: The prevalence of diabetes in nursing homes is 15 to 18 percent, which is twice as common as in the general population. Physicians prescribe therapeutic diets as a part of a disease treatment to eliminate, decrease, or add certain substances in the diet. A typical, no-concentrated-sweets diet differs from a regular diet in that the therapeutic diet has no added sugar but uses a sugar substitute, diet syrup, or a diet dessert. However, a regular diet prescription may allow subjects to consume a more palatable, less restrictive, more economical diet in nursing homes without impairing control of diabetes. This article reports on a study that examined the effects of a regular diet in the management of type 2 diabetes in a nursing home. The authors compared 28 residents (14 in each group) with type 2 diabetes during the study period; participants were given either a regular diet or a no-concentrated-sweets diet. At 3 months after the diet change, there was no difference between the 2 groups in body mass index (BMI), mean fasting blood glucose, mean blood glucose levels, serum albumin, and serum hemoglobin. The authors note that there is no evidence that carbohydrates from sugars are more rapidly absorbed compared with carbohydrates from starch, or that simple sugars aggravate hyperglycemia as compared with starch. The total amount of carbohydrates consumed rather than their source affects the blood glucose levels. The authors conclude that the residents with diabetes in long term care facilities can be successfully managed with a regular diet without a limitation on concentrated sweets. The authors further recommend that glucose levels should be monitored and medication adjusted, rather than restricting the diet for these high risk residents. 1 table. 2 figures. 27 references.

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Pharmacy Update: Clinical Importance of Postprandial Hyperglycemia Source: Diabetes Educator. 27(5): 624-637. September-October, 2001. Contact: Available from American Association of Diabetes Educators. 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: The role of elevated postprandial (after a meal) blood glucose levels in the etiology (cause) of diabetes related complications is of great concern. Interventions to manage both fasting and postprandial glucose levels are needed to reduce diabetes complications. This article helps diabetes educators understand these issues and the pharmaceuticals (drugs) available to help patients control hyperglycemia (high levels of blood glucose). One table summarizes the harmful effects of sustained hyperglycemia. Glycosylated hemoglobin (HbA1c, a measure of average blood glucose levels) measurements can be used to monitor both postprandial hyperglycemia (PPHG) as well as fasting plasma glucose (FPG) levels. Drugs discussed include insulin lispro (Humalog), insulin aspart (Novolog), acarbose (Precose), miglitol (Glyset), repaglinide (Prandin), natiglinide (Starlix), and tolbutamide (Orinase). The authors stress that the most efficient way to manage PPHG is to prevent it rather than to try to improve glucose disposal. Health care providers now have the medications that, when used in combination with self monitoring (SMBG), diet, and exercise, can near normalize blood glucose values, both fasting and after meals. Treatment programs for all appropriate diabetes patients should be intensified to bring HbA1c levels to less than 7 percent. 2 tables. 26 references.

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Macrovascular Risk and Diagnostic Criteria for Type 2 Diabetes Source: Diabetes Care. 26(2): 485-490. February 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: The use of fasting plasma glucose (FPG) levels (greater than 7.0 mmol per liter) leads to underdiagnosis of type 2 diabetes compared with the oral glucose tolerance test (OGTT). The OGTT is of limited use for population screening. Most of the increase in cardiovascular risk in relation to increasing blood glucose occurs before the threshold at which the diagnosis of type 2 diabetes is made. This article reports on a study that evaluated the use of HbA1c (glycosylated hemoglobin, a measure of glucose over time) and FPG as predictors of type 2 diabetes and cardiovascular risk and how they can be used to develop a rational approach to screening for abnormalities of glucose tolerance. OGTT and measurement of HbA1c and FPG levels were performed in 505 subjects screened for type 2 diabetes. The subjects were aged 19 to 88 years (mean 53.8 years). The incidence of type 2 diabetes was 10.4 percent based on the OGTT and 4 percent based on the FPG levels. HbA1c testing predicted with certainty the absence or presence of type 2 diabetes as defined by the OGTT. However, the majority (75 to 85 percent) of subjects in each case had intermediate values, which were therefore nondiagnostic. The authors conclude that measurement of FPG and HbA1c levels will diagnose or exclude type 2 diabetes with certainty in a minority (15 percent) of people. There is a continuous relationship between FPG and HbA1c and cardiovascular risk. The authors also present a cost-effective approach to screening patients. 2 figures. 1 table. 29 references.

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Control of Cardiovascular Risk Factors in Patients with Diabetes and Hypertension at Urban Academic Medical Centers Source: Diabetes Care. 25(4): 718-723. April 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: There are national mandates to reduce blood pressure (BP) to less than 130 over 85 mmHg, to reduce LDL cholesterol to less than 100 milligrams per deciliter, and to reduce HbA1c (glycosylated hemoglobin, a measure of blood glucose over time) levels to less than 7 percent, and to institute aspirin therapy in patients with diabetes. This article reports on a study undertaken to determine the proportion of patients in urban institutions with diabetes and hypertension (high blood pressure) who meet these treatment goals. Using American Diabetes Association (ADA) guidelines, the authors evaluated the control of cardiovascular disease (CVD) risk factors in 1,372 patients receiving medical care at two major urban medical centers in Brooklyn and Detroit. Information was extracted from charts of outpatient clinics. Of 1,372 active clinic patients with diabetes and hypertension, 1,247 (90.9 percent) had type 2 diabetes, and 26.7 percent met the target blood pressure. A total of 35.5 percent met the LDL cholesterol goal, 26.7 percent met the HbA1c goal, and 45.6 percent were on antiplatelet therapy (such as aspirin). Only 3.2 percent of patients met the combined ADA goal for blood pressure, cholesterol and glycosylated hemoglobin. The authors conclude that optimal control of CVD risk factors in adults with diabetes was achieved only in a minority of patients. Results reflect the inherent difficulties in achieving these complex guidelines in the present health care systems. 3 tables. 36 references.

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Validation of a Counseling Strategy to Promote the Adoption and the Maintenance of Physical Activity by Type 2 Diabetic Subjects Source: Diabetes Care. 26(2): 404-408. February 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: There is enough evidence that physical activity is an effective therapeutic tool in the management of type 2 diabetes. This article reports on a study designed to validate a counseling strategy that could be used by physicians in their daily outpatient practice to promote the adoption and maintenance of physical activity by people with type 2 diabetes. The long term (2 year) efficacy of the behavioral approach (n = 182) was compared with usual care treatment (n = 158) in two matched, randomized groups of patients with type 2 diabetes who had been referred to the authors' Outpatient Diabetes Center. After 2 years, 69 percent of the patients in the intervention group and 18 percent of the control group achieved the target with significant improvements in body mass index (BMI) and HbA1c (glycosylated hemoglobin, a measure of blood glucose over time). The authors conclude that these results show that physicians can motivate most patients with type 2 diabetes to exercise long term and emphasize the value of individual behavioral approaches in daily practice. 3 tables. 25 references.

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Preparing for a Healthy Pregnancy Source: Diabetes Forecast. 54(6): 75-76, 78-79. June 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article addresses issues related to pregnancy for women who have diabetes. Women who have preexisting diabetes can have safe pregnancies with adequate planning, thorough medical follow up, and tight diabetes control. Before becoming pregnant, women who have diabetes should have glycosylated hemoglobin levels as close to 7 percent as possible and be as healthy as possible. Prior to attempting to become pregnant, all women who have diabetes should undergo eye, kidney, heart, thyroid, breast, and pelvic examinations, and they should have their blood pressure and glycosylated hemoglobin level checked. In addition, a woman's health practitioners will need to perform a thorough review of current medications to evaluate their safety for use prior to and during pregnancy. Other issues that women who have diabetes need to address prior to conceiving include blood glucose and ketone monitoring, diabetes medication use, nutrition, exercise, and hyperglycemic and hypoglycemic events. The article uses several case examples to explore pregnancy related issues for women who have diabetes.

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Expecting the Best: Diabetes, Pregnancy, and Blood Glucose Control Source: Diabetes Self-Management. 18(4): 87-94. July-August 2001. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (800) 234-0923. Website: www.diabetes-self-mgmt.com. Summary: This article addresses the issue of blood glucose control during pregnancy. Regardless of whether a woman has type 1 diabetes, type 2 diabetes, or gestational diabetes, she must maintain control of her blood glucose level during pregnancy for both her health and that of her baby. Glucose in the mother's blood crosses the placenta to her baby, thus affecting the baby's blood glucose level. A baby that is constantly

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exposed to high levels of glucose will gain weight and increase in size, resulting in a condition known as macrosomia. In addition, the baby may experience hypoglycemia or complications when the umbilical cord is cut. The American Diabetes Association recommends that pregnant women check their blood glucose levels once before each meal, again one hour after each meal, at bedtime, and once in the middle of the night. Daily urine ketone testing is often advised for pregnant women with diabetes. All women with type 1 diabetes and some with type 2 diabetes either inject or infuse insulin during pregnancy. Women with gestational diabetes may not need to inject insulin. However, women need to be aware of the fact that insulin needs change during pregnancy. Women who have type 1 or type 2 diabetes need to have optimal blood glucose control prior to conception. They should strive for a near normal glycosylated hemoglobin test result at least 3 months prior to pregnancy. Women who are diagnosed with gestational diabetes may need the guidance of a diabetes educator or an endocrinologist during their pregnancy. The tools used to maintain blood glucose control during pregnancy include meal planning, exercise, and insulin management. The article discusses each of these aspects of blood glucose management and addresses the issue of blood glucose management during labor and delivery, recovery, and breast feeding. The article includes a list of information resources. 2 tables. •

Heart Rate Variability in Adolescents and Adults with Type 1 Diabetes Source: Nursing Research. 50(2): 95-104. March-April 2001. Contact: Available from Educational Services Division, American Journal of Nursing Company. 555 West 57th Street, New York, NY 10019-2961. (800) 627-0484 or (303) 6041464. Summary: This article describes a correlational study that examined differences in heart rate variability among 55 adolescents with type 1 diabetes, 62 adults with type 1 diabetes who have coexisting renal failure, 28 healthy adolescent controls, and 67 healthy adult controls. Convenience samples of adult patients with diabetes awaiting kidney or pancreas and kidney transplants and adolescent patients were recruited from university based clinics. Volunteers served as healthy controls. The short term R-R variability measures included in the study were changes in heart rate with deep breathing and with the Valsalva maneuver. Twenty-four ambulatory heart rate monitoring with power spectral analysis was also obtained to assess long term R-R variability. The study found that adult patients awaiting transplantation had significantly poorer heart rate variability measures than any of the other three populations studied. Adult control values also were significantly lower than either adolescent controls or youths with diabetes. Although most long term R-R variability measures were lower in adolescents with diabetes versus controls, only one measure of parasympathetic modulation was significantly lower. There were significant negative associations between glycosylated hemoglobin and sympathetic modulation in both the adult group and the adolescent group with diabetes. The article concludes that type 1 diabetes is associated with decreased heart rate variability, with the extent of the decrease related to the age of the person and the severity of the disease. 1 figure. 6 tables. 56 references. (AA-M).

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Disordered Eating, Body Mass, and Glycemic Control in Adolescents with Type 1 Diabetes Source: Diabetes Care. 24(4): 678-682. April 2001.

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Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article describes a cross sectional study that examined the relationship between disordered eating attitudes and behaviors, body mass index (BMI), and glycemic control in adolescents with type 1 diabetes. The study population consisted of 152 adolescents aged 11 to 19 years who completed the body dissatisfaction, drive for thinness, and bulimia scales from the Eating Disorders Inventory (EDI). All participants had diabetes for more than 1 year. Glycemic control was assessed by glycosylated hemoglobin. Height and weight were measured to assess BMI. Adolescents with type 1 diabetes did not report more disordered eating attitudes and behaviors than the normative comparison sample. Male subjects with type 1 diabetes reported fewer symptoms of bulimia, and female subjects with type 1 diabetes reported greater body satisfaction than the normative group. A higher BMI was a significant predictor of greater body satisfaction, more so for female than male subjects. Symptoms of bulimia were associated with older adolescence and female gender. Those with more symptoms of bulimia were also more likely to have a higher BMI. Female gender and greater body dissatisfaction predicted a stronger desire to be thin. Longer duration of disease, more symptoms of bulimia, and obesity all predicted poorer glycemic control. The article concludes that female patients aged 13 to 14 years seem to be at greatest risk for developing disordered eating patterns. Using the clinical cutoff score of the EDI bulimia subscale as a screener in diabetes clinics may help identify adolescents whose disordered eating patterns are likely to compromise their glycemic control. 1 figure. 3 tables. 31 references. (AA-M). •

Culturally Competent Dietary Education for Southern Rural African Americans with Diabetes Source: Diabetes Educator. 28(2): 245-257. March-April 2002. Contact: Available from American Association of Diabetes Educators. 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: This article describes a culturally competent, dietary self-management intervention designed to improve physiological outcomes, diabetes self-management, and costs of care for high risk African Americans with type 2 diabetes. A longitudinal, quasi experimental design was used to evaluate the effectiveness of the intervention for 23 adult African Americans from a physician practice group in rural South Carolina. The intervention consisted of 4 dietary education classes (on the low fat diet), 6 discussion groups, and follow up. Intervention sessions were provided by a dietitian and nurse case managers, and framed as social events; families were encouraged to participate. Data suggest that the intervention significantly improved fat-related dietary habits, A1C values (glycosylated hemoglobin, a measure of blood glucose over time), fasting blood glucose, and frequency of acute care visits. A trend in reduction of lipids (dietary fats) and weight also was observed. The authors conclude that culturally competent dietary self-management provides a meaningful approach to focused diabetes education for rural African Americans. Integrating nursing case management provides an innovative method of addressing the more global issues of delivery of care to underserved rural populations and decreasing the high costs of care. 1 figure. 5 tables. 63 references.

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Home A1C Test: On the Way Source: Diabetes Forecast. 55(6): 47-48. June 2002.

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Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article describes a new monitoring device with which people with diabetes can measure their A1C values. The A1C measures the concentration of hemoglobin molecules, which are found in red blood cells, that have sugar (glucose) attached to them (glycosylated hemoglobin). The results are given in a percentage and provide an overview of the person's blood glucose control for the previous three months or so. The A1C test gives a broader picture of the patient's overall diabetes control, so the American Diabetes Association recommends that the test be done four times a year. However, this recommendation comes with a great deal of inconvenience. The author describes a disposable one-use device, called the A1c Now, which is about the size of a pager and has a digital display that reveals results in eight minutes. For the first few months of availability (expected in late 2002), the device will require a physician's prescription. However, early in 2003, the company plans to release the A1c Now for sale over the counter without a prescription. The company anticipates pricing the A1c Now at less than $20 each when it becomes available to consumers. Medicare currently reimburses for the test when given at the doctor's office. For more information, readers are referred to www.metrika.com. 1 figure. •

Potential Short-Term Economic Benefits of Improved Glycemic Control: A Managed Care Perspective Source: Diabetes Care. 24(1): 51-55. January 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article describes a retrospective study that examined the potential impact of improved glycemic control on selected short term complications of diabetes and associated costs in a managed care setting. The study was based on a retrospective cohort design and used automated enrollment, medical, and pharmacy claims, as well as laboratory data from a multispecialty group clinic in Worcester, MA, with a predominantly managed care patient base. The study population consisted of adult plan members who had a diagnosis of diabetes between January 1, 1994 and June 30, 1998 and who also had multiple glycosylated hemoglobin (HbA1c) values available. These patients were assigned to study cohorts based on their mean levels of HbA1c: a good control group for those with HbA1c values of less than 8 percent, a fair control group for those with HbA1c values of 8 to 10 percent, and a poor control group for those with HbA1c values of more than 10 percent. Inpatient admissions for selected short term complications, represented by selected infections, hyperglycemia, hypoglycemia, and electrolyte disturbances, and the associated medical charges were evaluated across the three HbA1c groups. Multivariate analyses were used to control for differences in several potential confounding factors among the study groups. Of 2,394 patients who had diabetes, approximately 10 percent had at least one inpatient stay for a short term complication, accounting for 447 admissions. Over 3 years, the adjusted rate of inpatient treatment ranged from 13 per 100 patients with good glycemic control to 16 per 100 patients with fair glycemic control and 31 per 100 patients with poor glycemic control. The corresponding mean adjusted charges were approximately $970, $1,380, and $3,040, respectively. Among the 30 percent of the study population with long term diabetic complications, the results were more marked. The adjusted admissions per 100 patients were estimated to be 30, 38, and 74 over 3 years for patients with HbA1c of less than 8 percent, 8 to 10 percent, and more than 10 percent, respectively. The associated charges were $2,610, $3,810, and $8,320, respectively. The article concludes that, in typical

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practice, better glycemic control is associated with a reduced rate of admission for selected short-term complications, and, therefore, reduced medical charges for these complications over a 3 year period. The potential short term economic benefits are important to consider when making decisions regarding the adoption and use of new interventions for the management of diabetes. 3 tables. 15 references. (AA-M). •

Dissemination of Diabetes Care Guidelines: Lessons Learned from Community Health Centers Source: Diabetes Educator. 27(1): 101-110. January-February 2001. Contact: Available from American Association of Diabetes Educators. 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: This article describes a study that evaluated the impact of a provider problem based learning (PBL) intervention on screening for complications of diabetes in community health centers. A successive sampling design was used to compare selected standards of diabetes care delivered preintervention with the care delivered postintervention at two community health centers and one comparison center. Two randomly assigned intervention sites received a PBL intervention focused on care guidelines for prevention of diabetes complications, with telephone follow up over 12 months. Effects of the intervention were determined from an audit of 200 charts from each site. The odds of having a glycosylated hemoglobin test more than doubled from preintervention to postintervention, and the odds of having a foot examination more than tripled across centers. Measurement of creatinine and glycosylated hemoglobin were associated, with the odds of having one test tripling when the other had been measured. Both intervention centers had significant improvement in the documented screening or referral for retinopathy. Rates for documentation of patient education were significantly lower at the intervention site where free patient education booklets were distributed. The article concludes that the improvements in diabetes care were not consistent among community health centers. Interventions involving system and policy changes may be more effective than just provider education. 4 tables. 31 references. (AAM).

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Know Your Value! Source: Diabetes Forecast. 54(3): 66, 68. March 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article discusses the importance of the hemoglobin A1c (HbA1c) value. This value is important because it is the only way people who have diabetes can tell how well they are controlling their diabetes over time. A small portion of the glucose that circulates in the blood after being absorbed from the intestine combines with hemoglobin. Once binding with hemoglobin A1c occurs, it remains until the individual red blood cells die after 2 or 3 months. People who have good control of their diabetes should have an HbA1c value below 8 percent, and people who are doing especially well may have an HbA1c value below 7 percent. Keeping the HbA1c value as far under 8 percent as possible will help people prevent the long term complications of diabetes such as kidney failure, blindness, painful nerve disease, coronary heart disease, and strokes. People who have type 1 diabetes should have the test for HbA1c four times a year, and those with type 2 should have it at least twice a year. 1 table.

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Know Your ABC's: 'A' is for A1C Source: Diabetes Forecast. 55(10): 34-36. October 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article is the first in a series written to introduce people with diabetes to a new program by the American Diabetes Association (ADA) called 'Be Smart About Your Heart: Control the ABCs of Diabetes.' The ABC numbers that every person with diabetes and their health care providers should know are hemoglobin A1C, Blood pressure, and Cholesterol. In this article, the author explains the hemoglobin A1C (a measure of blood glucose over time), how it is related to diabetes and cardiovascular disease, and why it is important to keep the A1C number under control. The author explains the chemistry of glycation and the Maillard reaction.

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A Is for A1C: Are Your Numbers Where They Should Be? Source: Diabetes Forecast. 56(1): 133-134. January 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article is the second in a four part series on diabetes and cardiovascular disease. In this article, the author discusses the usefulness of monitoring A1C values. The A1C measures the concentration of hemoglobin molecules, which are found in red blood cells, that have sugar (glucose) attached to them (glycosylated hemoglobin). The results are given in a percentage and provide an overview of the person's blood glucose control for the previous three months. The A1C test gives a broader picture of the patient's overall diabetes control, so the American Diabetes Association recommends that the test be done at least two times a year. The author notes that lowering the A1C just one percentage point translates into a 30 percent to 35 percent reduction in eye, kidney, and nerve complications, and cuts the risk of fatal and nonfatal heart attacks by 18 percent. The article concludes with brief suggestions for strategies to lower one's A1C level. For more information, readers are referred to diabetes.org/makethelink. 1 figure.

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Intensive Diabetes Management: Implications of the DCCT and UKPDS Source: Diabetes Educator. 28(5): 735-738, 740. September-October 2002. Contact: Available from American Association of Diabetes Educators. 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: This article offers an official position statement of the American Association of Diabetes Educators (AADE) on the implications of the DCCT (Diabetes Control and Complications Trial) and the UKPDS (United Kingdom Prospective Diabetes Study) on intensive diabetes management. These studies demonstrated that intensive diabetes management can achieve HbA1c (glycosylated hemoglobin, a measure of blood glucose over time) levels close to the American Diabetes Association (ADA) treatment goal of 7 percent, resulting in significant reductions in diabetes complications in persons with both type 1 and type 2 diabetes. This position statement offers brief background of the studies, a discussion, and a list of 9 recommendations. The article concludes that diabetes self-management education is an essential component of diabetes treatment. Diabetes educators play a vital role in recognizing and addressing potential barriers to self-care, facilitating appropriate selection of treatment strategies and tools, and fostering the integration of diabetes care practices into daily life. 12 references.

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Tight Control: The Risk-Versus-Benefit Game Source: Diabetes Forecast. 55(4): 30-32. April 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article outlines the benefits of tight blood glucose control for patients with diabetes, noting that there are certain risks also associated with this diabetes management approach. Achieving recommended HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time) levels reduces future risk of developing eye, kidney, and nerve damage. The author reports on current controversy regarding exactly how low an HbA1c level patients should be encouraged to achieve, the risks of hypoglycemia (low blood glucose reactions), hypoglycemia in patients with type 2 diabetes, and the importance of balancing risks with benefits. Readers are encouraged to monitor their blood glucose frequently, schedule well balanced meals, take medications as directed, and communicate with their physicians; all essential steps to help prevent low blood glucose levels. Regardless of any increased risk of low blood glucose, tight control is still the most effective way to reduce or prevent long term complications. One side bar offers a review of concerns regarding exercise and hypoglycemia, including strategies to prevent or handle a low blood glucose event.

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How Do We Diagnose Diabetes and Measure Blood Glucose Control? Source: Diabetes Spectrum. 14(2): 67-71. May 1, 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article presents a clinical basis for the diagnosis of diabetes. In 1979, criteria for the diagnosis of diabetes were selected based on levels of glycemia on the oral glucose tolerance test (OGTT) that were associated with the subsequent development of retinopathy. Since then, five long term studies have demonstrated that when glycosylated hemoglobin (HbA1c) levels are maintained below 7 percent, development of retinopathy and microalbuminuria almost never occurs. Approximately 60 percent of people with fasting plasma glucose (FPG) concentrations of 126 to 139 milligrams (mg) per deciliter (dl) and 70 percent of those with 2 hour values on the OGTT of 200 to 239 mg per dl have normal HbA1c levels, with another third having values between 6 percent and 7 percent. The article presents an alternative approach to diagnosis using both FPG and HbA1c values. This diagnostic algorithm uses measurements of FPG concentrations followed by HbA1c levels in people whose FPG values are neither normal nor meet the older criterion for the diagnosis of diabetes. The HbA1c level determines whether a person with an FPG concentration of 110 to 139 mg per dl has diabetes or a milder degree of hyperglycemia. An HbA1c level one percentage point or more above the ULN for the assay used, if confirmed, makes the diagnosis of diabetes. A lower value makes the diagnosis of impaired glucose tolerance. The article contends that, using this approach, diabetes will be diagnosed in people at clear risk for developing the microvascular and neuropathic complications. People with milder degrees of hyperglycemia will also be identified so that appropriate measures can be instituted to reduce their chances of developing diabetes or cardiovascular disease. 1 figure. 3 tables. 41 references. (AA-M).

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Consensus Statement: Postprandial Blood Glucose Source: Diabetes Spectrum. 14(2): 71-74. May 1, 2001.

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Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article presents the consensus position developed by a seven member panel of experts in diabetes, endocrinology, and metabolism with regard to issues related to postprandial blood glucose (PPG). Most patients who have diabetes fail to achieve their glycemic goals, and elevated PPG concentrations may contribute to suboptimal glycemic control. The panel developed a consensus position on questions related to the definition of PPG; the relationship among PPG, fasting plasma glucose, and glycosylated hemoglobin; the contribution of PPG to the long term complications of diabetes; the circumstances under which people with diabetes should be tested for PPG; the benefits and risks of specifically lowering PPG in an effort to achieve better glycemic control; and the additional research that needs to be performed to clarify the role of PPG in the medical management of diabetes. 1 appendix. 7 references. •

Insulin Lispro Update Source: Diabetes Educator. 28(2): 269-277. March-April 2002. Contact: Available from American Association of Diabetes Educators. 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: This article provides a review of the literature and clinical studies for insulin lispro and updated information on its advantages over regular insulin for various populations of people with diabetes. Information was gathered from a search of Medline articles and from review of clinical studies. Patients in various special populations using insulin lispro, with proper adjustment of basal insulin, had a greater reduction in hemoglobin A1c (glycosylated hemoglobin, a measure of blood glucose over time), and fewer episodes of hypoglycemia than patients on regular insulin. More recently published literature shows that due to its faster onset and shorter duration of action, insulin lispro is useful for not only lowering A1c values, but also for reducing hypoglycemic (low blood glucose) events in various populations with diabetes, including pediatric and pregnant patients, those with gastroparesis, and insulin pump users. 3 figures. 3 tables. 18 references.

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Diabetes and Erectile Dysfunction Source: Clinical Diabetes. 19(1): 45-48. February 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article provides clinicians with information on the etiology, diagnosis, and treatment of erectile dysfunction (ED). Awareness of ED as a significant and common complication of diabetes has increased in recent years. Studies suggest that the prevalence of ED in men with diabetes ranges from 35 to 75 percent versus 26 percent in the general population. Although the causes of ED are numerous, they generally fall into the categories of organic and psychogenic. The organic causes can be subdivided into the categories of vascular, traumatic/postsurgical, neurological, endocrine induced, and drug induced. Examples of psychogenic causes include depression, performance anxiety, and relationship problems. The natural history of ED in men who have diabetes is normally gradual. Both vascular and neurological mechanisms are commonly involved. Autonomic neuropathy is a major contributor to the high incidence of ED in men who have diabetes. The first step in evaluating ED is a thorough sexual and medical history and physical examination. Although few simple laboratory tests can

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help identify obvious causes of organic ED, initial tests should include glycosylated hemoglobin, free testosterone, thyroid function tests, and prolactin levels. Preventive measures such as improving glycemic control and hypertension, quitting smoking, reducing excessive alcohol intake, and avoiding medications that may contribute to ED may help reduce the risk of developing ED. However, once ED has developed, oral agents such as sildenafil and yohimbine are considered first line therapy. Intracavernosal injections are an acceptable alternative for men who are not candidates for oral therapy. Mechanical therapy with vacuum assisted erection devices is also effective, and penile prosthesis is a viable option. The article is accompanied by a patient information sheet. •

Clinical Outcomes and Insulin Secretion After Islet Transplantation with the Edmonton Protocol Source: Diabetes. 50(4): 710-719. April 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article provides further data on 12 patients with type 1 diabetes who have had successful islet transplantations. Details of metabolic control, acute complications associated with islet transplantation, and long term complications related to immunosuppression therapy and diabetes were noted. Insulin secretion, both acute and over 30 minutes, was determined after intravenous glucose tolerance tests (IVGTTs). The median follow up was 10.2 months, and the longest was 20 months. Glucose control was stable, with pretransplant fasting and meal tolerance stimulated glucose levels of 12.5 plus or minus 1.9 and 20.0 plus or minus 2.7 mmol per liter, respectively, but decreased significantly, with posttransplant levels of 6.3 plus or minus 0.3 and 7.5 plus or minus 0.6 mmol per liter, respectively. All patients had sustained insulin production, as evidenced by the most current baseline C-peptide levels of 0.66 plus or minus 0.06 nmol per liter, increasing to 1.29 plus or minus 0.25 nmol per liter after the meal tolerance test. The mean glycosylated hemoglobin (HbA1c) level decreased from 8.3 plus or minus 0.5 percent to the current level of 5.8 plus or minus 0.1 percent. Four patients had normal glucose tolerance, five had impaired glucose tolerance, and three had postislet transplant diabetes. Three patients had a temporary increase in their liver function tests. One patient had thrombosis of a peripheral branch of the right portal vein, and two of the early patients had bleeding from the hepatic needle puncture site; however, these problems were resolved. Two patients had transient vitreous hemorrhages. The two patients with elevated creatinine levels posttransplant had a significant increase in serum creatinine in the long term, although the mean serum creatinine of the group was unchanged. Cholesterol increased in five patients, and lipid lowering therapy was required for three patients. No patient has developed cytomegalovirus infection or disease, posttransplant lymphoproliferative disorder, malignancies, or serious infection to date. None of the patients have been sensitized to donor antigen. In 11 of the 12 patients, insulin independence was achieved after 9,000 islet equivalents (IEs) per kilogram were transplanted. The acute insulin response and the insulin area under the curve (AUC) after IVGTT were consistently maintained over time. The insulin AUC from the IVGTT correlated to the number of islets transplanted, but more closely correlated when the cold ischemia time was taken into consideration. Islet transplantation has successfully corrected labile type 1 diabetes and problems with hypoglycemia, and results show persistent insulin secretion. After a minimum of 9,000 IEs per kilogram are provided, insulin independence is usually attained. An elevation of creatinine appears to be a contraindication to this

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immunosuppressive regimen. When considering islet transplantation for people with labile type 1 diabetes that is difficult to control, the risk to benefit ratio should be in favor of islet transplantation. 6 figures. 35 references. (AA-M). •

Diabetes Care in the U.S. and Canada Source: Diabetes Care. 25(7): 1149-1153. July 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reported on a study undertaken to compare the glycemic control of patients with type 1 diabetes treated in the United States and Canada. The authors analyzed a large multicenter randomized clinical trial conducted in the U.S. and Canada. Patients with type 1 diabetes, screened from 1983 to 1989 for enrollment in the Diabetes Control and Complications Trial (DCCT), were categorized as treated in the U.S. (n = 2,604) or Canada (n = 245). In general, volunteers screened for the DCCT were highly educated and following healthy lifestyles. Canadians were somewhat younger (25 years versus 27 years of age), less likely to be college educated (62 percent versus 71 percent), more likely to receive care through a family doctor (41 percent versus 28 percent), and had a higher frequency of outpatient visits (4 versus 3 per year). Despite these differences in health care delivery, the mean HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time) at baseline was identical in the two countries. Adjustment for demographic, lifestyle, and clinical predictors of HbA1c yielded similar findings. The authors conclude that differences in care delivery patterns do not yield large differences in glycemic control for patients with type 1 diabetes who were recruited in the U.S. and Canada for a large randomized trial. 1 figure. 3 tables. 30 references.

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Lifetime Costs of Complications Resulting from Type 2 Diabetes in the U.S Source: Diabetes Care. 25(3): 476-481. March 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a model designed to estimate the costs of managing the complications of type 2 diabetes over time. A cohort of 10,000 patients with diabetes was simulated using a model based on existing epidemiological studies. Complication rates were estimated for various stages of macrovascular disease, nephropathy (kidney disease), retinopathy (eye disease), neuropathy (nerve disease), and hypoglycemia (low blood glucose levels). At the beginning of the simulation, patients were assumed to have been treated for 5 years and to have a mean HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time) of 8.4. From the United Kingdom Prospective Diabetes Study, it was estimated that on current therapies, the HbA1c would drift upward an overage 0.15 percent per year. Direct medical costs of managing each complication were estimated (in United States dollars at the year 2000) from all-payor databases, surveys, and literature. Macrovascular disease was estimated to be the largest cost component, accounting for 85 percent of cumulative costs of complications over the first 5 years. The costs of complications were estimated to be $47,240 per patient over 30 years, on average. The management of macrovascular disease is estimated to be the largest cost component, accounting for 52 percent of the costs; nephropathy accounts for 21 percent, neuropathy accounts for 17 percent, and retinopathy accounts for 10 percent of the costs of complications. The authors conclude that if improving glycemic control prevents complications, it will also reduce these costs. 4 figures. 1 table. 57 references.

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Hemoglobin

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Increasing Problem Solving in Adolescents with Type 1 Diabetes: The Choices Diabetes Program Source: Diabetes Educator. 28(1): 115-124. January-February 2002. Contact: Available from American Association of Diabetes Educators. 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: This article reports on a pilot study undertaken to test the hypothesis that adolescents with type 1 diabetes can learn to become better problem solvers in diabetes self-care and thereby improve their metabolic control. In the study, 53 adolescents aged 13 to 17 years with type 1 diabetes were randomly assigned to either a 6 week problem solving diabetes education program or to a control group (usual care). The Choices program provides an opportunity for teens to work through problems in a structured way so that they can begin to take ownership of diabetes problem solving. HbA1c (glycosylated hemoglobin, a measure of blood glucose over time) levels were obtained as were assessments of problem solving, frequency of behavior, level of responsibility, and 24 hour behavior recall at baseline and 6 months. The experimental group participants showed significantly improved problem solving test scores and HbA1c values from baseline to 6 months, changes not evident in the control group. At 6 months, the experimental group participants were doing blood glucose testing more often than those in the control group. However, there was no significant changes in degree of responsibility for self-care behaviors. The authors conclude that this 6 week intervention for adolescents with diabetes resulted in better problem solving skills, more frequent blood glucose testing, and improved HbA1c values. The results suggest that a diabetes problem solving program for adolescents can be effective in improving metabolic control. 3 tables. 43 references.

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Quality Improvement Initiative to Integrate Teaching Diabetes Standards Into Home Care Visits Source: Diabetes Educator. 28(6): 1009-1020. November-December 2002. Contact: Available from American Association of Diabetes Educators (AADE). 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: This article reports on a quality improvement project that was initiated to determine the quality of diabetes care for clients of a home health agency and to integrate the teaching of diabetes standards of care into home care nursing visits. A descriptive study design was used to evaluate the effectiveness of teaching materials and the Standards of Care Teaching program. Performance indicators and outcomes measures were used to determine the baseline status of diabetes care and for comparing performance measures from 50 home care clients. The educational materials and care plan interventions helped nurses learn the standards and facilitated tracking interventions and performance measures. These results showed statistical significance in performance measures for eye, foot, lipid tests, and diabetes self-management education, but not for hemoglobin A1C, urine protein, and medical nutrition therapy (MNT). The author concludes that the Standards of Care Teaching Program was a useful way to integrate the standards into a diabetes program and home care visits. Comparing clients' diabetes performance measures with national standards helped identify specific areas for quality improvement. 4 tables. 25 references.

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Self-Management Education for Adults with Type 2 Diabetes: A Meta-analysis of the Effect on Glycemic Control Source: Diabetes Care. 25(7): 1159-1171. July 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a review undertaken to evaluate the effectiveness of self management education on GHb (glycosylated hemoglobin, a measure of blood glucose levels over time) in adults with type 2 diabetes. A total of 31 studies of 463 initially identified articles met the authors' selection criteria. On average, diabetes self management education (DSME) intervention decreased GHb by 0.76 percent more than the control group at immediate follow up; by 0.26 percent at 1 to 3 months of follow up; and by 0.26 percent at longer than 4 months of follow up. GHb decreased more with additional contact time between participant and educator; a decrease of 1 percent was noted for every additional 23.6 hours of contact. The authors call for further research to develop interventions effective in maintaining long term glycemic control. 1 appendix. 2 figures. 4 tables. 82 references.

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Prevalence and Predictors of Sexual Dysfunction in Patients With Type 1 Diabetes Source: Diabetes Care. 26(2): 409-414. February 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study aimed to measure the prevalence of sexual dysfunction in patients with diabetes; describe how descriptive variables, psychological variables, diabetic complications, and sexual dysfunction relate in patients with diabetes; and describe the predictors of sexual dysfunction in patients with diabetes. A total of 240 adults type 1 diabetes patients visiting the outpatient diabetes clinic of an university hospital completed questionnaires evaluating psychological adjustment to diabetes and sexual functioning. Medical records were used to obtain HbA1c (glycosylated hemoglobin, a measure of blood glucose over time) values as well as information on microvascular diabetes complications. Sexual dysfunction was reported by 27 percent of women and 22 percent of men. No differences were found between sexes in type of reported sexual dysfunction. In men, but not in women, sexual dysfunction was related to age, body mass index (BMI), duration of diabetes, and diabetes complications. No correlation with HbA1c was found in either sex. In women, but not in men, sexual dysfunction was related to depression and the quality of the partner relationship. Analyses demonstrated that, in men, the significant predictors of sexual dysfunction were higher age and presence of complications, whereas, in women, sexual dysfunction was related to depression. The authors conclude that both women and men with diabetes are at increased risk for sexual dysfunction. 4 tables. 30 references.

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Initiative to Improve Diabetes Care Standards in Healthcare Organizations Serving Minorities Source: Diabetes Educator. 28(4): 581-589. July-August 2002. Contact: Available from American Association of Diabetes Educators. 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426.

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Summary: This article reports on a study designed to assess changes of diabetes care standards in health care organizations that participated in a 2 year initiative to improve diabetes care and expand outreach in minority communities. In the study, an independent sample of the medical records of adults with type 2 diabetes was randomly drawn at 3 points of time (n = 829). Rates of compliance with 20 selected measures of standards of basic diabetes care were measured and compared over time. Significant improvements in compliance rates from baseline to the end point were found in 11 measures including annual hemoglobin A1c testing, annual lipid profile, and biannual lower extremity examination. The authors conclude that improvements in diabetes care were credited with giving providers feedback on their compliance and increasing support of patient self-care, especially through tailoring outreach and services to minorities. 3 tables. 25 references. •

Effect of Orlistat in Overweight and Obese Patients with Type 2 Diabetes Treated with Metformin Source: Diabetes Care. 25(7): 1123-1128. July 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study of the effect of orlistat, a gastrointestinal lipase inhibitor, on body weight, glycemic control, and cardiovascular risk factors in metformin-treated patients with type 2 diabetes. The 1 year, multicenter, randomized, double blind, placebo controlled trial of 120 milligrams orlistat (n = 249) or placebo (n = 254) combined with a reduced calorie diet was conducted in overweight and obese patients with suboptimal control of type 2 diabetes. After 1 year of treatment, mean weight loss was greater in the orlistat than in the placebo group (minus 4.6 percent of baseline weight versus minus 1.7 percent of baseline weight, respectively). Orlistat treatment caused a greater improvement in glycemic control than placebo, as evidenced by a greater reduction in serum HbA1c (glycosylated hemoglobin, a measure of blood glucose over time), adjusted for changes in metformin and sulfonylurea therapy. Compared with the placebo group, patients treated with orlistat also had greater decreases in total cholesterol, LDL cholesterol, and systolic blood pressure. Although more subjects treated with orlistat experienced gastrointestinal side effects than placebo, more subjects in the placebo group withdrew prematurely from the study than in the orlistat group (44 percent versus 35 percent). The authors conclude that orlistat is a useful adjunctive treatment for producing weight loss and improving glycemic control, serum lipid levels, and blood pressure in obese patients with type 2 diabetes who are being treated with metformin. 1 figure. 2 tables. 31 references.

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Metformin as an Adjunct Therapy in Adolescents with Type 1 Diabetes and Insulin Resistance Source: Diabetes Care. 26(1): 138-143. January 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study that evaluated whether, in adolescents with type 1 diabetes, the addition of metformin to insulin and standard diabetes management results in higher insulin sensitivity and lower HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time), fasting glucose, insulin dosage, and body mass index (BMI). This randomized, placebo-controlled 3 month trial of metformin therapy included 27 adolescents with type 1 diabetes, high insulin dosage, and HbA1c

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greater than 8 percent. Results showed that metformin treatment lowered HbA1c and decreased insulin dosage with no weight gain in teens with type 1 diabetes in poor metabolic control. Changes in insulin sensitivity were not documented in this study. 1 figure. 2 tables. 32 references. •

Acarbose Improves Glycemic Control in Overweight Type 2 Diabetic Patients Insufficiently Treated with Metformin Source: Diabetes Care. 26(2): 269-273. February 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study undertaken to investigate the efficacy and safety of acarbose as add-on therapy in overweight patients with type 2 diabetes inadequately controlled by metformin. After a 4 week placebo run-in period, subjects were randomized to either acarbose or placebo. The primary efficacy variable was the change in HbA1c (glycosylated hemoglobin, a measure of blood glucose over time) from baseline to the end of the 24 week treatment period. The intention to treat analysis from baseline to week 24 (81 patients for HbA1c and 82 for fasting blood glucose) showed statistically significant differences between acarbose and placebo treatment in HbA1c and fasting blood glucose. In all, 18 patients (47 percent) in the acarbose group were classified as responders with a greater than 5 percent reduction in HbA1c (relative to baseline) at the end point compared to 6 (14 percent) in the placebo group. The safety profiles were similar for both treatment groups except for the higher incidence of gastrointestinal side effects during acarbose therapy. The authors conclude that the addition of acarbose to metformin monotherapy provides an efficacious and safe alternative for glycemic improvement in overweight type 2 patients inadequately controlled by metformin alone. 1 figure. 2 tables. 27 references.

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Hepatitis C: What Recent Advances in Therapy Mean for Your Patients Source: Consultant. 39(2): 436-440, 443-444, 446-447. February 1999. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Box 4010, Greenwich, CT 06831-0010. Summary: This article reviews recent advances in the management of chronic hepatitis C that have greatly improved long term results for these patients. Combination therapy with interferon alfa and ribavirin has afforded sustained viral eradication in up to 41 percent of patients treated. The authors caution physicians to avoid being misled by the absence of symptoms and the mild to modest elevations in alanine aminotransferase levels. Liver biopsy findings provide the only means of assessing disease severity with certainty. The decision to treat should be based on the severity of liver damage, the patient's age, comorbid conditions, and the presence of contraindications to therapy. Patients must be counseled about the side effects of therapy. Flu like symptoms and bone marrow suppression are most frequently associated with interferon; depression is also a common side effect. Ribavirin is associated with hemolytic anemia; because of this, hemoglobin levels should be monitored weekly or every other week, particularly during the first 2 months of therapy. Alcohol use is one of the most important factors in accelerating progression of the disease. Patients with hepatitis C should abstain from alcohol totally, regardless of the severity of disease on liver biopsy. 6 figures. 2 tables. 15 references.

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Hemoglobin

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Diabetes Nutrition Recommendations for 2002: Separating Facts from Assumptions Source: Practical Diabetology. 21(4): 40. June 2002. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (800) 234-0923. Summary: This article reviews the diabetes nutrition recommendations for 2002, as established by the American Diabetes Association (ADA). Basic to all nutrition recommendations for diabetes is the importance of optimal nutrition through healthful food choices and an active lifestyle. The author discusses goals and priorities for diabetes nutrition; the intake of macronutrients, including carbohydrates, protein, and fats; other dietary components, including micronutrients and alcohol; and the role of nutrition and lifestyle in the prevention of diabetes. The author concludes that monitoring of glucose, glycosylated hemoglobin (HbA1c, a measure of blood glucose over time), lipids, blood pressure, body weight, and renal (kidney) function, as well as quality of life, is essential in patients with diabetes to assess the need for changes in therapy and to ensure successful outcomes. These patients require ongoing nutrition education and support as they make and maintain lifestyle changes. 1 figure. 22 references.

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Detecting Hereditary Hemochromatosis Source: Nurse Practitioner. 25(7): 64, 69, 73-74, 76. July 2000. Contact: Available from Nurse Practitioner. Circulation Department, P.O. Box 5053, Brentwood, TN 37024-5053. (800) 490-6580. Fax (615) 377-0525. Summary: This article reviews the diagnosis of hereditary hemochromatosis (HH), the most commonly inherited autosomal recessive disorder. Hemochromatosis is a current or potential progression of abnormally high accumulations of iron in the liver. If left untreated, the condition can lead to chronic or irreversible hepatic (liver) fibrosis, cirrhosis (scarring), hepatocellular carcinoma (liver cancer), arthritis, and organ failure. Common signs and symptoms seen in the primary care setting include fatigue, weakness, abdominal pain, palpitations, skin pigmentation (coloring) changes, and arthropathy, but any symptom associated with organ damage may be reported. Because prompt intervention can cease or reverse the debilitating effects of iron overload, prompt disease diagnosis and treatments are imperative. The author notes that often an HH diagnosis is delayed in asymptomatic patients or patients with vague complaints of fatigue and arthropathy. The goal is to identify patients prior to symptom onset and organ damage; recent gene typing studies have made this a possibility. Early manifestations of HH include vague symptoms of weakness, fatigue, weight loss, skin pigmentation changes, abdominal pain, loss of libido, and diabetes mellitus symptoms. Advanced physical signs include liver and spleen enlargement, skin pigmentation changes, spider angiomas, arthropathy, ascites, cardiac arrhythmias, heart failure, testicular atrophy, and jaundice. Because HH is an inherited disorder, the family history should be specific and complete. Routine assays are the most commonly used testing. A definitive diagnosis is made via liver biopsy. Patients with HH should be instructed to increase their dietary protein, as hemoglobin is 96 percent protein; folic acid of 1 mg daily will assist in hemoglobin formation. Vitamin or mineral supplements that contain iron should be avoided. And because alcohol is a hepatotoxin and wine contains iron, alcohol should be avoided. 1 figure. 31 references.

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Colitis: Key Components of the Evaluation Source: Consultant. 38(2): 375-378, 381-383. February 1998. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Box 4010, Greenwich, CT 06831-0010. Summary: This article reviews the key components of the evaluation of colitis. Colitis is a nonspecific condition that has a variety of causes, including inflammatory bowel disease, infections, ischemia, radiation, and antibiotic therapy. The mainstays of evaluating patients who have colitis include the history and physical examination, sigmoidoscopy with mucosal biopsy, stool examination, and barium radiography. These tools are used to determine if colitis is present, how severe it is, the cause of the colitis, and the anatomic extent of the disease. In addition to the typical symptoms of colitis (diarrhea, abdominal pain, and tenesmus), the authors recommend that physicians look for signs of more severe disease, such as orthostasis, pallor, fever, fatigue, and tachycardia. Also, physicians should be alert for extraintestinal manifestations of chronic inflammatory bowel disease (IBD), such as mouth ulcers, erythema nodosum, and arthritis. Laboratory findings that may suggest severe colitis include a low hemoglobin level, leukocytosis, an elevated erythrocyte sedimentation rate, and hypoalbuminemia. After confirming the presence of colitis with proctosigmoidoscopy or flexible sigmoidoscopy, stool cultures and parasite testing should be ordered to identify the specific cause. Complications of colitis include toxic megacolon, perforation, hemorrhage, and obstruction in ischemic disease. 4 figures. 3 tables. 16 references. (AAM).

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Monitoring Activity in Ulcerative Colitis Source: Alimentary Pharmacology and Therapeutics. 16(Supplement 4): 3-6. July 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: This article reviews therapeutic strategies and the monitoring of patients with ulcerative colitis (UC, a type of inflammatory bowel disease, or IBD). The authors note that monitoring is easier in these patients than in patients with Crohn's disease (another type of IBD) for several reasons. The severity of symptoms and activity of inflammation tend to run parallel in UC when involvement of the large bowel is more extensive. The easy accessibility of the colonic mucosa by endoscopic and histologic examination provides further information concerning the degree of inflammation. In severe attacks, the patients must be admitted to the hospital and monitored carefully. Clinical and laboratory parameters (such as daily stools, CRP, fever, hemoglobin, albumin, etc) and plain abdominal x-ray are useful in monitoring the activity of the disease and to predict the outcome. In mild to moderate attacks, endoscopic and histologic evaluation are the best methods for choosing the appropriate treatment and for assessing response. 2 tables. 18 references.

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Effect of Intensive Therapy on the Microvascular Complications of Type 1 Diabetes Mellitus Source: JAMA. Journal of the American Medical Association. 287(19): 2563-2568. May 15, 2002. Summary: This article summarizes and integrates the findings of the Diabetes Control and Complications Trial (DCCT), a randomized controlled clinical trial, and the

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succeeding observational follow up of the DCCT cohort in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, regarding the effects of intensive treatment on the microvascular complications of type 1 diabetes mellitus. The DCCT proved that intensive treatment reduced the risks of retinopathy (eye disease), nephropathy (kidney disease), and neuropathy (nerve disease) by 35 to 90 percent compared with conventional treatment. The absolute risks of retinopathy and nephropathy were proportional to the mean glycosylated hemoglobin (HbA1c) level over the follow up period preceding each event. Intensive treatment was most effective when begun early, before complications were detectable. These risk reductions, achieved at a median HbA1c level difference of 9.1 percent for conventional treatment versus 7.3 percent for intensive treatment have been maintained through 7 years of EDIC. The further rate of progression of complications from their levels at the end of the DCCT remains less in the former intensive treatment group. Thus, the benefits of 6.5 years of intensive treatment extend well beyond the period of its most intensive implementation. Intensive treatment should be started as soon as is safely possible after the onset of type 1 diabetes mellitus and maintained thereafter, aiming for a practicable target HbA1c level of 7 percent or less. 4 figures. 2 tables. 29 references. •

Dietary Adequacy in Patients with Diabetic Gastroparesis Source: Journal of the American Dietetic Association. 97(4): 420-422. April 1997. Summary: This brief research report describes a study undertaken to investigate dietary intake and adequacy in patients with diabetic gastroparesis (delayed gastric emptying due to diabetes mellitus). Approximately 50 percent of patients with diabetes have some delay in gastric emptying as one component of autonomic neuropathy. Diabetic gastroparesis is most commonly found in patients with insulin-dependent diabetes mellitus (IDDM) who have a long-standing history of poorly controlled diabetes. In this cross-sectional study, 10 patients were studied throughout a 5 week period. Study measures included gastroparesis (by gastric emptying study), height and weight of subjects, body mass index (BMI), glycated hemoglobin (HbA1c) levels, home blood glucose measurements, physical activity (self-recorded), and gastrointestinal symptoms (measured with a daily questionnaire). Symptoms of appetite, abdominal pain after meals, difficulty swallowing, acid regurgitation, bloating, belching, nausea, vomiting, halitosis (bad breath), heartburn, flatulence (gas), constipation, and diarrhea were recorded. Outcome variables of primary interest were dietary intakes of energy (calories) and macronutrients. The authors had hypothesized that postprandial (after meal) difficulties may influence a patient to reduce the quantity and frequency of food intake. Also, blood glucose control may be difficult to achieve because of slow and unpredictable gastric emptying. Their results did not observe any significant associations between symptom severity and dietary variables, or between dietary adequacy and age, BMI, HbA1c level, and medication use. However, patients who are not physically active (versus active patients) may be at greater risk of consuming inadequate diets. The small sample size is noted as a limitation of the study. The authors conclude that relationships between dietary intake, food choices, and gastrointestinal symptoms might be evident with a larger group. 2 tables. 16 references. (AA-M).

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Patients Ask Source: Practical Diabetology. 21(1): 37-41. March 2002. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (800) 234-0923.

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Summary: This column, one in a regular series, answers common questions that patients with diabetes may have. Topics include what happens if insulin is injected into a vein; management techniques for high blood pressure (hypertension); coping with appetite fluctuations; the connection between diabetes and Bell's palsy; how to manage postprandial (after a meal) hyperglycemia (high levels of blood glucose); problems with glyburide, a commonly prescribed sulfonylurea drug; strategies for mixing insulins; and how to adjust insulin regimens to prepare for medical tests that require fasting. Appended to the section of question and answers is a commentary on the ongoing, changing role of patient monitoring tests (such as those for blood glucose and for glycosylated hemoglobin or A1c) and its impact on health insurance and reimbursement policies. 1 reference. •

Self-Monitoring of Blood Glucose in Type 2 Diabetes: Time for Evidence of Efficacy (editorial) Source: Diabetes Care. 24(6): 977-978. June 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This editorial addresses the issue of self monitoring of blood glucose in type 2 diabetes. The editorial reviews a study, which used data from the Third National Health and Nutrition Examination Survey, that showed that the majority of patients treated with oral agents or diet alone monitored their blood glucose only rarely, if at all. Self monitoring at least once per day was undertaken by only 5 to 6 percent of patients, while 80 percent of those on diet therapy and 65 percent of those treated with oral agents admitted to having monitored either never or less than once per month. There was no correlation between frequency of monitoring and glycosylated hemoglobin levels in any of the treatment categories. The editorial comments on the apparent apathy toward this self help activity and considers whether health care professionals should be concerned that many noninsulin treated patients are not self monitoring regularly or frequently. 14 references.

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Organizing Diabetes Care: Identify, Monitor, Prioritize, Intensify Source: Diabetes Care. 24(9): 1515-1516. September 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This editorial reviews the common strategies involved in improving the quality of diabetes care. Strategies include identifying patients with diabetes, monitoring one or more important clinical parameters, prioritizing patients based on their clinical status and readiness to change, and intensifying care through active outreach or visit planning. In addition, the editorial discusses an automated method to systemically identify patients at high risk. This multivariate risk measure includes previous complications, high glycosylated hemoglobin levels, and elevated creatinine levels. The editorial identifies factors that limit the usefulness of this multivariate risk measure, including the lack of up to date HbA1c or serum creatinine tests by many patients, the failure to separate macrovascular and microvascular complications, and the difficulty in applying the measure in smaller practice settings. The editorial contends that a more balanced clinical approach to the care of adults who have type 2 diabetes is needed. 26 references.

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Adult-Onset Still Disease: Identification and Management Source: Journal of Musculoskeletal Medicine. 17(10): 589-591,595-598. October 2000. Summary: This journal article provides health professionals with information on the clinical and laboratory features that distinguish adult onset Still disease (AOSD) from other rheumatic disorders and presents an approach to management. AOSD is a rare rheumatic condition that usually affects young adults; however, it can target persons of any age. The differential diagnosis, which is broad, can be confusing. Hallmarks of AOSD include high spiking fevers, an evanescent rash that is most pronounced during febrile episodes, and arthritis. The form of arthritis associated with AOSD is a fairly destructive kind that may involve only one or two joints in an asymmetric distribution. Patients who have AOSD experience clinical symptoms suggestive of an inflammatory process, such as morning stiffness, pain that improves with movement, gelling phenomenon, and a response to antiinflammatory medications. Serum autoantibodies such as rheumatoid factor and antinuclear antibody are usually absent. Levels of acute phase reactants and serum ferritin, as well as white blood cell (WBC) count, are significantly elevated. Conditions that need to be ruled out before confirming the diagnosis of AOSD include granulomatous disorders, vasculitis, infection, malignancy, and connective tissue disease. AOSD tends to be variable in its course. Treatment begins empirically with aspirin and nonsteroidal antiinflammatory drugs, or NSAIDs. For patients who have more severe disease, options broaden to include systemic corticosteroids and even methotrexate. The erythrocyte sedimentation rate, hemoglobin and serum ferritin levels, and WBC count reflect disease activity and are useful for long term followup. 2 figures, 4 tables, and 24 references. (AA-M).

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Spring-Loaded Finger-Stick Device Transmits Hepatitis B Source: Hepatitis B Coalition of Minnesota News. 2(3): 3. April 1992. Contact: Available from Hepatitis B Coalition. 1573 Selby Avenue, Suite 229, St. Paul, MN 55104. (612) 647-9009. Summary: This newsletter article summarizes two reports regarding the transmission of hepatitis B with a spring-loaded finger-stick device of the type used by people with diabetes. This article briefly reports on articles in the Morbidity and Mortality Weekly Report and the New England Journal of Medicine, and notes that the Food and Drug Administration is issuing a safety alert concerning the use of all spring-loaded fingerstick devices. The editor notes that many medical offices continue to use these devices when checking hemoglobin and blood glucose levels, and they do not change or sterilize the platforms between patients.

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Personal Models of Diabetes in Relation to Self-Care, Well-Being, and Glycemic Control: A Prospective Study in Adolescence Source: Diabetes Care. 24(5): 828-833. May 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This review article describes a prospective study that tested the utility of illness beliefs, conceptualized as personal models of diabetes, in predicting self care, well being, and subsequent glycemic control in adolescents with diabetes. Of 74 adolescents recruited from four regional hospitals in southern England, 54 completed the 1 year follow up. They completed questionnaires assessing diabetes self care, well being, and personal models of diabetes at baseline and 1 year follow up. Glycosylated

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hemoglobin assays performed as part of their usual diabetes care were used to assess glycemic control. After controlling for baseline anxiety, change in perceived impact of diabetes prospectively predicted adolescents' anxiety. After controlling for baseline dietary self care, change in perceived effectiveness of the diabetes treatment regimen to control diabetes predicted dietary self care. Poorer dietary self care and being female were predictive of poorer glycemic control. Socioeconomic status did not enter the regression to predict follow up dietary self care, suggesting that the perceived impact of diabetes mediates the association between socioeconomic status and dietary self care. The article concludes that the study provides further support for the role of personal models of illness in determining responses to illness. As adolescents take responsibility for the management of their diabetes, parents, clinicians, educators, and interventionists should consider these adolescents' beliefs about their diabetes and its treatment as key factors influencing self care, emotional well being, and glycemic control. 2 tables. 33 references. (AA-M). •

Diabetes, Impaired Fasting Glucose, and Elevated HbA1c in U.S. Adolescents: The Third National Health and Nutrition Examination Survey Source: Diabetes Care. 24(5): 834-837. May 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This review article describes a study that used data from the Third National Health and Nutrition Examination Survey to estimate the prevalence of diabetes, impaired fasting glucose, and elevated glycosylated hemoglobin (HbA1c) levels in U.S. adolescents during 1988 to 1994. The prevalence of diabetes was calculated for 2,867 adolescents who attended any physical examination and had glucose measured. The prevalence of impaired fasting glucose was calculated for the subsample of 1,083 adolescents who were assigned to the morning half sample, attended a morning examination, and fasted for at least 8 hours. The prevalence of elevated HbA1c was calculated for 2,852 adolescents who attended any physical examination and had HBA1c measured. The study found that 13 of the 2,867 adolescents who had glucose measured were considered to have diabetes. Of these, nine reported using insulin, two reported using oral agents only, and two did not report any treatment but had high glucose levels. Four of the cases were considered to have type 2 diabetes. The four adolescents not using insulin were non-Hispanic blacks or Mexican Americans. The estimated prevalence of diabetes per 100 adolescents ages 12 to 19 years was 0.41 percent. The prevalence of impaired fasting glucose among adolescents without diabetes who had fasted for at least 8 hours was 1.76 percent. The prevalence of elevated HbA1c was 0.39 percent. The article concludes that the national data reflect the presence of type 2 diabetes in U.S. adolescents, but the survey sample size was not large enough to obtain precise prevalence estimates because of the relatively low prevalence. 2 tables. 15 references. (AA-M).

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Diabetes Quality Improvement Project Source: Diabetes Care. 24(10): 1815-1820. October 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This review article describes the Diabetes Quality Improvement Project (DQIP), which has developed and implemented a comprehensive set of national measures for evaluation and quality improvement (QI). The public and private

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partnership of the DQIP brought together groups ranging from consumers to purchasers of health care to the American Diabetes Association, and providers of health care. The DQIP resulted in a set of guidelines, not standards of care, released in August 1998. The measures were broadly implemented across multiple health care settings within 1 year of their release, in part due to the multifaceted group that developed the measures. The DQIP included glycosylated hemoglobin testing, lipid testing, blood pressure control, foot examination, eye examination, and monitoring of kidney disease (diabetic nephropathy). In 2000, a set of patient survey-derived measures was added after being extensively field tested. These measures included smoking cessation counseling, selfmanagement, nutritional education, satisfaction, interpersonal skills of the health care team, and functional status. DQIP measures provide readily available methods to evaluate interventions to improve diabetes care. The authors conclude that the factors that have contributed to the success of the DQIP include a broad appreciation of the opportunities to reduce the diabetes burden in the United States and a conviction that assessment of the quality of care would lead to improvements; a concern that multiple independent efforts to develop performance measures introduce burden without added benefit; a need for standardized, uniform performance measures capable of accurately and reliably assessing the quality of care within and across health care systems; and the partnerships forged early in the project that helped the DQIP gain valuable input from both the public and private sector. 2 figures. 2 tables. 29 references. •

Type 2 Diabetes in Children and Adolescents: An Emerging Disease Source: Journal of Pediatric Health Care. 15(4): 187-193. July-August 2001. Contact: Available from Mosby. 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 6542452 or (407) 345-4000. Fax (407) 363-9661. Summary: This review article presents pediatric nurse practitioners with the most recent information about type 2 diabetes in children and adolescents, summarizes current understanding about diagnosis, and outlines treatment options. Although children and adolescents are usually diagnosed with type 1 diabetes, within the past 10 years children as young as 8 years old have been diagnosed with the type 2 diabetes. Type 2 diabetes in youth is an emerging disease, so its natural history is not well understood. Risk factors for type 2 diabetes in children and adolescents are similar to those in adults, including non-European ancestry, family history of type 2 diabetes, obesity, insulin resistance, and age. African American and Hispanic youth are at greater risk than white youth. The initial assessment of children and adolescents with a potential diagnosis of diabetes is critical. Although youth with type 2 diabetes may or may not have the classic symptoms of polydipsia, polyuria, and polyphagia, they often have features associated with insulin resistance syndrome such as dyslipidemia, hyperglycemia, obesity, hypertension, polycystic ovarian syndrome, and acanthosis nigricans. Blood glucose levels are essential to the diagnosis of diabetes, but additional laboratory measures are also important. The aim of treatment is to normalize blood glucose and glycosylated hemoglobin values. Fundamental to this aim is an individualized plan for nutrition and activity. The choice of pharmacologic management will depend on the child's clinical presentation. Currently, insulin and metformin are the only drugs approved by the Food and Drug Administration for the treatment of diabetes in children; however, selected oral medications have been used with success. Diabetes self management education is also an essential component in the management of diabetes. Education must focus on psychomotor skills, medical nutrition therapy, and physical activity. Routine follow up care should occur every 3 to 4 months. Primary prevention activities include counseling all patients about the importance of a healthy diet and exercise and

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monitoring physical development. The article presents a case study and discusses the nursing and research implications of type 2 diabetes in youth. 1 figure. 2 tables. 28 references. (AA-M). •

Postprandial Blood Glucose Source: Diabetes Care. 24(4): 775-778. April 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This review article presents the consensus position developed by a seven member panel of experts in diabetes, endocrinology, and metabolism with regard to issues related to postprandial blood glucose (PPG). Most patients who have diabetes fail to achieve their glycemic goals, and elevated PPG concentrations may contribute to suboptimal glycemic control. The panel developed a consensus position on questions related to the definition of PPG; the relationship among PPG, fasting plasma glucose, and glycosylated hemoglobin; the contribution of PPG to the long term complications of diabetes; the circumstances under which people with diabetes should be tested for PPG; the benefits and risks of specifically lowering PPG in an effort to achieve better glycemic control; and the additional research that needs to be performed to clarify the role of PPG in the medical management of diabetes. 1 appendix. 7 references.

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What's Ahead in Glucose Monitoring? Source: Postgraduate Medicine. 109(4): 41-49. April 2001. Contact: Available from McGraw-Hill, Inc. 1221 Avenue of the Americas, New York, NY 10020. (612) 832-7869. Summary: This review article, the second of four articles on diabetes, discusses the latest technological advances in glucose monitoring. Self monitoring of blood glucose (SMBG) allows people who have diabetes to measure their blood glucose levels at home, adjust treatment regimens as needed, and achieve near normal blood glucose levels. Data from the Diabetes Control and Complications Trial (DCCT) showed that improvements in glycemic control, through intensive insulin therapy and SMBG, significantly reduced the microvascular complications of diabetes. The frequency of SMBG depends on the current glycemic state of the patient. People who have type 1 diabetes should test four or more times daily, whereas for people who have type 2 diabetes, SMBG can less intensive if insulin is not part of the treatment regimen and if glycosylated hemoglobin values are less than 7 percent. Since the publication of the DCCT findings, glucose monitoring has become a big business. As a result, new technologies have evolved rapidly. The new meters for intermittent monitoring are smaller and less dependent on technical aptitude than older models. They require less blood, and many provide downloadable information for glucose analysis. Data systems used with new meters provide valuable information that can greatly improve glycemic control. Continuous glucose sensing is another major breakthrough in diabetes management. An artificial, mechanical islet cell may be the next advance in bringing diabetes under control. The article includes case reports that illustrate the possible value of a continuous glucose monitoring system. 2 tables. 16 references. (AA-M).

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Comparison of Insulin Lispro and Buffered Regular Human Insulin Administered Via Continuous Subcutaneous Insulin Infusion Pump Source: Journal of Diabetes and its Complications. 15(6): 295-300. November-December 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This study compared glycemic (blood glucose) control achieved with insulin lispro or buffered regular human insulin in patients with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) using an external insulin pump. In this 24 week multicenter, randomized, two way crossover open label trial, 58 patients on CSII with adequate glycemic control receive either insulin lispro or buffered regular human insulin for 12 weeks, followed by the alternate treatment for another 12 weeks. Effectiveness and safety measures included hemoglobin A1c (HbA1c, a measure of blood glucose levels over time) at baseline and endpoint, home blood glucose monitoring, hypoglycemia (low levels of blood glucose), and frequency of pump catheter occlusion (blockage). Patients consumed a standard test meal on three occasions, with determinations of fasting, 1 hour, and 2 hour postprandial (after a meal) glucose values. Insulin lispro use was associated with a significantly lower HbA1c than was buffered regular human insulin. Fasting serum glucose values before the test meal were similar between the two therapies. The 1 hour and 2 hour postprandial glucose concentrations were significantly lower during treatment with insulin lispro. No differences between treatments were observed in basal or bolus insulin doses, weight gain, or the incidence and rate of hypoglycemia, hyperglycemia (high levels of blood glucose), or pump occlusions. The authors conclude that, when used in external pumps, insulin lispro provides better glycemic control than buffered regular human insulin with a similar adverse event profile. 3 figures. 1 table. 24 references.

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Diabetic Retinopathy, Visual Acuity, and Medical Risk Indicators: A Continuous 10year Follow-up Study in Type 1 Diabetic Patients Under Routine Care Source: Journal of Diabetes and its Complications. 15(6): 287-294. November-December 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This study describes the incidence and progression of diabetic retinopathy (diabetes associated eye disease) in relation to medical risk indicators as well as visual acuity outcome after a continuous follow up period of 10 years in patients with type 1 diabetes treated under routine care. The incidence and progression of retinopathy and their association to HbA1c (glycosylated hemoglobin, a measurement of blood glucose levels over time), blood pressure, urinary albumin (protein in the urine), serum creatinine levels (a measure of kidney function), and insulin dosage were studied prospectively in 452 patients with type 1 diabetes. In patients still alive at follow up (n = 344), 61 percent (69 patients) developed any retinopathy, 45 percent (51 patients) developed background retinopathy, and 16 percent (18 patients) developed sight threatening retinopathy. Progression from background to sight threatening retinopathy occurred in 56 percent (73 patients out of 131 patients). In 2 percent (6 patients of 335), visual acuity dropped to less than 0.5 and in less than 1 percent (3 patients of 340) to less than 0.1. Patients who developed any retinopathy and patients who progressed to sight threatening retinopathy had higher mean HbA1c levels over time compared to those who remained stable. Patients who developed any retinopathy had higher levels of

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mean diastolic blood pressure, whereas no differences were seen in systolic blood pressure levels between the groups. Analysis showed mean HbA1c to be an independent risk indicator for both development and progression of retinopathy, whereas mean diastolic blood pressure was only a risk indicator for the incidence of retinopathy. The authors stress that metabolic control is an important risk indicator for both development and progression of retinopathy, whereas diastolic blood pressure is important for the development of retinopathy in type 1 diabetes. However, overall the number of patients who became blind during 10 years of follow up was low. 3 figures. 3 tables. 40 references. •

Serum ACE Predicts Severe Hypoglycemia in Children and Adolescents With Type 1 Diabetes Source: Diabetes Care. 26(2): 274-78. February 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This study investigated whether risk of severe hypoglycemia is related to serum (S) ACE (a genotype) level during intensive treatment in children with type 1 diabetes. The study included a cohort of 86 patients with intensively treated type 1 diabetes. Severe hypoglycemia (low blood glucose) was correlated to S-ACE. Patients with S-ACE at the median level of above reported a mean of 3.0 yearly events of severe hypoglycemia compared with 0.5 events in patients with S-ACE lower than the median. Of the patients with an S-ACE at the median level or above, 27 (61 percent) reported severe hypoglycemia, compared with 17 (40 percent) patients with an S-ACE lower than the median. Insulin dose, HbA1c (glycosylated hemoglobin, a measure of blood glucose over time), age, onset age, duration, C-peptide, and sex did not differ between these two groups. The authors conclude that the elevated rate of severe hypoglycemia among patients with higher A-ACE suggests, among other factors, that a genetic determinant for severe hypoglycemia exists. Further evaluation is needed before the clinical usefulness of this test can be elucidated. 1 figure. 2 tables. 34 references.

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Differential Effects of Metformin and Troglitazone on Cardiovascular Risk Factors in Patients with Type 2 Diabetes Source: Diabetes Care. 25(3): 542-549. March 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Traditional cardiovascular risk factors (CVRF) only partly explain the excessive risk of cardiovascular disease in patients with type 2 diabetes. There is now an increasing appreciation for many novel CVRF that occur largely as a result of insulin resistance and hyperinsulinemia. This article reports on a study that investigated whether diabetes medications that vary in their mechanism of action and ability to reduce insulin resistance may differ in their effects on both traditional and novel CVRF. The authors compared the addition of metformin or troglitazone therapy on CVRF in 22 subjects with type 2 diabetes who remained in poor glycemic control while taking glyburide 10 milligrams twice daily. After 4 months of treatment, both metformin and troglitazone led to similar decreases in fasting plasma glucose and HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time). The reduction in insulin resistance was nearly twofold greater with troglitazone than metformin. The authors conclude that for patients with type 2 diabetes in whom maximal sulfonylurea therapy failed, the addition of the insulin sensitizer troglitazone seemed to have greater benefits

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on several traditional and novel CVRF than metformin therapy. These data suggest that medications that more effectively address this underlying metabolic defect may be more beneficial in reducing cardiovascular risk in type 2 diabetes. 1 figure. 4 tables. 56 references. •

Impact of Outpatient Diabetes Management on Serum Lipids in Urban AfricanAmericans with Type 2 Diabetes Source: Diabetes Care. 25(1): 9-15. January 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Treating dyslipidemia (disordered levels of fats in the blood) in patients with diabetes is essential, particularly among minority populations with increased risks of complications. Because little is known about the impact of outpatient diabetes management on lipid outcomes, the authors of this article examined changes in lipid profiles in urban African-Americans who attended a structured diabetes care program. The study featured retrospective analysis of initial and 1 year follow up lipid values in 345 patients (91 percent African-American and 95 percent with type 2 diabetes) selected from a computerized registry of an urban outpatient diabetes clinic. In this population, HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time) decreased from 9.3 percent at the initial visit to 8.2 percent at 1 year; total and LDL cholesterol and triglyceride levels were significantly lower, and HDL cholesterol was higher. After stratifying based on use of lipid specific therapy, different outcomes were observed. In 243 patients not taking dyslipidemia medications, average total cholesterol, LDL cholesterol, and triglyceride concentrations at 1 year were similar to initial values. However, in 102 patients receiving pharmacotherapy, these lipid levels were all lower at 1 year relative to baseline. Mean HDL cholesterol increased regardless of lipid treatment status. Lipid therapy, improved glycemic control, and weight loss were not independently related to changes in HDL cholesterol and therefore could not account for the positive changes observed. Use of lipid-directed medications, improvement in glycemic control, and weight loss all resulted in significant declines in triglyceride levels but only improved HbA1c and weight loss had an independent effect. The authors stress that initiation of drug therapy to treat high LDL cholesterol levels should be considered early in the course of diabetes management to reach recommended targets and to reduce the risk of cardiovascular complications in this patient population. 2 figures. 2 tables. 35 references.

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Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes Mellitus Source: New England Journal of Medicine. 346(22): 1692-1698. May 30, 2002. Contact: Available from New England Journal of Medicine. 860 Winter Street, Waltham, MA 02451-1413. (781) 893-3800. Website: www.nejm.org. Summary: Type 1 diabetes mellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes on insulin-producing beta cells. This article reports on a study of the effects of a nonactivating humanized monoclonal antibody against CD3 (hOKT3y1 Ala Ala) on the loss of insulin production in patients with type 1 diabetes mellitus. Within 6 weeks after diagnosis, 24 patients were randomly assigned to receive either a single 14 day course of treatment with the monoclonal antibody or no antibody, and were studied during the first year of disease. Treatment with the monoclonal antibody maintained or improved insulin production after one year in 9 of the 12 patients in the treatment group, whereas only 2 of the 12 controls had a sustained

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response. The treatment effect on insulin responses lasted for at least 12 months after diagnosis. Glycosylated hemoglobin (a measure of blood glucose levels over time) levels and insulin doses were also reduced in the monoclonal antibody group. No severe side effects occurred, and the most common side effects were fever, rash, and anemia. The authors hypothesize that the mechanism of action of the anti-CD3 monoclonal antibody may involve direct effects on pathogenic T cells, the induction of populations of regulatory cells, or both. 2 figures. 3 tables. 38 references. •

HbA1c Levels Among American Indian/Alaska Native Adults Source: Diabetes Care. 25(12): 2178-2183. December 2002. Contact: Available from American Diabetes Association (ADA). 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Type 2 diabetes is a major public health problem among many American Indian and Alaska Native communities. Elevated levels of HbA1c (glycosylated hemoglobin, a measure of blood glucose over time) have been observed in younger American Indian and Alaska Native adults. This article reports on a study undertaken to determine whether HbA1c levels were elevated among this population nationally and to determine the relationship between HbA1c levels and age due to treatment type, body mass index (BMI), renal (kidney) disease, duration of diabetes, survival, or a poor diabetes health care index. The national Indian Health Service Diabetes Care and Outcomes Audit was completed for a total of 11,419 American Indian or Alaska Native adults with type 2 diabetes from tribes across the U.S. in 1998. The results showed HbA1c levels decreased with increasing age. This inverse relationship was not accounted for by differences in BMI, diabetes duration, treatment type, proteinuria (protein in the urine, a measure of kidney function), or health care index. The authors conclude that with increasing number of young American Indian or Alaska Native adults with diabetes, poorer glucose control is expected to bring concomitant increased morbidity and mortality unless more effective and efficient interventions are developed to improve glucose control in this population. 1 figure. 4 tables. 29 references.

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Are Lower Fasting Plasma Glucose Levels at Diagnosis of Type 2 Diabetes Associated with Improved Outcomes?: U.K. Prospective Diabetes Study 61 Source: Diabetes Care. 25(8): 1410-1417. August 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Type 2 diabetes may be present for several years before diagnosis, by which time many patients have already developed diabetic complications. Earlier detection and treatment may reduce this burden, but evidence to support this approach is lacking. This article reports on a study in which glycemic control and clinical and surrogate outcomes were compared for 5,088 of 5,102 United Kingdom Diabetes Prospective Study participants according to whether they had low, intermediate, or high fasting plasma glucose (FPG) levels at diagnosis. Individuals who presented with and without diabetes symptoms were also compared. Fewer people with FPG in the lowest category had retinopathy (eye disease), abnormal biothesiometer measurements, or reported erectile dysfunction (ED). The rate of increase in FPG and HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time) during the study was identical in all three groups, although absolute differences persisted. Individuals in the low FPG group had a significantly reduced risk for each predefined clinical outcome except stroke, whereas those in the intermediate group had significantly reduced risk for each outcome, except

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stroke and myocardial infarction. The low and intermediate FPG groups had a significantly reduced risk for progression of retinopathy, reduction in vibration sensory threshold, or development of microalbuminuria (protein in the urine, a sign of kidney disease). The authors conclude that people presenting with type 2 diabetes with lower initial glycemia who may be earlier in the course of their disease had fewer adverse clinical outcomes despite similar glycemic progression. Since most such people are asymptomatic at diagnosis, active case detection programs would be required to identify them. 2 figures. 3 tables. 20 references. •

Choosing a Meter For Home Glucose Monitoring Source: Practical Diabetology. 22(1): 40-48. March 2003. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. Summary: With the development of glucose meters for home use, it has become possible for the person with diabetes to measure his or her blood glucose level and obtain a result within seconds. Used in combination with glycosylated hemoglobin testing (a measure of blood glucose levels over time), glucose monitoring provides a fairly accurate picture of overall glucose control and has become an invaluable tool in the care of the patient with diabetes. This article describes the features of various blood glucose meters so that health care providers can choose the most appropriate model for their patients. The author first discusses patient compliance and possible psychosocial factors that might result in a patient's reluctance to use a blood glucose monitor. The author then reviews the different meters available, describes recent improvements in meters, and discusses meters for special needs, alternate-site testing, teaching meter technique, scheduling glucose testing, displaying and analyzing the results, and the development of continuous glucose sensors. A two-page table summarizes the features of the presently available blood glucose meters. 1 table. 3 references.

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

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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Project Title: A COMPARATIVE REGULATION/THALASSEMIA

APPROACH

TO

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GLOBIN

Principal Investigator & Institution: Zon, Leonard I.; Professor; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2003; Project Start 01-FEB-1998; Project End 31-JAN-2008 Summary: (provided by applicant): The synthesis of hemoglobin involves globin chain production, heme-biosynthesis and iron utilization. We have undertaken a genetic approach to understanding the process of hemoglobin production using the zebrafish as a model system. Mutagenesis screens have previously identified five complementation groups of zebrafish mutants with defects in hemoglobin production. In the previous grant period, we isolated the sauternes gene, which encodes ALAS2, the first enzyme in the home-biosynthesis pathway. Mutations in ALAS2 cause congenital sideroblastic anemia in humans, and the zebrafish sau mutant represents an animal model of this disease. We also isolated the ferroportin 1 gene as the defect in the weissherbst mutant. Ferroportin 1 proved to act as the basolateral iron transporter of the gut as well as the placental iron transporter in mammals. Subsequently, it was found that mutations in ferroportin 1 are associated with hemochromatosis in humans. Our studies established the fish system as a means to study human disease and to isolate novel genes. During this new grant period, we will further sequence and characterize the zebrafish globins and establish the structure of the globin loci. We plan to isolate and characterize two newly identified hypochromic mutant genes. A dominant suppressor screen will be done to delineate genes that participate in the ferroportin 1 pathway of iron utilization. A chemical genetics approach will be used to understand hemoglobin production. A library of sixteen thousand compounds will be examined for effects on rescue of our hypochromic mutant phenotypes and another screen will look for chemicals that induce fetal globin gene expression in adults. These pharmaceutical compounds may ameliorate disease conditions in other vertebrates. Our studies should provide a better understanding of the basic biology of hemoglobin production and may have a therapeutic impact on patients with thalassemia, sickle cell anemia, and hemochromatosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A QTL CHROMOSOME 8Q

FOR

FETAL

HEMOGLOBIN

AND

F

CELLS

ON

Principal Investigator & Institution: Thein, Swee L.; U of L King's College London King's College London London, Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant): Current treatment for Sickle cell disease (SCD) and beta thalassemia is, at best, symptomatic involving blood transfusions, the use of drugs to remove iron and to control pain, and in cases with HLA-compatible siblings, bone marrow transplantation. Our studies and others, have shown that in both disorders, high levels of fetal hemoglobin (Hb F, alpha1gamma2) have a major beneficial effect. The ability to produce Hb F in response to disease varies enormously from patient to patient, and is one of the major factors underlying the remarkable diversity in the severity of these disorders. This has prompted an intense search for approaches to augment fetal hemoglobin production in patients with SCD and beta thalassemia, one of which involves the use of drugs such as hydroxyurea and butyrate analogues. However, these agents are limited by their toxicity and they are effective in only a proportion of patients. The long term objective of this proposal is to obtain a better

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understanding of the genetic factors which modify fetal hemoglobin and F cell (FC) levels in normal adults and in response to disease. We have demonstrated for the first time that Hb F and F cell levels are highly heritable and transmitted as a complex genetic trait, influenced by several factors including a common sequence variant (C to T) in the Ggamma-promoter region, referred to as the Xmn1-Ggamma site. In earlier studies, as part of a systematic search for loci that may regulate gamma globin gene expression in beta thalassemia and SCD, we have identified an extensive kindred which includes individuals with beta thalassemia and hereditary persistence of fetal hemoglobin (HPFH). A quantitative trait locus (QTL) modifying fetal Hb production has been mapped to chromosome 6q23 in this kindred but variance components analysis revealed that a significant amount of FC variance remained unaccounted for. Furthermore, other QTLs for Hb F and FC have been implicated in different family studies. The presence of the Xmn1-Ggamma site is a major determinant for FC levels, and its location suggests that it is involved in transcriptional activation of the Ggamma globin gene. A linkage re-analysis of the genome-wide data in the kindred was carried out under a two-locus genetic model, with one of the loci being the Xmn1-Ggamma site. A new locus on chromosome 8q has now been identified using this method. Now, in an integrated program, we propose to isolate and characterize the 8q QTL by three approaches: (1) positional (candidate) gene cloning, (2) functional cloning by complementation assays in transgenic mice, and (3) differential gene expression analysis, in parallel with the 6q project. The delineation of these genetic factors should increase our understanding of the trans-acting factors for the fine tuning in the control of Hb F production after birth in normal adults and in response to disease with implications for pharmacogenomics. The discovery of these factors may also suggest new approaches for therapeutic augmentation of fetal hemoglobin production in patients with SCD and beta thalassemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALLOGENEIC CHIMERISM IN MURINE SICKLE CELL DISEASE Principal Investigator & Institution: Archer, David R.; Assistant Professor; Pediatrics; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 08-JUL-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Sickle cell disease is a debilitating inherited hemoglobin disorder that is the most common single-gene disease in the world. Hematopoietic stem cell transplantation is the only curative therapy for SCD; however toxic myeloablative conditioning regimens and barriers to allotransplantation have limited its use to children with major complications and HLA matched donors. New myelosuppressive/immunosuppressive transplant strategies are emerging to reduce morbidity and mortality and to make cell transplantation available to a larger number of patients by intentionally inducing mixed hematopoietic chimerism. However, these protocols raise significant issues that can be best addressed in a preclinical model. Using a murine model of sickle cell disease that expresses exclusively human sickle hemoglobin we have defined a non-myeloablative transplant protocol that induces mixed hematopoietic chimerism and tolerance to MHC disparate donors while correcting hematologic and pathologic manifestations of the disease. In Aim 1, we will extend these studies to determine the levels of donor chimerism that provide hematologic and/or physiologic cure of sickle cell disease. We will determine if very low levels of stem cell chimerism can induce and maintain allogeneic tolerance, and whether genetically modified cell populations can be expanded to provide a permanently corrective mixed chimeric state. Sickle cell disease is now recognized as

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having complex inflammatory interactions between multiple cell types that lead to pathological outcomes. These interactions may also be responsible for the increased rate of rejection found in stem cell transplantation for sickle cell disease. In Aim 2 we will investigate inflammatory and immunological mechanisms involved in this rejection process. We will investigate co-stimulation blockade resistant rejection, immune effector populations, adhesion molecules and cytokines for their involvement and contribution to allogeneic rejection. These aims provide a comprehensive systematic approach to studying the relationship between mixed chimerism and sickle pathophysiology and the enhanced rejection rate found in transplantation for sickle cell disease. Both Aims address basic mechanisms of transplantation tolerance and rejection as well as providing the critical preclinical data that are required for the design of future nonmyeloablative transplants protocols. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ASSESSING NEUROVASCULAR COUPLING WITH FUNCTIONAL MAPPING Principal Investigator & Institution: Sheth, Sameer A.; Neurology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): The objective of this proposal is to investigate the coupling between brain activation and cerebral perfusion. The details behind this neurovascular coupling are yet unclear, but form the basis for several widely used imaging modalities such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and optical imaging of intrinsic signals (OIS). To help clarify the properties of this relationship, this proposal outlines two specific goals: (l) to characterize the spatial and temporal evolution of hemoglobin oxygenation changes within and between vascular and parenchymal compartments; and (2) to determine how well these perfusion signals are coupled to underlying neuronal activity. OIS is wellsuited for the proposed studies because if offers high spatial and temporal resolution, as well as the opportunity for simultaneous electrophysiological recording. A technique for extracting hemoglobin (Hb) concentration changes from the OIS images in two spatial dimensions is presented and, in combination with field potential recording, used to study spatial and temporal aspects of neurovascular coupling in rodent somatosensory cortex. The results of these experiments will influence the design and interpretation of perfusion-based brain imaging techniques, especially fMRI. Identifying aspects of the fMRI signal that more closely reflect underlying neuronal activity will improve the technique's ability to localize brain activity. This development would significantly increase its utility for pre-operative surgical planning, for example. Determining whether coupling breaks down in certain instances will also identify possible limitations to these techniques. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BREAST CANCER HYPOXIA ASSESSED BY NITRIC OXIDE Principal Investigator & Institution: Chance, Britton; Professor; Medical Diagnostic Research Foundation 349 Lancastor Ave, #103 Haverford, Pa 19041 Timing: Fiscal Year 2001; Project Start 16-JUL-2001; Project End 31-MAY-2003 Summary: (Applicant's Description) It is our intent here to lay the groundwork for a translational study of the efficacy of NIR optical method in deternining the level of hypoxia in human breast cancer by NIR optical spectroscopy and imaging. The test

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requires a gold standard of breast tumor hypoxia which is to be provided by pO2 deterninations where the instrumentation, expertise and technology is available at the Leipzig University while the expertise and technology for NIR spectroscopy and imaging is available at the University of Pennsylvania affording an opportunity for translational research. It is our intent to mobilize activities at these two locations in order that a initial test of 50 breast cancers can be made to validate that the spectroscopy and imaging of breast tumor hypoxia gives values comparable to those obtained with the gold standard of pO2 determination and that the tumor localization is consistent with other modalities particularly ultrasound, mammography and biopsy. Thus these studies require validation that these two groups can work together; the Philadelphia group providing instrumentation and personnel skilled in use of the instrumentation, whilst the Leipzig group will provide not only expertise in pO2 determination, ultrasound, biopsy, marnnography, but also the capability of making available a large population of high risk breast cancer patients who are willing to accept the complete protocol for breast cancer examinations. It is our intent to provide two types of NIR information: I) localized and quantitative spectroscopy of the desaturation of hemoglobin and the blood content in the same breast canceri region as that in which the pO2 deternination takes place. 2) A NIR imaging system which gives rapid and effective imaging of the deoxygenation of hemoglobin and blood concentration relative to nearby normal breast tissue. While the pO2 determinations and NIR hemoglobin spectroscopy and imaging currently afford the basis for calibration in models, the comparative study has never been done before in human breast cancers. If ourintended goals of demonstrating feasibility are achieved, then application for support through regular RO1channels would appear to be justified. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELL-FREE 02 CARRIERS: CEREBROVASCULAR CONTROL & STROKE Principal Investigator & Institution: Koehler, Raymond C.; Professor; Anesthesiology/Crit Care Med; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 01-JAN-2000; Project End 31-DEC-2003 Summary: Anemia results in increased cerebral blood flow attributable to decreased blood viscosity and O2 carrying capacity. Attenuating the decrease in O2 carrying capacity by exchange transfusion with cell-free tetrameric crosslinked hemoglobin attenuates the increase in blood flow at reduced hematocrit independent of potential nitric oxide scavenging. During focal cerebral ischemia, in contrast, blood flow is promoted in the ischemic regions. In the present proposal, cell-free polymeric hemoglobin, which has a higher O2 carrying capacity than tetrameric hemoglobin, will be used as a physiologic tool to dissociate effects of viscosity from O2 carrying capacity on cerebrovascular regulation. Further, experimental studies of anemia are largely based on acute reductions in hematocrit, yet clinical anemia is usually a chronic condition. The overall goals of the proposal are to determine a) the mechanisms of changes in cerebral blood flow, baseline arteriolar diameter and vascular reactivity during acute and chronic reductions in hematocrit with and without reductions in O2 carrying capacity, and b) the role of heme oxygenase in ameliorating focal ischemic injury when plasma-based hemoglobin is exchanged for red cell- based hemoglobin. Specifically, the role of cytochrome p450 omega-hydroxylase activity, ATP-sensitive potassium channels and endothelin in the differential pial arteriolar diameter responses to albumin versus hemoglobin exchange transfusions will be determined pharmacologically. P450 omega-

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hydroxylase activity is O2 dependent in the physiological range and produces 20-HETE, a potent constrictor, whereas K-ATP channels are involved in hypoxic vasodilation. Endothelin has been reported to increase after tetrameric hemoglobin transfusion and may contribue to cerebral vasoconstriction. The role of P450 metabolites and endothelin in depressed vascular CO2 reactivity two days after hemoglobin transfusion will be studied. The contribution of heme oxygenase to endothelial dependent dilation and potential upregulation of this contribution during chronic anemia will be investigated both pharmacologically and in transgenic animals deficient in heme oxygenase -2. Reduction of infarct volume by hemoglobin transfusion at reduced hematocrit during focal cerebral ischemia may depend on adequate amounts of heme oxygenase to metabolize extravasated hemoglobin into antioxidant bilirubin. This mechanism will be investigated by using transgenic animlas deficient constitutive heme oxygenase -2 and inducible heme oxygenase -1, by infusion or bilirubin, and by prior hemoglobin transfusion as a preconditioning stimulus to upregulate heme oxygenase -1 before ischemia. These studies will render new insights into cerebrovascular regulation during anemia and into novel methodologies for hemodynamically ameliorating injury from stroke. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELLULAR MECHANISMS OF HB F REGULATION Principal Investigator & Institution: Stamatoyannopoulos, George; Professor of Medicine and Genetics; Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-APR-1992; Project End 31-MAR-2003 Summary: (Investigator's abstract) The goals of this research are to determine the mechanisms of fetal hemoglobin regulation in the adult, delineate the molecular control of induction of fetal hemoglobin, discover new pharmacologic inducers of Hb F synthesis and clone and characterize trans-acting factors which can activate gamma globin gene transcription. The specific aims are to: 1) Test the hypothesis that the program of globin gene expression changes from fetal to adult in the course of differentiation of adult erythropoiesis, by analyzing globin gene transcription in single erythroid cells using probes detecting primary globin gene transcripts. 2) Investigate the molecular mechanisms of pharmacologic induction of fetal hemoglobin synthesis. Identify the cis elements which are responsive to butyrate, 5-azacytidine, erythropoietin or hydroxyurea; characterize and clone the trans-acting factors interacting with these elements; and test the role of histone hyperacetylation on the induction of Hb F by butyrate. 3) Investigate the induction of fetal hemoglobin by analogues and derivatives of short chain fatty acids. Develop new assays allowing detection of compounds which induce fetal hemoglobin; determine structural features associated with the property of fetal hemoglobin induction; search for new inducers of fetal hemoglobin synthesis among FDA approved derivatives of short chain fatty acids. 4) Clone transcriptional activators of gamma globin gene expression from human fetal liver or GM979 cell cDNA libraries, a) use PCR based approaches to clone EKLF-type transcriptional factors specifically transactivating the gamma globin gene; b) use modified MEL/beta-YAC cells as target cells to clone gamma gene activators by an immunoselection procedure. 5) Clone the genes responsible for heterocellular hereditary persistence of fetal hemoglobin using a novel functional complementation assay based on transfer of YACs into target cells or transgenic mice carrying the human beta globin locus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHANNEL-MEDIATED RBC DEHYDRATION IN SICKLE CELL DISEASE Principal Investigator & Institution: Rivera, Alicia; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2004 Summary: (Applicant's abstract) The objective of this application is to provide the applicant with an in-depth training experience that will result in her becoming an independent and funded investigator at the end of this work. Our long-range goal is to study ion transport modulation in red cells and other tissues in an over-stimulated environment that may lead to additional pathology. Dehydration of hemoglobin Scontaining erythrocytes favors the formation of dense cells due to increased hemoglobin S polymerization in sickle cell disease. The preliminary results indicate that the potent vasoactive peptide endothelin-1 induces dehydration of sickle erythrocytes. In addition, it was found that endothelin-1 induced activation of Ca(2+)- activated K(+) channel (Gardos channel) via an endothelin receptor type B- mediated process in normal and sickle erythrocytes. The central hypothesis of this application is that the elevated systemic and local concentrations of endothelin-1 contributes to the pathogenesis of vaso-occlusive episodes by induced dehydration via the Gardos channel. This hypothesis will be tested by defining the regulatory mechanism(s) by which endothelin1 induces Gardos channel activation and red cell dehydration in sickle cell disease. To this end, the functional properties of the Gardos channel will be evaluated in mouse and human erythrocytes containing Hb A and S by following these specific aims: 1) Establish the mechanism(s) by which endothelin-1 activates Gardos channel in sickle erythrocytes: to test the hypothesis that endothelin-1 induced a signaling pathway that changes the Ca(2+) affinity constant of the Gardos channel via a protein kinase C-mediated mechanism(s) in normal and sickle erythrocytes. 2) Identify the mechanism(s) by which endothelin-1 induces dehydration in sickle erythrocytes: to define the physiological pathway(s) of endothelin-1 induced dense red cell formation in normal and sickle cells and its regulatory mechanism(s) by specific blockers of endothelin-1 receptors. Erythrocytes from mice transgenic for hemoglobin S will be studied in vitro and in vivo to assess the role of endothelin receptors in sickle cell dehydration by using endothelin-1 selective receptor antagonists. It is the expectation that this work will determine the mechanism(s) identified are expected to provide critical information on pathological activation of the Gardos channel in sickle erythrocytes. Finally, it is expected that these data will provide preliminary results for the subsequent planned submission of an R01 application. The research proposed in the application is significant because it will provide us with a more comprehensive knowledge of erythrocyte volume regulatory mechanism(s). These, in turn, will help to develop a novel therapeutic strategy to reduce sickle cell formation, and decrease the occurrence of vaso-occlusive episodes. It is additionally significant, because it will provide the means for the applicant to establish an independent research career and to become competitive for a tenure-track assistant professional position. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHARACTERIZATION OF A ALPHA-GLOBIN CHAPERONE PROTEIN Principal Investigator & Institution: Weiss, Mitchell J.; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007

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Summary: Recent discoveries in our laboratory offer new insights into normal erythroid biology and beta-thalassemia. The high- level production of hemoglobin that occurs during erythroid maturation is tightly coordinated so as to minimize toxicities caused by accumulation of individual alpha- and beta- globin subunits, which tend to precipitate in cells. Prior studies of normal and beta-thalassemic erythroid precursors predict that compensatory mechanisms exist to neutralize free alpha-globin. To learn more about the control of hemoglobin production, we isolated RNA transcripts that are induced by the essential transcription factor GATA-1, a global regulator of erythropoiesis. We identified Erythroid Differentiation Related Factor (EDRF), a small, abundant highly erythroid-specific protein that is strongly upregulated during terminal erythroid maturation and appears to be a direct GATA-1 target gene. We determined that alpha-globin is a specific EDRF binding partner in two independent protein interaction screens. EDRF interacts with free alpha-globin but not with beta-globin or hemoglobin A (alpha2beta2). Moreover, EDRF markedly inhibits precipitation of free alpha-globin in solution and in mammalian cells. Our findings raise the possibility that EDRF acts as a chaperone protein to prevent precipitation and subsequent toxicity of free alpha-globin in erythroid cells. Now that we have established a physical and functional connection between EDRF and alpha-globin in vitro and in heterologous cells, we will study the significance of this association in normal erythropoiesis. Structure-function analyses in Aim 1 will define the domains that are required for physical and functional interactions between EDRF and alpha-globin. In Aim 2, we will assess the biological role of EDRF and its association with alpha-globin in established cell lines and in primary erythroid cells derived from in vitro culture of EDRF genetargeted embryonic stem (ES) cells. To this end, we have developed EDRF heterozygous and homozygous-null ES cells. In Aim 3, we will determine the hematopoietic consequences of altered EDRF expression in mice. By genetically manipulating EDRF and free alpha-globin levels, we will determine how their relative stoichiometry affects viability and differentiation of erythroid cells. Specifically, we will establish whether EDRF-null animals exhibit excessive alpha- globin precipitation in erythroid precursors, and whether altered EDRF gene expression affects the severity of beta-thalassemia, a disorder that is distinguished by alpha-globin precipitation. Our studies to characterize a highly expressed erythroid specific protein that prevents aggregation of free alphaglobin are important for understanding how hemoglobin chain balance is modulated by non-globin proteins during normal erythropoiesis and might provide a novel approach to alleviate the deleterious effects of excessive alpha-globin in beta-thalassemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHEMICAL & RECOMBINANT STUDIES ON SICKLE CELL HEMOGLOBIN Principal Investigator & Institution: Manning, James M.; Professor; Biology; Northeastern University 360 Huntington Ave Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-JUL-1982; Project End 31-DEC-2002 Summary: This proposal describes the use of recombinant DNA (for single-site substitutions or for regional substitutions of larger segments and novel chemical modifications to study sickle hemoglobin (HbS) polymerization. The important regions of HbF, of current clinical interest and of HbA2, in inhibition of HbS polymerization and their relative strengths will be evaluated. Our recent finding of the 70-fold lower tetramer-dimer dissociation constant of HbF compared to HbS, HbA and HbA2 will be expanded. Studies will be continued on a hybrid HbA/F containing the amino acids of the a1gamma1 and alpha1gamma2 interfaces of HbF and the remaining sequence of the

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beta-chain. The mechanism by which the subunit interface properties are influenced by other parts of the sequence will be studied. A candidate is helix A (N-terminal amino acids 1-18) of the chain whose contribution both to subunit interface properties and to HbS polymerization will be evaluated. The a source of the proton uptake for both HbA and HbF dissociating to dimers will be investigated by mutagenesis of potential sites common to both Hbs. Dimer to monomer dissociation will continue to be studied with the aid of a recombinant Hb with a substitution in the alpa1beta1 interface. Inhibition of polymerization with recombinant HbS mutants will focus on obtaining quantitative information on the contributions of sites known to be at contact points between tetramers, either inter or intra-strand. We propose to establish which sites function independently and whether they are at lateral or axial contacts in order to identify them as important targets for anti-sickling agents. The second region that we propose to study is the central cavity where we will identify the most important sites in keeping HbS in the more open (sickling) conformation. A novel class of chemical anti-polymerization inhibitors directed at the central cavity will be synthesized based on familiar chemistry and tested to maintain the central cavity of HbS less open (non-sickling). Certain recombinant mutants with either selective or regional substitutions will be supplied to our collaborators for crystallographic studies (Rover), electron microscopy (Josephs) or kinetics of polymerization (Ferrone). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPREHENSIVE SICKLE CELL CENTER Principal Investigator & Institution: Steinberg, Martin H.; Professor of Medicine and Pediatrics; Boston Medical Center Gambro Bldg, 2Nd Fl, 660 Harrison Ave, Ste a Boston, Ma 02118 Timing: Fiscal Year 2001; Project Start 10-APR-1977; Project End 31-MAR-2003 Summary: The BCSCC continues committed to achieve its goals: To provide accurate hemoglobin phenotype testing of the population at risk for the hemoglobin S gene, in particular in the childbearing ages; to provide education and non-directive counseling to individuals and couples identified with hemoglobin traits; to increase the knowledge and awareness of sickle cell trait and sickle cell disease of health care providers and the general public; to provide comprehensive care and to promote a better quality of life for patients with sickle cell disease; through research projects to increase knowledge of sickle hemoglobin and cell disease and translate this into improve methods of detection of traits and treatment of patients with sickle cell disease; through collaboration among the comprehensive centers to maximize and enhance the productivity and effectiveness in achieving the centers' goals; and through the administrative core to coordinate the activities of the five BCSCC core components allowing for continuing exchanges of information between the research and service projects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMPREHENSIVE SICKLE CELL CENTER Principal Investigator & Institution: Stuart, Marie J.; Professor; Pediatrics; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2001; Project Start 08-JUN-1998; Project End 31-MAR-2003 Summary: Although Sickle Cell Anemia (SCA) has been characterized at the molecular level, the pathophysiology of its protein manifestation the vasocclusive crisis (VOC) still remains obscure. The exact events that lead to microcirculatory impairment and obstruction by sickled erythrocytes involve a complex and dynamic sequence of events

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that dependent presumably as much on microcirculatory tone, the activation state of the endothelium, white cells, platelets, and the fluid phases of coagulation as it does on the surface and internal characteristics of the red cell and its content of sickle and fetal hemoglobin. This Center grant will attempt to address the areas enumerated above in a unique and prospective fashion with focus on the crucial window of time during which a watershed change occurs in the erythrocyte's internal characteristics i.e.-its hemoglobin content of S and F. We will meticulously correlate how these physiologic changes in hemoglobin content during the first few years of life will affect the state of activation of the other cellular elements of blood, coagulation factors and endothelium, and how these changes effect the protein clinical manifestations of the disease-VOC and the occurrence of pain. The incidence and the attributes of sickle pain in these infants and young children will be assessed in a comprehensive and prospective longitudinal study. Additionally, our research program will explore at the cellular and molecular level the rationale for potential use of interventional strategies directed at one of the life threatening complications of Sickle Cell Disease, the acute chest syndrome, and also investigate a second and interventional program designed for our children in late childhood and early adolescence which will increase their resilience and perceived control over their lives and illness. Thus, this Center Grant seeks to address various aspect of basic and translational research besides providing the support our patients require to lead independent and productive lives. The research projects will be supported by the traditional aspects of a Comprehensive Sickle Cell Center including education and counseling services, a diagnostic and laboratory core, and appropriate statistical and administrative support. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONTROL OF THE GAMMA TO BETA GLOBIN SWITCH Principal Investigator & Institution: Gumucio, Deborah L.; Associate Professor; Cell and Developmental Biology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: The switch from gamma to beta globin gene expression during development is controlled by a complex regulatory network that includes autonomous regulation of gamma gene expression mediated by sequences near the gene and cis competition between gamma and beta for interaction with a Locus Control Region (LCR), located upstream of the cluster. The goal of this proposal is to exploit documented differences in the timing of the gamma to beta switch among primate globin clusters as a tool to dissect these complex regulatory influences: the galago gamma to beta switch occurs at the end of embryonic life, the capuchin monkey exhibits a mid- fetal switch, while the human switch occurs at birth. Three hypotheses are tested: 1) Specific cis differences linked to the gamma genes themselves control the different patterns of autonomous regulation of the human, capuchin and galago gamma gene in transgenic mice. Chimeric galago/human or capuchin/human gamma genes will be analyzed in transgenic mice using a cosmid construct, LCR-epsilongamma, to identify elements that confer stage-specific control of gamma expression and silencing. 2) The expression of human globin genes will be altered (via changes in competitive interactions) when galago globin sequences are substituted into an intact human globin locus. In the context of a human beta cluster YAC, human sequences will be replaced by 4- 10 kb segments of othologous galago sequences (from gamma or beta gene regions or LCR regions), and expression of the remaining human genes will be assessed in transgenic mice. These experiments will allow dissection of the sequences involved in competitive interactions

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under conditions in which the beta cluster remains intact. 3) Knowledge of in vivo globin gene expression patterns in extant primates will allow reconstruction of the evolutionary pathway that led to their different characteristic gamma to beta switch patterns. To construct an evolutionary model that can explain the generation of the different patterns of globin gene expression observed in extant primates requires careful documentation of those gene expression patterns in vivo. Thus, globin protein and mRNA will be examined in extant primates to document the patterns of gamma to beta switching; this information will be integrated into an evolutionary model that correlates cis sequence changes with alterations in the detailed switching pattern characteristic of each species. This comparative functional analysis of primate globin genes in transgenic mice, combined with studies in extant primates will provide new insights into mechanisms of hemoglobin switching. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COOA: A HEMOPROTEIN CO SENSOR Principal Investigator & Institution: Burstyn, Judith N.; Professor; Chemistry; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: The long-term goal of this project is to understand how CO functions as a cellular signal. There is considerable evidence supporting a role for CO as a regulator in human vascular and neural tissue, but the mechanism of action of CO is as yet incompletely understood. This project is to investigate the only known CO sensor, the hemoprotein CooA from the photosynthetic bacterium Rhodospirillum rubrum, in order to elucidate the mechanism by which this protein senses CO. The presumed receptor for CO in mammalian tissue, soluble guanylyl cyclase, is also a hemoprotein and a number of other hemoproteins are now known to serve as gas sensors. Understanding the function of the CO sensor CooA will provide a foundation for understanding hemoprotein sensors in human physiology. CooA is a member of the CRP (cAMP receptor protein) family of transcription regulators. In the presence of CO, CooA binds to DNA and turns on the expression of a multicomponent CO-oxidation system in R. rubrum. The cooperative binding of oxygen to hemoglobin is the paradigm for understanding how heme can function as a regulator of protein function. Like hemoglobin, CooA is proposed to undergo a conformational change that is triggered by the binding of CO to the heme cofactor. The overall objective of the studies outlined in this proposal is to correlate changes in the heme coordination state of CooA with changes in protein conformation in order to understand how the heme serves to regulate protein function. It is our hypothesis that changes in the coordination environment of the heme upon CO binding alter the conformation of CooA, enabling the protein to bind to DNA. There are three Specific Aims that we propose to address in this project period: 1) we will identify the unique coordination characteristics of the Nterminal proline ligand, 2) we will correlate CO binding and oxidation state with changes in protein conformation, and 3) we will identify the changes in heme coordination that induce DNA binding activity. Control of protein conformation through changes in metal coordination geometry is a general mechanism for gas sensing, and it is likely that many proteins that employ this mechanism remain to be discovered. Understanding the mechanism by which CooA senses CO will add to our knowledge of how heme is used as a gas sensor in biology and suggest mechanisms by which CO functions as a signal in human tissues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--HUMAN CHALLENGE FACILITY Principal Investigator & Institution: Cohen, Myron S.; Professor of Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2002 Summary: The Human Challenge Core is available to assess the infectiousness of Neisseria gonorrhoeae isogenic mutants developed in this application, or mutants generated by investigators at other CRCs. Specifically, we will examine the requirements for heme and hemoglobin receptors, and requirement for opa proteins. In addition, the Core will test gonococcal isolates that have already been developed as part of the CRC Program. Specifically, mutants less likely to resist the microbicidal action of the neutrophil inflammatory response have been generated. The Core can also support vaccine research, if a vaccine with adequate immunogenicity is developed. Core facilities include the Microbiology laboratory in the Division of Infectious Disease, and the patient care areas of the General research Center. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEVELOPMENT OF AN HA2 DOMAIN BASED PERIODONTITIS VACCINE Principal Investigator & Institution: Decarlo, Arthur A.; President and Chief Science Officer; Agenta Biotechnologies, Inc. Box 531032 Birmingham, Al 35253 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2002 Summary: ( Applicant's Abstract) Periodontal disease can be diagnosed in >50 percent of adults and may contribute to poor health through oral and systemic infection. The disease process is induced by bacteria and the severity of the disease seems due in large part to the immune response of the host. Over the past decades certain microorganisms have become highly implicated in the pathogenesis of periodontal disease including the gram negative Porphyromonas gingivalis (P. gingivalis). We have recently described and patented a small protein domain from P. gingivalis (HA2) that may be essential for the acquisition of iron and the porphyrin molecule, and, therefore, essential for survival of P. gingivalis in the periodontal pocket. Data indicated that the HA2 domain was detectable in clinical plaque samples and its detection was associated with hemoglobin binding activity within the plaque as well as with periodontal disease severity. Further, data indicated that an IgG humoral antibody response against the HA2 domain was stimulated with periodontal therapy and that this serum IgG could functionally inhibit hemoglobin-binding of the gingipains. These data implicate the HA2 domain of P. gingivalis as a good candidate for vaccine development to inhibit periodontal disease initiation and progression. PROPOSED COMMERCIAL APPLICATION: An effective vaccine against periodontal disease could be applicable to the entire population for the prevention of abatement of bone loss around the teeth that is often accompanied by acute abscess formation and loss of teeth. Notwithstanding malnourishment that accompanies partial or complete edentulism, periodontitis has significant untoward systemic effects so the value of this vaccine in terms of overall medical cost savings is enormous. Current treatment and prevention of periodontitis is ineffective or timeconsuming and expensive. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIET THERAPY IN DIABETES MANAGEMENT OF MEXICAN AMERICANS Principal Investigator & Institution: Briones, Esperanza R.; Univ of Texas-Pan American Edinburg, Tx Timing: Fiscal Year 2002; Project Start 01-JUN-1977; Project End 31-JUL-2006 Summary: (provided by applicant): Diabetes in Hispanic Americans is a serious health problem. It affects 1.2 million or 10.6% of the Mexican American population. Approximately 24% of Mexican Americans in the U.S. between the ages of 45-74 have diabetes. In Hispanic adults, diabetes is primarily type 2, and its incidence is correlated with the occurrence of obesity. The purpose of the study is to conduct a two and half (21/2) year randomized trial of a culturally appropriate dietary and lifestyle education intervention designed for Mexican Americans with type 2 diabetes residing in Rio Grande Valley. Both males and females, with type 2 diabetes will be recruited, with two age subgroups, ages 45-59 and 60 and above. Eligible participants will be randomized into two groups. Group 1 will receive the conventional dietary counseling and group 2 will receive additional sessions and follow-up. The specific objectives of the study are: to assess the effectiveness of a culturally appropriate intervention to improve participants' adherence to dietary modifications, medication schedules, and promote sustained improvements in lifestyle behaviors; to assess the anthropometric measurements, health habits, and nutrient consumption of subjects at baseline and after dietary and educational sessions; to determine fasting serum glucose and glycosylated hemoglobin in assessing the level of diabetes control; and to assess the lipid profile (serum cholesterol, triglycerides, high density lipoprotein cholesterol) which are associated with the development of coronary heart disease in diabetes. Statistical calculations will be used to evaluate the differences between the two groups. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIETARY COMPOSITION, OBESITY, AND CARDIOVASCULAR RISK Principal Investigator & Institution: Schaefer, Ernst J.; Professor; None; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2001; Project Start 01-JUL-1999; Project End 31-MAY-2004 Summary: Coronary heart disease (CHD) is a major cause of death and disability in our society. Obesity increases CHD risk by adversely affecting glucose, lipoproteins, and blood pressure. There is consensus that dietary saturated fat and cholesterol (C) restriction is beneficial for low density lipoprotein (LDL) lowering and CHD risk reduction, but there controversy about other aspects of the diet. We propose to examine the effects of three diets meeting National Cholesterol Education program Step 2 diet criteria on body weight and composition and on CHD risk factors (LDL C, HDL C, remnant lipoprotein C, Lp(a) C, insulin, glycosylated hemoglobin, glucose, and blood pressure) in the fasting and nonfasting state (4 hours after a meal) in 80 men and women (men greater than or equal to 50 and less than 65 years of age, women postmenopausal and less than 65) with LDL C values greater than or equal to 130 mg/dI and a body mass index greater than or equal to 28 and less than 38 kg/m2. A four phase study will be conducted in which all food and drink is provided during the first 3 phases, while diet is recommended but not provided in the fourth phase. In phase 1, all subjects will initially be placed on an average isoweight U.S. diet for 5 weeks (15 percent protein, 35 percent fat; 15 percent saturated fat; 15 percent monounsaturated (mono) fat; 6 percent polyunsaturated (poly) fat, with 150 mg of cholesterol/1000 calories and 10 g/1000 cal.

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of fiber). For phase 2, subjects will then be equally randomized to one of 3 diets, all containing 15 percent protein, 5 percent saturated fat and 60 mg of cholesterol/1000 calories: 1) high complex carbohydrate (CHO): 15 percent fat, 5 percent mono, 5 percent poly, and 70 percent CHO (mainly complex with relatively high glycemic index), 16 g/1000 cal of fiber, and low dietary caloric density of 1.10 cal/gm; 2) high mono: identical to diet 1 except that the fat content will be 30 percent (15 percent mono) and 55 percent CHO with CHO of high glycemic index and high caloric density, 1.25 cal/gm; and 3) composite: identical to diet 2 except that there will be lower glycemic index and low dietary caloric density of 1.10 g/1000 cal). These diets will be given ad libitum, and subjects can adjust their calorie level using 200 calorie casseroles from 66 percent to 133 percent of calories needed to maintain weight, for a 12 week period. Subjects will then be continued on these same diets isoweight for an additional 5 weeks under controlled circumstances in phase 3, and then for one year (phase 4) under uncontrolled circumstances where they will receive dietary instruction and menus, but not food. Body weight and blood pressure will be assessed three times per week, and plasma lipoproteins (LDL, HDL, remnants, and Lp[a]), glucose, glycosylated hemoglobin, and insulin levels will be assessed three times in the fasting state and once in the fed state at the end of each controlled dietary period and at 3, 6, 9, and 12 months in the long-term follow-up period. In addition, body weight, body energy expenditure, physical activity, body composition, anthropometics, and metabolic rate will be measured at regular intervals during all phases. Our hypothesis is that the fat-restricted diet rich in complex carbohydrate and low in caloric density and the composite diet low in caloric density and glycemic index will have a more favorable effect on CHD risk factors, body weight, body composition and energy expenditure than the Step 2 diet higher in mono fat, glycemic index, and caloric density. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DNA METABOLITES

AND

HEMOGLOBIN

ADDUCTS

OF

BUTENEDIOL

Principal Investigator & Institution: Powley, Mark W.; Environmental Sciences & Engr; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-JAN-2005 Summary: (provided by applicant): The main purpose or the proposed research is to determine the formation of potentially mutagenic metabolites in the 1,3-butadiene (BD) metabolic pathway leading to MI, a major urinary metabolite in humans. To understand this pathway, tissues from female mice and rats exposed to 3-butene-1,2-diol (BD-diol) will be used. BD-diol is the hypothesized immediate precursor of two potentially mutagenic metabolites, hydroxymethylvinylketone (HMVK) and 3,4-epoxy-1,2butanediol (EB-diol), and is also a precursor to MI. The first hypothesis to be tested is that HMVK, but not EB-diol, is formed in B-diol exposed animals in an exposuredependent manner and therefore contributes to mutagenicity observed in animals exposed to BD-diol and BD. The second hypothesis is that a hemoglobin adduct of HMVK can serve as a biomarker of BD-diol and BD exposure. In testing these hypotheses we will accomplish several aims. The first specific aim is to develop methods to measure promutagenic adducts formed by HMVK, specifically 1,N2propanodeoxyguanosine adducts, in BD-diol exposed animals. Another specific aim is to develop methods to measure the hemoglobin adduct of HMVK in the exposed animals. The third specific aim is to measure DNA and hemoglobin adducts of EB-diol. The results of these experiments will demonstrate the formation and possible

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contribution to mutagenicity, of HMVK and EB-diol following metabolism of BD-diol. The final specific aim is to measure the HMVK adducts in BD exposed animals and humans. The proposed research will help explain a critical, but not fully understood, BD metabolic pathway. This will improve our understanding of BD metabolism as a whole and ultimately increase our ability to accurately assess the risk of BD to humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DNA METHYLATION, CHROMATIN, AND GLOBIN GENE SILENCING Principal Investigator & Institution: Desimone, Joseph; Geneticist; Medicine; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 18-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Increased level of fetal hemoglobin (HbF) is clinically beneficial ill patients with sickle cell anemia. Experiments performed in the baboon model demonstrated that HbF levels could be elevated using pharmacologic agents such as 5-aza-2'-deoxycytidine (decitabine), butyrates, and hydroxyurea. The usefulness of these drugs in patients with sickle cell disease was confirmed in a number of clinical trials. The MSH study demonstrated that hydroxyurea therapy reduced the number of pain crises, incidence of acute chest syndrome, and transfusion requirements in patients. A significant number (10-40%) are refractory to treatment as evidenced by minimal changes in HbF levels. Furthermore, because the increased HbF is distributed heterogeneously among red cells, a large percentage of erythrocytes remain unprotected from intracellular polymerization of deoxy-HbS molecules. New and improved agents and therapies must therefore be developed which increase HbF to higher levels in a greater proportion of patients and maximize the number of F cells produced. It is our goal to develop a better therapeutic regimen for patients with sickle cell disease based upon the use of the demethylating drug decitabine, histone deacetylase inhibitors, and growth factors. We intend to investigate the mechanism of action of these agents by determining the role of DNA methylation and histone acetylation in both the development regulation of globin gene expression and the reactivation of HbF expression in the adult. Analysis of the methylation and histone acetylation status of genes in small numbers of highly purified hematopoietic progenitor cells is now possible using FACS, bisulfite sequencing and immunoprecipitation of formaldehydefixed chromatin fragments (CHIP) in combination with PCR. We propose to follow changes in gamma-globin gene expression, DNA methylation, and histone acetylation during fetal development and normal erythroid differentiation, and following augmentation of HbF production induced by administration of decitabine and histone deactylase inhibitors. We will use an in vitro culture system and an in vivo baboon model system that we have used for the past 20 years to study these mechanisms. These studies will define the mechanisms of gamma-globin gene silencing, and will aid in the development of new procedures to augment HbF production in patients with sickle cell disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECT OF INDUCIBLE ANTIOXIDANTS ON HEMOGLOBIN TOXICITY Principal Investigator & Institution: Regan, Raymond F.; Surgery; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2003; Project Start 01-DEC-2002; Project End 30-NOV-2006

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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 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: ELECTRON TRANSFER WITHIN PROTEIN COMPLEXES Principal Investigator & Institution: Hoffman, Brian M.; Professor; Chemistry; Northwestern University 633 Clark St Evanston, Il 60208 Timing: Fiscal Year 2003; Project Start 15-MAR-1999; Project End 31-DEC-2007 Summary: (provided by applicant): This program in the study of inter-protein electron transfer (ET) aims to understand the fundamental structural, dynamic and energetic features that control, * lnterfacial recognition and reactive docking between protein ET partners; *The actual process of ET between docked partners.We study three protein systems, each offering distinct opportunities to address these issues: mixed-metal [Zn, Fe3+L] hemoglobin hybrids allow us to study ET within a 'predocked' protein-protein complex, across a crystallographically defined, non-covalently coupled interface; the complex of cytochrome c peroxidase (CcP) with cytochrome c (Cc) involves CcP as the archetypical protein which has two ET-active and communicating redox centers, as well as two distinct surface domains for binding its ET partner; the physiologically important ET complexes of cytochrome b5 with myoglobin (Mb) and hemoglobin (Hb) represent a new 'dynamic docking' paradigm in which there are many docked configurations, but the most reactive are not the most favorable for binding. Among a broad array of individual goals subsumed under the above aims, we merely note several that are central to our efforts in the coming period: (i) Characterize the ways in which protein

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fluctuations control interprotein ET, and the degree to which they can be modulated by coupling to the external medium.(ii) Establish the role of ET between the two CcP sites in the kinetics of ET between CcP and Cc. (iii) Implement a plan to experimentally establish the degree to which dipole forces, rather than monopole interactions, control protein-protein docking. To realize our aims, we shall apply and extend a broad range of kinetic, thermodynamic, spectroscopic, and theoretical methods. New approaches and strategies include, among others, extensive studies of protein-protein ET in sol-gels. The issues we address and the strategies we develop have applications extending far beyond the ET reaction we study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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

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Project Title: EVALUATION OF HYPOXIA BY EF5 BINDING IN CERVIX CANCER Principal Investigator & Institution: Evans, Sydney M.; Associate Professor; Radiation Oncology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 20-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): It has been known for many years that anemic cervix cancer patients have a poorer prognosis and response to radiation therapy than similar patients with normal blood hemoglobin levels. The Gynecologic Oncology Group (GOG) is performing the first Phase III trial (GOG191) to determine whether modifying patient hemoglobin levels with recombinant human erythropoietin will improve outcome following radiation therapy and cisplatin. One possible mechanism underlying the poor prognosis of anemic cervix patients is that their tumors are hypoxic. This would make the tumors radiation resistant and/or more biologically aggressive due to hypoxia-mediated molecular/cytokine changes. The methodology to evaluate the importance of pretreatment tumor hypoxia was not incorporated into the GOG191 trial for logistical reasons but the GOG has identified this to be a critical biologic question. The GOG is supporting this analysis by providing us with access to patient tissues; the trial is referred to as GOG8002. We have proposed to assess tumor hypoxia in patients entered onto GOG191 and to determine the clinical significance of this finding. Our overall hypothesis is that hypoxia, as determined by EF5 binding, is a critical determinant of cervix cancer biology and treatment response. EF5 has been studied in detail using quantitative fluorescence immunohistochemistry and can be used to measure both hypoxic area and absolute tissue pO2. This technique is compatible with large multi-institutional trials because the drug is safely and easily administered and tissue can be sent to a central facility for processing. Our specific aims are to: 1: Determine the relationship between the level of EF5 binding and pre-treatment hemoglobin level, tumor size, and stage; 2: Explore whether pre-treatment tumor hypoxia (as measured by EF5 binding) is associated with overall survival, progressionfree interval and local control and 3: Explore the relationships between EF5 binding and CD-31 labeling (tumor vasculature), and EF5 binding and Ki-67 labeling (cellular proliferation). EF5 binding will be quantified in several ways. The maximum binding rate will be determined in vitro and the in situ binding will be assessed as a percent of maximum. This will allow conversion of binding to tumor pO2. Further analyses will incorporate the area of tissue involved at various binding levels. Patient follow-up and statistical evaluations will be provided by the GOG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FUNCTIONAL NEAR INFRARED IMAGING SYSTEM Principal Investigator & Institution: Barbieri, Beniamino F.; President; Iss, Inc. 1602 Newton Dr Champaign, Il 61822 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-JUL-2003 Summary: (Provided by Applicant): ISS will develop a novel instrument for the noninvasive imaging of functional activation of the brain. The system will consist of novel hardware and software. The hardware will include 32 laser diode emitters, and 8 photomultiplier tube detectors. Novel features of the hardware will include a customized frequency synthesizer and a customized data acquisition card, both of which will significantly improve imaging performance over current equipment. The software will include real time video maps of multiple tissue properties (hemoglobin oxygen saturation, hemoglobin concentration, and tissue optical parameters). These maps will be generated from a variety of methods including calibrated frequency

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domain multiple distance (C-FDMD) method, absolute frequency domain multiple distance method, continuous wave differential path length method, and crossed sourcedetector (CSD) path method. This multiplicity of methods will allow maps which benefit from the special characteristics of each method, from the high quantitation of C-FDMD method to the high localization of the CSD method. The system will be tested on phantoms, and in human subjects in conjunction with functional Magnetic Resonance Imaging (fMRI). Upon completion of its design and test, the system will be the world's only commercially available research system for near infrared tissue hemoglobin dynamics imaging. PROPOSED COMMERCIAL APPLICATION: 1. Optical imaging of brain activation and localization of stimulated brain cellular aggregates; 2. Cognitive neuroscience; 3. Brain oxygenation monitoring during cardiac bypass surgery; 4. Sleepapnea studies; 5. Attention deficit disorder investigations Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MYOGLOBINS

FUNCTIONAL

PROPERTIES

OF

HEMOGLOBINS

AND

Principal Investigator & Institution: Olson, John S.; Professor; Biochemistry and Cell Biology; Rice University 6100 S Main Houston, Tx 77005 Timing: Fiscal Year 2001; Project Start 01-DEC-1976; Project End 31-MAR-2003 Summary: Our long range goals are to derive complete mechanistic descriptions of the functional properties of hemoglobins and myoglobins, using site-directed mutagenesis, conventional rapid mixing and equilibrium methods, ultrafast laser photolysis techniques, vibrational and NMR spectroscopies, X-ray crystallography, and various computational methods. Our strategy is to use mammalian myoglobin (Mb) as a simple prototype for identifying the roles of specific amino acids, structural motifs, and stereochemical effects in regulating O2 binding and protein stability. The resultant ideas will then be tested in the alpha and beta subunits of recombinant human hemoglobin and other heme proteins that function in O2 transport, storage, and sensing. Six specific aims are proposed: (1) to test the distal electrostatic mechanism for ligand discrimination in myoglobin; (2) to examine proximal mechanisms for regulating O2, CO, and NO binding; (3) to map out specific pathways for ligand movement into and out of myoglobin; (4) to determine quantitatively the structural compromises between globin stability and physiological function; (5) to establish an allosteric kinetic mechanisms for O2 binding to recombinant human deoxyhemoglobins; and (6) to evaluate the different stereochemical factors that control ligand binding to the alpha and beta subunits of recombinant human hemoglobin. The significance of this work is fourfold. First, the mechanisms involved in regulation of O2 affinity, discrimination against CO binding, cooperativity, and inhibition of oxidation are applicable to all heme proteins. Second, our library of Mb and Hb mutants provides the testing ground for developing computational methods to predict heme protein structure and function. Third, recombinant myoglobin and hemoglobins are excellent model systems for understanding the evolutionary compromises between protein expression, stability, and function. Fourth, these basic biophysical studies provide rational strategies for designing efficient and safe hemoglobin-based 02 delivery pharmaceuticals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GORDON RESEARCH CONF--NITRIC OXIDE IN BIOCHEM & BIOLOGY Principal Investigator & Institution: Beckman, Joseph S.; Professor; Gordon Research Conferences Box 984, 512 Liberty Ln West Kingston, Ri 02892

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Timing: Fiscal Year 2001; Project Start 02-FEB-2001; Project End 31-JAN-2002 Summary: The Gordon Research Conference on "Nitric Oxide in Biochemistry and Biology" is designed to provide chemists, biologists, biochemists, cell biologists, clinicians, and other biomedical scientists with state of the art knowledge on nitric oxide and reactive nitrogen species in chemical and biological systems. This research conference is held every two years; the next meeting will be held February 4-8, 2001, at the Four Points Sheraton Harbortown Hotel, Ventura, California. Three conferences have been held since 1995 and they have proven to be extremely productive based on the large number of applicants and the post-meeting evaluations. Funding is specifically requested to support young investigators as session chairman and speakers as well as to partially support productive post docs and graduate students to attend the meeting. The speakers listed in this program were selected based on suggestions from previous chairs, co-chairs and attendees at the past conferences. Virtually all speakers have accepted the invitation to present their latest research on the biology and chemistry of nitric oxide. Topics to be covered include the roles of reactive nitrogen species in neurodegeneration, vascular disease and wound healing, novel strategies for the selective inhibition of nitric oxide synthase isozymes, reactions of NO with hemoglobin and other heme proteins and the biological effects of tyrosine nitration. In addition, Professor Louis Ignarro, the recipient of the 1998 Nobel Prize in Medicine, will present a Plenary Lecture entitled "The physiological role for N-hydroxyarginine during the synthesis of nitric oxide." Two separate poster sessions of two days each are scheduled for an anticipated 50-70 posters. Total attendance is limited to 135 by Gordon Conference rules. The Gordon Research Conference provides an excellent and needed forum for the diversity of both participants and research areas. The main strength of this Gordon Research Conference is the opportunity offered for scientists in different disciplines to interact in an extended and uninterrupted fashion. This type of interaction generally results in new collaborative research initiatives. The Gordon Research Conference focused on the biological chemistry of nitric oxide plays a crucial role in exploring frontier research in this important and clinically relevant field. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: H.INFLUENZAE HEMOGLOBIN/HEMOGLOBIN-HAPTOGLOBIN BINDING Principal Investigator & Institution: Stull, Terrence L.; Professor; Pediatrics; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2001; Project Start 01-DEC-1990; Project End 31-MAY-2006 Summary: Current vaccines against Haemophilus influenzae type b reduced the incidence of H. influenzae invasive diseases. However, nontypeable H. influenzae are a common cause of pneumonia and otitis media, which is associated with hearing loss and language deficits. H. influenzae has an absolute growth requiremnet for heme and the human body is its sole niche. Previously, we characterized a family of genes encoding proteins, Hgp, which bind human hemoglobin and the hemoglobinhaptoglobin complex. Mutation of all the hgp genes in a strain does not abrogate hemoglobin binding. We have identified a putative gene product encoding this residual hemoglobin utilization activity. Expression of Hgps is repressible by heme, but not by elemental iron. The upstream region of each gene lacks the Fur consensus site suggesting that the Fur repressor does not directly regulate the Hgps. We have isolated H. influenzae fur mutants and fur-independent mutants with altered hgp expression. Thus, regulation is more complex thatn the classic ferric uptake repressor system described for a wide range of bacterial species. Sequence analysis of Hgps reveals four

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highly conserved regions. Preliminary data about the complex regulation of hgp expression, localization of a binding region of HgpA, and the identification of conserved regions provide an opportunity to investigate the structure/function, gene regulation, and immunobiology of the Hgps. The current project will determine ligands bound by Hgp, identify binding sites, characterize the conserved regions, and determine the relative growth advantage of multiple Hgps in a strain. In addition, the role of fur and fur-independent elements in the regulation of Hgp will be examined. Finally characterization of the immunobiology of the Hgps will determine the protective capacity of antisera to the conserved regions of the Hgps in animal models of invasive and noninvasive disease. These experiments will provide insight into how heme acquisition is related to pathogenicity. These studies will lay the foundation for longterm studies focusing on prevention of all H. influenzae related disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEME OXYGENASE-1 VS ENOS GENE TRANSFER TO CEREBRAL ARTERIES TO PREVENT VASOSPASM Principal Investigator & Institution: Katusic, Zvonimir S.; Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: Brain ischemia due to cerebral vasospasm is a major cause of morbidity and mortality in patients with subarachnoid hemorrhage. Our long-term goal is to develop a safe and effective gene therapy approach for the prevention and treatment of cerebral vasospasm. The focus of our previous studies was on the development and optimization of adeno-virus mediated transfer of endothelial nitric oxide synthase (eNOS) gene into the cerebral circulation. In these studies we demonstrated that eNOS gene transfer increases local production of nitric oxide and significantly enhances vasodilator activity of transduced cerebral arteries. However, the exact mechanism of protection is unclear and appears to involve restoration of nitric oxide production in spastic arteries. Most importantly for this application, a number of previous studies demonstrated that nitric oxide increases expression of heme oxygenation-1 (HO-1). Furthermore, existing evidence suggests that vascular oxidative injury caused by hemoglobin and heme released into the subarachnoid space plays a key role in the pathogenesis of cerebral vasospasm. Clearance of heme from the subarachnoid space is dependent on the enzymatic activity of HO-1, the rate-limiting enzyme in heme catabolism. Increased enzymatic activity of HO-1 may protect cerebral arteries from vasospasm by stimulating formation of the antioxidants, bilirubin and biliverdin, as well as the vasodilator gas, carbon monoxide. Thus, the central hypothesis of this application is that expression of recombinant HO-1 in cerebral arteries may prevent development of cerebral vasospasm after subarachnoid hemorrhage. To test this hypothesis we will overexpress HO-1 in cerebral arteries by adenovirus-mediated gene transfer. Our preliminary findings indicate that expression of recombinant HO-1 protects cerebral arteries from hemoglobin-induced injury. We propose to study the expression and function of recombinant HO-1 in cerebral arteries by immunohistochemistry, electron microscopy, measurements of HO-1 enzymatic activity, radioimmunoassay of cyclic GMP and both in vitro and in vivo analysis of vasomotor reactivity of transduced arteries. The "double hemorrhage" canine model of cerebral vasospasm will be used to study the therapeutic value of recombinant HO-1 expression in the prevention and treatment of cerebral vasospasm. The effects of HO-1 will be compared with the effects of recombinant eNOS. We anticipate that experiments proposed in this application will determine whether recombinant HO-1 can be used in the development of gene therapy for cerebral

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vasospasm. Our studies will also expand the knowledge base concerning the mechanisms underlying the vascular effects of recombinant eNOS and the role of HO-1 in protections of cerebral arteries against hemoglobin-induced oxidative stress. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOST MODULATION/PERIODONTAL THERAPY EFFECTS ON DIABETES Principal Investigator & Institution: Ryan, Maria E.; Assistant Professor; Oral Biology and Pathology; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2003 Summary: (provided by applicant): Of the approximately 16 million Americans suffering from diabetes mellitus, about 10 percent have Type 1 diabetes. The complication of this chronic disease, i.e. nephropathy, retinopathy, neuropathy, angiopathy, impaired wound healing and periodontitis, significantly, impact the diabetic individuals quality of life. In recent years new adjunctive treatments, to classic insulin therapy, targeting factors know to play a role in these long-term complications have been developed and are being tested clinically. Diabetics tend to have an exaggerated host response to local microbial factors resulting in unusually destructive periodontal breakdown. In addition, periodontal infections resulting in excessive production of cytokines (1L1, 1L-6 and TNF (a)) induce insulin resistance and decrease insulin action. Tetracycline's, including a sub-antimicrobial dose of doxycycline (SDD), by virtue of non-antimicrobial properties can reduce level of these cytokines and other factors (matrix metalloproteinase {MMPs}), nitric oxide [NO]) known to play a role in diabetic complications, including periodontitis. These biological properties make SDD a compelling candidate for use in diabetics with periodontitis. Therefore, the objective of this research is to investigate the therapeutic potential of SDD in diabetic complications, such as periodontitis. The hypothesis of this proposal is that adjunctive periodontal therapy with SDD (compared to placebo) can improve clinical and local biochemical parameters of periodontitis as well as systemic biochemical and physiological parameters indicative of the likelihood of he progression or severity of long-term complications of diabetes. Accordingly, the specific aim of this proposal is to use a 9 month double -blind, placebo-controlled trail of Type 1 diabetics to determine the effect of SDD on: a) the clinical efficacy of non-surgical periodontal therapy; b) the oral microflora; c) oral, serum and urine levels of cytokines (1L-1, 1L6, TNF (a)), MMPs and NO; d) hemoglobin Aic, serum non-fasting glucose and fructosamine; and e) microalbuminuria and proteinuria. It is postulated that SDD, developed initially for the improved management of periodontitis, may be potential adjunct to insulin therapy in diabetic patients for the improved overall management of diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HYPERSPECTRAL IMAGING OF OXYGEN SATURATION IN THE ONH Principal Investigator & Institution: Khoobehi, Bahram; Professor; Ophthalmology; Louisiana State Univ Hsc New Orleans New Orleans, La 70112 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): The development of a non-invasive means of measuring oxygen saturation in the fundus of the human eye would be useful in the diagnosis and monitoring of numerous disorders, including diabetic retinopathy, arterial venous occlusion disease, and glaucoma. In these studies, a practical system to

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evaluate oxygen saturation in the retina and optic nerve head using a recent innovation, hyperspectral imaging, will be developed. The hyperspectral technique measures spectral changes within the visible and infrared spectra and provides information on the molecular state of hemoglobin. The hyperspectral imaging device will allow measurement - non-invasively and in real time - of reduction and/or elevation in tissue oxygenation. The distinct optical signature of biological materials such as oxyhemoglobin and deoxy-hemoglobin as a function of their reflectance spectra will enable determination of their relative concentrations. In recent years, reflectance oximetry has been developed for the non-invasive measurement of oxygen saturation changes in the vessels of the fundus using double, triple, and multiple wavelength reflectance imaging. The hyperspectral reflectance oximetry that will be employed in these studies will permit the first non-invasive measurement for oxygen saturation in the optic nerve head tissue, and the hyperpectral data to be collected will intrinsically include all of the multiple wavelength spectra obtained in earlier approaches. The new system will be tested in two specific aims: 1) hyperspectral imaging will be used to non-invasively evaluate the stimulus-response relationship between perturbations in intraocular pressure (lOP) (10-50 mm Hg) and oxygen saturation in optic nerve head tissues and in retinal artery/vein pairs for a graded series of hypoxic states, and 2) the same studies will be performed in eyes with early stage experimental glaucoma. With this new approach, it will be possible to determine how acute changes in lOP alone or in combination with chronic lOP elevation (glaucoma) affect the three distinct microcirculations of the optic nerve head (surface nerve fiber layer; prelaminar region; lamina cribrosa) independently and/or collectively. The proposed studies are motivated by the potential for clinical application of this innovative technology in the early diagnosis of and monitoring of therapy for ocular vascular diseases in which the associated hypoxia may eventually lead to loss of vision. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HYPOXIC PULMONARY VASOCANSTRICTION AND RED BLOOD CELLS Principal Investigator & Institution: Deem, Steven A.; Anesthesiology; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-JAN-1998; Project End 31-DEC-2002 Summary: (Adapted from applicants' abstract) There is evidence that nitric oxide (NO) is important in red blood cell (RBC)-mediated modulation of hypoxic pulmonary vasoconstriction (HPV). NO may be involved directly in this modulation, or may act indirectly through its combination with hemoglobin (Hb) to form S-nitrosohemoglobin (SNO-Hb). In addition, the purines adenosine and adenosine triphosphate (ATP) may play a role in modulation of pulmonary vascular tone by RBCs. The interactions between RBCs and HPV are clinically relevant because of the common coexistence of anemia and pulmonary disease in critically ill patients. The specific aims of this project are: 1. To determine the effects of manipulation of NO production and metabolism or exogenously administered NO on pulmonary vascular tone during normoxia and hypoxia. 2. To distinguish between the roles played by the intact RBC and its constituent Hb alone in NO metabolism and modulation of HPV, and to determine the potential role of SNO-Hb in modulation of pulmonary vascular tone. 3. To measure pulmonary artery endothelial cell production of NO in a closed system, and to determine the effects of hypoxia and RBCs on endothelial NO production. 4. To elucidate the role of RBCs in purinergic modulation of pulmonary vascular tone by blocking uptake of adenosine by RBCs, by blocking purine receptors, and by assaying purinergic mediator production

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under normoxic and hypoxic conditions. 5. To determine whether purines affect release of NO by pulmonary artery endothelial cells in a closed system. These aims will be investigated using an isolated, perfused rabbit lung model with quantitiation of HPV done during repeated hypoxic gas challenges at different hematocrits, and with a cultured pulmonary artery endothelial cell model. Mediators will be assayed using chemiluminescence for measurement of expired NO and NO metabolites in perfusate, photolysis chemiluminescence for measurement of SNO-Hb, and high pressure liquid chromatography for measurement of purines in perfusate. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMAGING CMRO2 WITH COMBINED DOT AND MRI Principal Investigator & Institution: Boas, David A.; Assistant Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 09-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Though widely used for functional neuroimaging, BOLD fMRI measures a relative change in blood oxygenation and is subject to confounds due to variations in baseline physiology and the competing effects of changes in blood flow and oxygen metabolism. These uncertainties currently limit BOLD imaging and have stymied applications that depend on repeatability. An attractive strategy for working around these BOLD limitations is to pursue a quantitative measure of the relative change in the cerebral metabolic rate of oxygen (rCMRO2) synthesized from a complete set of hemodynamic parameters, fMRI, by itself, is currently unable to provide this complete set of hemodynamic parameters in humans during brain activation without relying on untested assumptions relating flow and volume changes. The goal of this grant is to develop and validate a multi-modality methodology for metabolic neuroimaging of the cortex through the integration of Diffuse Optical Tomography (DOT) and MRI. In this project, we will advance DOT technology to increase the quantitative accuracy of estimated baseline and dynamic hemoglobin concentrations. A novel hybrid time domain and continuous wave brain imaging system will be combined with MRI guided reconstruction methods. The quantitative baseline and functional optical measures of total hemoglobin, and deoxyhemoglobin will be combined with fMRI arterial spin labeling measures of the relative change in cerebral blood flow (rCBF) to calculate images of rCMRO2. Validation will be pursued through a combination of graded global and focal modulations and through comparison with analogous fMRI measures. We anticipate that validation of this metabolic imaging method will have wide applications both in studies of metabolic-vascular response in normal and diseased humans and use as a quantitative functional neuroimaging method to facilitate future longitudinal and across subject studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LC-MS/MS METHODS FOR ANALYSIS OF HEMOGLOGBIN ADDUCTS Principal Investigator & Institution: Fennell, Timothy R.; Research Triangle Institute Box 12194, 3040 Cornwallis Rd Research Triangle Park, Nc 27709 Timing: Fiscal Year 2002; Project Start 19-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant): Adducts formed between hemoglobin and reactive chemicals or their metabolites provide a means of monitoring of the long-term exposure to chemicals. However, the methods that are generally used for measuring these adducts are selective for one or at most several chemicals, are difficult to perform, and

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typically involve gas chromatography with mass spectrometry for adduct analysis. The objective of this study will be to develop methods that can be used to study exposure to a variety of agents, rather than selectively targeted to a single analyte. A widely used method for analysis of adducts formed on reaction with the N-terminal valine residue of hemoglobin is the modified Edman degradation. In this technique, the pentafluorophenylthiohydantoin derivative of the valine adduct is quantitated by negative ion chemical ionization mass spectrometry. Preliminary studies conducted in our laboratory indicate that the analysis of hemoglobin adducts of acrylamide and glycidamide released by a modified Edman degradation can be accomplished by liquid chromatraphy-mass spectrometry (LC-MS) of phenylthiohydantoin derivatives, using multiple reaction monitoring on a triple quadruple mass spectrometer. Solid phase extraction has reduced sample preparation time. Our new method of analysis provides considerable time savings both in sample preparation and analysis time. Objectives of the proposed research will be to adapt the methodology to the quantitation of a number of adducts derived from a variety of different chemicals of concern in the same samples, and to derive methods for analysis of adducts that are present in globin using less selective methods. The detection of adducts with valine using the modified Edman degradation coupled with LC-MS analysis on an ion trap MS will provide the necessary sensitivity for identification of the adducts present. The qualitative evaluation of adduct formation in globin by protein digestion and mass spectrometry has been carried out primarily in vitro, with applications in vivo in a limited number of cases. A further aim of these studies will be to apply protein digestion and tandem mass spectrometry to the evaluation of adduct formation in vivo, and to evaluate the sensitivity of this approach for the qualitative evaluation of exposure. However, measuring adducts is still relatively low throughput methodology that is not amenable to large-scale epidemiological studies involving thousands of samples, although this is faster than what is currently available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM AND KINETICS OF SICKLE CELL HEMOGLOBIN Principal Investigator & Institution: Kim-Shapiro, Daniel B.; Physics; Wake Forest University 2240 Reynolda Rd Winston-Salem, Nc 27106 Timing: Fiscal Year 2001; Project Start 01-FEB-1998; Project End 31-JAN-2003 Summary: Sickle cell disease is characterized by the polymerization of a mutant form of hemoglobin under hypoxic conditions which increases red blood cell rigidity leading to microvascular occlusion. The severity of the disease is most likely partially dependent on the kinetics of polymerization during hypoxic conditions and on the kinetics of depolymerization (melting) upon reoxygenation at the lungs. Although the mechanism and kinetics of polymerization have been extensively studied, much less work has concentrated on polymer melting. The focus of this study is to elucidate the mechanism and kinetics of sickle cell hemoglobin polymer melting. Special attention will be put on investigating the role of ligand (oxygen or carbon monoxide) binding to hemoglobin molecules in the polymer during melting. Other factors that may affect melting kinetics such as the length of the polymers will be studied as well as the link between polymer melting kinetics and changes in sickle cell shape and deformability. This study is not only important in regard to understanding the physics of polymerization and depolymerization but also in regard to understanding sickle cell disease thereby providing potential for a new form of treatment. The proposed work will be accomplished by a novel combination of spectroscopic techniques. A special instrument capable of simultaneously conducting spectral measurements of absorption, linear

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dichroism, circular dichroism, circularly polarized luminescence, and polarized light scattering is being built for application to this project. The spectral measurements will be accomplished with millisecond resolution so that the amount of sickle cell polymer, the ligation state of the polymer and solution phase molecules, and the quaternary state of the hemoglobin molecules can be simultaneously determined as polymer melting is induced. The use of these spectroscopic techniques (and their combination) in this project could lead to applications in other studies. Special attention will be paid in evaluating polarized light scattering (previously shown to be extremely sensitive to polymer concentration) as a biophysical tool. The novel technology that is providing the ability to perform this unique combination of measurements ensures the potential of the discovery of new phenomena. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM OF THE HUMAN BETA-GLOBIN LOCUS CONTROL REGION Principal Investigator & Institution: Bresnick, Emery H.; Professor; Pharmacology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2001; Project Start 16-JUL-1996; Project End 31-JAN-2006 Summary: (Investigator's abstract) We propose to study how the beta-globin locus control region (LCR) confers high-level transcriptional activity to the beta-globin genes over a long distance on a chromosome. Mechanisms of long-range transactivation are poorly understood. In Specific Aim 1, we will define protein components of the LCR in living cells and will determine if they differ during erythroid differentiation. Despite extensive in vitro studies, little is known about the composition of native LCR complexes. We hypothesize that the components of the LCR vary during erythropoiesis to accommodate differential requirements for transactivation during development. A chromatin immunoprecipitation (ChIP) assay will be used to measure the binding of candidate proteins to the LCR. In Specific Aim 2, we will define the histone acetylation and phosphorylation patterns of the beta-globin locus and will determine if the patterns change during erythroid differentiation. We hypothesize that the LCR recruits coactivators that establish a specific pattern of histone modifications throughout the beta-globin locus, which is necessary for long-range transactivation. We will define the pattern of histone modifications, will assess whether it changes during erythropoiesis, and will determine whether pharmacological inducers of fetal hemoglobin specifically modulate the pattern. We hypothesize that the histone modification pattern is established via primary and modulatory determinants. In Specific Aim 3, we will identify primary determinants of the acetylation pattern. We have shown that the histone acetylase CBP/p300 is critical for LCR-mediated transactivation. We will test whether CBP/p300 is a primary determinant and will identify CBP/p300-interacting coactivators in erythroid cells. We will also assess whether specific histone deacetylases are primary determinants. The native structure of enhancer and LCR complexes and the histone modification pattern of a domain have not been defined in any system. Since long-range mechanisms control the transcription of multiple crucial genes that regulate cell proliferation and differentiation, our studies will yield principles of broad physiological and pathophysiological relevance. The long-term objective is to therapeutically modulate beta-globin gene expression in humans with hemoglobinopathies by perturbing specific steps of the mechanism by which the LCR regulate the beta-globin genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS NEUROTOXICITY

AND

PREVENTION

OF

HEMOGLOBIN

Principal Investigator & Institution: Panter, S Scott.; Northern California Institute Res & Educ San Francisco, Ca 941211545 Timing: Fiscal Year 2001; Project Start 01-SEP-1994; Project End 31-JUL-2003 Summary: (Adapted from investigator's abstract) The central hypothesis of this proposal is that hemoglobin is cytotoxic and will significantly worsen cellular injury produced by the original ischemic episode. This contribution of hemoglobin to neurological injury can be reduced by pretreatment with antioxidants, chelators, the hemoglobin binding protein haptoglobin, or agents that will plug the barrier, blocking the entry of hemoglobin. This proposal will focus on a rat model of focal ischemia and reperfusion that has been demonstrated to disrupt the blood-brain barrier. To attempt to model the clinical situation, stroma-free or purified human hemoglobin will be infused into the vasculature of rats at the start of reperfusion following focal ischemia. This procedure results in the direct deposition of hemoglobin into the ischemic area of the brain through the disrupted BBB. Increasing doses of hemoglobin will be administered to assess behavioral impairment and survivability. At different time intervals following stroke, the brains will be evaluated for infarct size, cerebral edema, and the degree of disruption of the blood-brain barrier. Neuronal degeneration will be assessed by conventional histology and fluorescence microscopy using fluoro-jade. Finally, animals will be pretreated with an antioxidant (polynitroxyl-albumin), an iron chelator (a starch deferoxamine conjugate), the normal hemoglobin-binding protein haptoglobin, or a subfraction of pentastarch that has been shown to physically plug the holes of a disrupted blood-brain barrier. These studies will delineate a hemoglobin-dependent contribution to neural injury following opening of the blood-brain barrier and will test several therapeutic candidates that could be used in the clinical setting of CABG surgery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF BRAIN EDEMA AFTER INTRACEREBRAL HEMORRHAGE Principal Investigator & Institution: Hoff, Julian T.; Professor and Head; Surgery; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 01-MAR-1981; Project End 30-NOV-2004 Summary: Brain edema plays an important role in the secondary brain injury following intracerebral hemorrhage (ICH). It is the long-term goal of our laboratory to identify the mechanisms involved in brain edema formation after ICH. Previous studies indicate that edema formation following ICH may involve several phages. These include a very early phase (first several hours) involving hydrostatic pressure, clot retraction, and transient ischemia around the clot, a second phase (first day) involving the clotting cascade and thrombin production and a third phase (about day 3 in the rat) involving erythrocyte lysis and hemoglobin-induced toxicity. Because of the delay in onset, this third phase may be more amenable to therapeutic intervention by either altering erythrocyte lysis or limiting hemoglobin- induced toxicity. This proposal has three specific aims concerning this third phase: (1) To determine whether erythrocyte lysis and hemoglobin release cause delayed brain edema formation following intracerebral hemorrhage by reducing blood flow, increasing blood-brain barrier permeability or by direct cytotoxicity. (2) To examine the role of hemoglobin breakdown products in ICH-

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induced brain edema by blocking or inducing heme oxygenase and by elucidating the effects of direct intracerebral infusion of hemoglobin breakdown products. (3) To determine whether complement system activation is involved in erythrocyte lysis in the hematoma following ICH and to examine whether activation of this system also exacerbates brain damage by direct neuronal effects or by inducing neutrophil migration into brain. Intracerebral hemorrhage (ICH) is a common and often fatal subtype of stroke which accounts for about 15% of stroke deaths (20,000/year). Although death may occur acutely after an ICH, in many cases there is a delayed neurological deterioration and death. These experiments are designed to explore these latter events and develop new therapeutic strategies to counter such deterioration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MICROVASCULAR HEMOGLOBINS

EFFECTS

OF

SURFACE

DECORATED

Principal Investigator & Institution: Intaglietta, Marcos; Chairman of Board of Trustees; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 05-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): We propose to determine the mechanisms that cause vasoconstriction when cell free hemoglobins are introduced into the circulation as the O2 carrier of an O2-carrying plasma expander (OCPE) by studying the vascular effects produced by polyethylene glycol (PEG) surface decorated hemoglobins (HbS) developed in this program. We will study the presser response to top loads of various formulations and quantify the reactions of the microcirculation in the hamster skinfold model, which can be studied without anesthesia, in the awake condition for periods of up to 2 weeks. The principal microvascular parameters to be evaluated in vivo are functional capillary density and intravascular oxygen tension distribution. Tests will analyze different hypothesis on the genesis of vasoactivity due to molecular hemoglobin in the circulation, namely: 1) NO scavenging by hemoglobin; 2) lowered viscosity in hemodilution, leading to lowered shear stress and production of endothelial relaxing factors; 3) Increased facilitated diffusion and O2 autoregulation by oxyhemoglobin; and, 4) Extent of hemoglobin surface shielding by PEG molecules. Efficacy of the OCPEs will be determined in conditions of isovolemic hemodilution and hemorrhagic shock. An effective OCPE must also insure sufficiently elevated blood viscosity, which is necessary for the maintenance of adequate microvascular function, and condition that can be obtained with PEG-Hbs. In hemodilution these molecules increase plasma viscosity, causing redistribution of hydraulic pressure in the circulation, decreasing systemic viscosity dependent pressure losses and increasing peripheral resistance. Additionally the O2 dissociation curve for these modified hemoglobins should be left shifted, so O2 release occurs only in anoxic regions and not from arterioles and where tissue oxygenation is adequate. Our goal is to obtain an understanding of vasoactivity in support of OCPE development that prioritizes maintenance of microvascular function in terms of capillary perfusion, which is as critical for tissue survival as adequate oxygenation, by using methods for the analysis at the cellular microscopic level, where blood performs its vital functions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOUSE MODEL FOR SICKLE CELL DISEASE & GENETIC THERAPIES Principal Investigator & Institution: Townes, Tim M.; Professor and Chairman; Biochem & Molecular Genetics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 30-SEP-1996; Project End 31-AUG-2004 Summary: (Investigator's abstract) This is the competitive renewal of a grant funded approximately three years ago to develop a mouse model of sickle cell disease. During the funding period we produced transgenic mice that switch from human fetal hemoglobin to human sickle hemoglobin around three weeks after birth. These animals were bred with our beta-thalassemic mice containing a knockout mutation of the betamaj and beta-min globin genes and with Paszty et al's alpha-thalassemic mice containing a knockout mutation of the alphal and alpha2 globin genes. The resulting animals synthesize only human hemoglobin in adult red blood cells. Similar to many human patients with sickle cell disease, the mice develop a severe hemolytic anemia and extensive organ pathology. Numerous sickled erythrocytes are observed in peripheral blood. Although chronically anemic, most animals survive for 2 to 9 months and are fertile. We now propose to correct sickle cell disease in these mice by transduction of hematopoietic stem cells with viral vectors containing anti-sickling genes under control of human beta-globin Locus Control Region (LCR) sequences. One limitation in this strategy has been the inefficiency of transduction into quiescent stem cells. We have now demonstrated that Sca-1+, c-Kit+, Lin- bone marrow stem cells that are isolated without cytokine prestimulation are efficiently transduced with modified lentiviral vectors carrying a GFP gene. The transduced cells fully reconstitute hematopoiesis in lethally irradiated mice and 10-15 percent of all cell lineages examined express GFP after 3 months. These results suggest that quiescent, hematopoietic stem cells are efficiently transduced by lentiviral vectors and that infection does not impair self renewal and lineage specification in stem cells which mediate long term reconstitution of lethally irradiated animals. Since the life span of sickle red cells is significantly shorter than normal., we speculate that correction of 10-15 percent of erythroid precursors in the marrow will translate to a major fraction in the peripheral blood because genetically corrected erythrocytes have a selective survival advantage. The anti-sickling gene we have developed will significantly reduce morbidity and mortality if the gene is expressed at 10 percent of betaS. If expression of the transduced gene is low, we propose to introduce a modified transcription factor (delta-EKLF) that will efficiently activate the human delta-globin gene. We have demonstrated that low levels of a modified EKLF activate the delta-globin gene at high levels, and HbA2 (alpha2 delta2) has powerful anti-sickling properties. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEONATAL OPTICAL NON-INVASIVE BRAIN OXYGENATION MONITOR Principal Investigator & Institution: Benni, Paul B.; Senior Res. Engineer, Scientist; Cas Medical Systems, Inc. Branford, Ct 06405 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-JUL-2003 Summary: (Applicant's abstract verbatim): There is a need for non-invasive, userfriendly cerebral oxygenation monitoring during one of the most vulnerable stages of life, the neonatal period. Near-infrared spectroscopy (NIRS) is an optically based technique that can be used to non-invasively and continuously monitor brain

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oxygenation by determining relative changes in oxyhemoglobin (delta HbO2) and deoxyhemoglobin (delta Hb) and absolute cerebral oxygen saturation (CrSO2). The summation of deltaHbO2 and delta Hb give changes in total hemoglobin (delta TotalHb). NIRS is based upon the use of the modified Beer-Lambert Law to distinguish between deltaHbO2 and delta Hb. By using low power laser diodes to effect the determination of the Beer-Lambert parameters, it will be possible to construct a small, relatively inexpensive NIRS device. This device will find great utility in neonatal centers and holds the promise of applications in other clinical situations where the degree of tissue oxygenation is desired. The primary objectives of this Phase II SBIR proposal are 1 ) to develop a low cost NIRS system to monitor delta Hb, delta HbO2, delta TotalHb, and CrSO2, specifically directed to neonatal monitoring, 2) to prove the clinical utility of NIRS in a neonatal ICU, and 3) to verify the NIRS parameters against blood samples drawn from the internal jugular vein of the neonate. PROPOSED COMMERCIAL APPLICATION: An instrument that can non-invasively and continuously monitor brain oxygenation changes of the neonate would be a valuable addition to every neonatal intensive care unit or medical facility. In 1995, there were ~3.9 million live births in the U.S. Of that, 0.76% of the infants died in the first year [27]. An analysis of the cause of death shows that ~74% (21,750infants) could have benefited from cerebral oxygenation monitoring. Low birth weight (<2,500g) is a risk factor associated with poor outcome [24]. In 1995, there were ~286,000 live low birth weight infants, with a mortality rate of 6.5% in the first year [27]. NIRS offers improved capability in neonatal monitoring to assist physicians in the care of several hundred thousand neonates and infants a year. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NIPRISAN FOR TREATING PATIENTS WITH SICKLE CELL DISEASE Principal Investigator & Institution: Pandey, Ramesh C.; Xechem, Inc. 100 Jersey Ave Bldg B, Ste 310 New Brunswick, Nj 80901 Timing: Fiscal Year 2003; Project Start 05-SEP-2003; Project End 31-JUL-2004 Summary: (provided by applicant): Sickle Cell Disease (SCD) is a hereditary blood disorder caused by an abnormal hemoglobin called sickle hemoglobin (Hb S). Although the Hb S of patients with SCD in the steady state can transport oxygen like normal hemoglobin, Hb S forms rigid fibers when the blood is exposed to hypoxia. The deoxy-Hb S fibers push the red blood cell membrane toward the outside, causing deformation of the cells to assume a sickle shape. Rigid sickled cells cannot pass through narrow capillaries and they occlude blood vessels, which may cause serious organ damage. Although the cause of SCD is well known and more than 200,000 drugs have been screened, hydroxyurea is the only drug that is currently available for the treatment of patients with SCD. One problem with hydroxyurea, however, is that it is not uniformly effective in all patients and some patients develop severe adverse effects. In an attempt to develop a new anti-sickling agent, Xechem, together with researchers at the Children's Hospital of Philadelphia, PA, proposes testing of a new phytopharmaceutical anti-sickling agent, NIPRISAN, for the treatment of patients with SCD. NIPRISAN is the extract of four kinds of plants in Africa and has been used in Nigeria for the treatment of SCD for a long time. However, since it was not studied scientifically and the remedies were prepared differently in different areas, the drug has never been used in other countries. Recently, the Nigerian government performed preliminary studies on NIPRISAN and showed that oral administration of NIPRISAN led to a significant reduction in the frequency of painful episodes. The effectiveness of NIPRISAN was also studied at the Sickle Ceil Disease Reference Laboratory at the

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Children's Hospital of Philadelphia, PA, using transgenic (tg) sickle mice that produce human HbS. The aim of this application is to prepare a novel, safe, standardized drug that will be uniformly effective in patients with SCD with minimum adverse effects. For this purpose, in the Phase 1 study, we will prepare a standardized optimal formulation of NIPRISAN that will be easily administered orally, has a consistent anti-sickling effect among different lots, and maintains the maximum activity during the shelf time. The development of an effective anti-sickling agent not only is beneficial to patients with SCD and their families, but also will reduce the financial burden on governments and healthcare systems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL GLOBIN GENE MODULATORS Principal Investigator & Institution: Perrine, Susan P.; Associate Professor of Medicine; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2001; Project Start 01-JUN-1998; Project End 31-MAY-2003 Summary: The overall goal of this research proposal is to test the hypothesis that stable gamma-globin inducers which do not inhibit erythroid cell proliferation and may be given frequently, will result in superior long-term hemoglobin F inducibility in the absence of hematologic suppression in vivo. Specific aims are to: 1) identify oral fetal globin gene inducers with favorable in vivo kinetics; 2) determine the effects of long term administration of oral hemoglobin F inducers in non-human primates; and 3) determine whether synergy results with their combined use with other compounds known to stimulate HbF production. The primary screen for gamma-globin inducibility will be performed using K562 cells alone and those stably transfected with promoter/reporter constructs, erythroid progenitor cultures and a responsive multilineage cell line. Hemoglobin F inducers which stimulate or do not inhibit erythropoiesis in vitro will be studied in baboons to determine oral pharmacokinetics, safety and to develop effective long-term regimens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TRANSPORT

NOVEL MECHANISM

OF ERYTHROCYTE

NITRIC OXIDE

Principal Investigator & Institution: Pawloski, John R.; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 08-APR-2002; Project End 31-MAR-2007 Summary: Circulating red blood cells (RBC) constitute the largest pool of biologically available nitric oxide (NO) in the mammalian organism. It has now been shown that NO-related bioactivity is released form human RBCs in an oxygen-dependent manner. The mechanism of NO export seems to involve a novel system whereby Snitrosohemoglobin (SNO- Hb) transnitrosylates cysteine thiols in the cytoplasmic domain of the membrane RBC anion-exchanger 1 protein (AE1). The details of this novel RBC function stand to be elucidated. To characterize this system, the following specific aims have been formulated. 1) To identify the chemical nature of released NO species and to specific the target thiols in the cytoplasmic domain of AE1. 2) Determine the effects of S-nitrosylation AE1 function. 3) Characterize the NO exporter in sickle cell RBCs, a prototypical disease model fo hemoglobin dysfunction. 4) Develop a transgenic murine model with site-directed mutagenesis of AE1 cytoplasmic domain thiols transnitrosylated SNOHb. The abiding goals of this project are to gain a greater understanding of mechanisms in the RBC in both normal and disease states. The results

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of these studies underscore the potential but largely unexplored role of Hb- membrane interactions in the pathogenesis of the thrombotic diathesis, ischemic syndromes, oxidative disorders and hypertensive states that are associated with altered hematocrit, hemoglobinopathies (like sickle cell disease), and RBC membrane defects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL ORGANIC REAGENTS FOR BIOMEDICAL APPLICATIONS Principal Investigator & Institution: Hosmane, Ramachandra S.; Professor; Chemistry and Biochemistry; University of Maryland Balt Co Campus Baltimore, Md 21250 Timing: Fiscal Year 2001; Project Start 30-SEP-1994; Project End 30-SEP-2002 Summary: We propose to synthesize a series of polyfunctional organic reagents (PORs) for chemically modifying cell-free human hemoglobins for use as oxygen-carrying blood substitutes in emergency transfusions. These PORs have been specifically designed to perform both infra- and intermolecular hemoglobin cross-linking, with a built-in quality control feature, to yield simultaneously cross-linked and oligomerized hemoglobin products with the desired molecular weights. One of the pressing issues in hemoglobin-based blood substitute research at the present time is to increase the intravascular retention time of the cross-linked hemoglobin, but the current methods employed for polymerization largely yield random, heterogeneous mixtures of products, most of which suffer from problems of auto-oxidation, high oxygen affinity and/or antigenicity. Proposed is a method of controlled oligomerization that yields a specific product of desired molecular weight each time the cross-linking is carried out. We will purify the modified hemoglobins, and investigate their physical, compositional, and functional properties, including molecular weight, methemoglobin levels, storage stability, oxygen affinity (P50), cooperativity (Hill n value), and dependence of P50 on pH (Bohr effect) as well as on anionic species (chloride and phosphate). We will also elucidate the sites of cross-links by a combination of tryptic digestion and MALDI MS analyses. We will then perform extensive animal studies, using rats and rabbits, on the most promising modified hemoglobins to evaluate their intravascular persistence, oxygen transport/delivery, and physiological responses, including hemodynamic reactivity and toxicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NOVEL PEG-HEMOGLOBIN MODIFICATION FOR BLOOD REPLACEMENT Principal Investigator & Institution: Vandegriff, Kim D.; Vice President; Sangart, Inc. 11189 Sorrento Valley Rd, Ste 104 San Diego, Ca 921211341 Timing: Fiscal Year 2001; Project Start 05-MAY-1999; Project End 31-AUG-2002 Summary: The goal of this Phase II proposal is to produce and test a new pegylated hemoglobin solution formulated under Phase I(HL 62818-01) with the long-term goal to commercialize this solution for blood replacement therapies based on oxygen transport and blood expansion properties. Critical physicochemical properties of hemoglobin solutions have been defined that work effectively at blood replacement. This is due to the absence of a vasoconstrictive response, a side-effect that is the rule rather than the exception for commercial hemoglobin-based oxygen carriers now in clinical trials. Key properties for an effective solution are: l) high viscosity, 2) high colloid osmotic pressure, and 3) high oxygen affinity. Phase I research formulated a specific hemoglobin solution using new, maleimide pegylation chemistry. This Phase II application proposes to produce pilot-scale batches of this protein (Specific Aim 1), and

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to test for in vitro diffusive oxygen transport using an artificial capillary system (Specific Aim 2), evaluation of blood pressure responses, cardiac output, and prevention of tissue hypoxia in a rat model (Specific Aim 3), and evaluation of effects on the microcirculation, including functional capillary density, vessel diameters, direct measurements of intravascular and tissue oxygenation, and NO levels in a hamster model (Specific Aim 4). PROPOSED COMMERCIAL APPLICATIONS: The method to modify hemoglobin with polyethylene glycol has significant potential to be developed into a commercial product for use as a blood replacement fluid. Such a product can be used in emergencies, wartime, or anytime blood is not available. Moreover, this product has the potential to be inexpensive and universally compatible with recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NURSING INTERVENTION FOR YOUTH WITH CHRONIC ILLNESS Principal Investigator & Institution: Grey, Margaret; Independence Foundation Professor of Nur; None; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 20-SEP-1995; Project End 31-MAY-2003 Summary: Given our experience in developing and testing coping skills training (CST) programs for adolescents with type 1 diabetes (DM) and the need to develop and test such programs with children younger than adolescence, we propose to conduct a clinical trial to determine: (1) whether the effects of CST seen in adolescents with DM can be generalized to children (age 8-12) with DM by conducting a randomized clinical trial designed to examine whether CST will improve metabolic control (Hemoglobin A1c/HbA1c) and adaptation (depression, self-efficacy, quality of life, family behaviors in the children; well-being, coping, family adaptability in the parents); (2) whether the improved metabolic control (HbA1c) and adaptation (depression, self-efficacy, quality of life) associated with CST in our initial study can be maintained over four years of follow-up; and (3) finally, because so little is known about the costs of care to provide intensive diabetes management to a general population of youth with diabetes, we will determine the costs of care provided to children and adolescents implementing intensive therapy regimens, the incremental costs of CST, and we will relate these costs to incremental changes in metabolic control and quality of life. To achieve aim 1, we will enroll 100 children (age 8-12) with DM and one of their parents and randomly assign them to one of two groups: intensive therapy with CST or intensive therapy with education. CST consists of a series of small group efforts designed to help youth cope with the management of their disease. Both groups will received intensive DM management from an established team of providers. Data will be collected pre and post intervention and at 3, 6, and 12 months following using HbA1c, Self-Efficacy for Diabetes Scale, Children's Depression Inventory, Issues in Coping with IDDM-Child, and Diabetes Quality of Life: Youth, Diabetes Family Behavior Scale for the children and the Beck Depression Inventory, Issues in Coping with IDDM-parent, and FACES II Scales in the parents. To meet aims 2 and 3, we will continue to follow the 80 youth with diabetes enrolled in our initial trial, collecting data every 6 months using the SelfEfficacy for Diabetes Scale, Children's Depression Inventory, Issues in Coping with IDDM, and the Diabetes Quality of Life: Youth Scales. It is expected that this important and timely study will yield valuable information to help other youth manage this devastating disease, and thereby decrease the potential for these children and youth to develop long-term physical and psycho-social complications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OPTICAL INTRINSIC SIGNAL IMAGING OF SEIZURE Principal Investigator & Institution: Chen, James Wy.; Neurology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): The development of both structural and functional neuroimaging has progressed significantly in the last decade. However, clinical application of functional neuroimaging techniques in epilepsy has been complicated by their unsatisfactory temporal and spatial resolution. Optical imaging of intrinsic signals (OIS) is a functional neuroimaging technique that measures cortical reflectance changes with millisecond temporal resolution and micron spatial resolution. These optical images are correlated with neuronal activity and are due to changes in cerebral blood volume, light scattering, and in hemoglobin and cytochrome oxidation state. In the preliminary studies, OIS was recorded from the somatosensory cortex of rats at, near infrared frequency (850 nm). OIS was shown to correlate well with seizure activities, in a recoverable and reproducible fashion. It was also noted that OIS changes could precede the initial EEG spikes for up to I minute. The goal of this project is to correlate multiplewavelength optical signals with both electrophysiological and immunohistochemical markers, and to establish a primary foundation of interpreting OIS seizure data. The results of this project can be applied in the future in various epilepsy models, such as in a cortical kindling model for the study of neuronal network behaviors during kindling process. OIS imaging might hold a promising potential of better understanding of epileptogenesis, seizure induction, cessation and propagation pathways. Additional application of OIS imaging during epilepsy surgery in defining the eloquent cortex and confirming the seizure focus should be explored thoroughly in the future. The candidate, Dr. Chen, is a neurologist and a cellular electrophysiologist who has the expertise of using patch clamp technique. His career goal is to elucidate the basic mechanisms of epilepsy by integrating all the research skills that he has learned or will learn in electrophysiology, optical imaging, neurochemistry and computer simulation. This project will be conducted at the UCLA School of Medicine under Drs. Toga and Wasterlain's guidance. Both mentors are internationally known authorities in their respective fields of research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OPTICAL MEASUREMENT OF FAST DRUG KINETICS IN TUMOR Principal Investigator & Institution: Bigio, Irving J.; Senior Scientist; Biomedical Engineering; Boston University Charles River Campus 881 Commonwealth Avenue Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 15-MAR-1999; Project End 31-AUG-2007 Summary: (provided by applicant): The goals of the original grant, titled "Noninvasive measurement of drug concentrations in tissue," have been successfully achieved. These entailed the development of the method of Optical Pharmacokinetics (OP) for noninvasive measurement in real time, and with site-specificity, of the concentrations of drugs or other compounds in tissue, and the demostration of the technology in pharmacokinetic studies of new agents with animal tumor models. Site-specific pharmacokinetics is important for chemotherapy, and especially for photodynamic therapy, since it is the difference between the dose-response curves of tumor tissue and normal tissue that must be exploited during treatment. By extending the OP method to rapid sequences of measurements, other areas of medical research are enabled. The goal of this Competing Renewal grant is to advance the OP technology and apply it to the

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assessment of angiogenesis and of the response to treatment by anti-angiogenic agents. OP measurements of the first-pass kinetics of optical contrast agents, administered in a short bolus, will be used to assess microvascular density. Further OP measurements over the subsequent tens of minutes will permit assessment of the leakage into the extracellular fluid space and evaluation of microvessel permeability (hence, assessing capillary integrity) in regions of cancer, with the goal of a noninvasive method to assess angiogenesis and response to anti-angiogenic treatment. The ability of the OP system to make a burst of many measurements within seconds will also permit evaluation of the biologic noise in concentration measurements. It is a goal to demonstrate that the OP method, in the case of superficial lesions, is able to provide information that is not available through CT and MRI techniques, and by use of a small, portable, and inexpensive device. We will design and assemble a next-generation OP system capable of >3 measurements per second, for determining local agent concentrations with fiberoptic probes. We will use this system to record the first-pass, and the subsequent-time, site-specific concentrations of test compounds that are labeled with both optical chromophores and radiotracers. Optical measurements will be benchmarked against the assay of the radioactive markers on the same compounds. This will verify the optical method, facilitating use with approved optical contrast agents. Following in-vitro experiments, we will utilize rabbit Vx2 tumors to test the measurement of the first-pass and following kinetics of optical agents and hemoglobin under controlled conditions. We will apply the OP method to estimate microvascular density (peak concentration of optical agent and hemoglobin concentration) and to characterize capillary leak (endothelial transfer rate constant using a tri-compartment kinetic model), two indices of the angiogenic response. We will also test the ability to sense changes in permeability caused by TNF-alpha and following treatment with anti-angiogenesis agents. Such application of the OP method can result in improved management of treatment in humans, especially for superficial lesions in which kinetics are difficult to assess by current imaging methods. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ORAL L GLUTAMINE THERAPY FOR SICKLE CELL ANEMIA Principal Investigator & Institution: Niihara, Yutaka; Harbor-Ucla Research & Educ Inst 1124 W Carson St Torrance, Ca 90502 Timing: Fiscal Year 2001; Project Start 10-APR-1998; Project End 31-MAR-2002 Summary: Sickle cell anemia is one of the most common and devastating hereditary disorders with significant morbidity and mortality affecting individuals of African American heritage. No safe, effective therapy is yet available. Within the last few years, hydroxyurea has been used in an increasing number of sickle cell anemia patients. However, hydroxyurea is a chemotherapeutic agent with myelosuppressive effects and its long term safety is still unknown. An ideal agent would be one that is readily available, effective and safe even with chronic use. Based on previous data from this laboratory on sickle red blood cell metabolism, we have conducted a pilot study recently using L-glutamine as an oral agent. The four week open label study involving seven homozygous hemoglobin S patients showed promising results by demonstrating improvement in redox potential and decrease in chronic pain in all patients. In addition a subsequent 12 week study involving 4 patients showed significant decrease in the frequency of painful sickle crises. On the basis of these data we propose to expand the study of L-glutamine therapy for sickle cell anemia to a double blind study to observe objectively the effect of the amino acid in sickle cell anemia patients in terms of their clinical status and hematological parameters. Our long term goal is to establish the

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usefulness and safety of L-glutamine in therapy of sickle cell anemia. Our specific aims in this project are to determine the effect of oral L-glutamine on 1) sickle red blood cells at cellular and biochemical level, 2) clinical status of the sickle cell anemia patients including the incidence of painful crisis, narcotic requirement for acute or chronic pain, 3) sickle cell anemia patients' hematological parameters including hemoglobin, hematocrit, reticulocyte count,and hexokinase level, and 4) adverse effects attributable to L-glutamine. L-glutamine is an amino acid that has been used widely for other purposes and shown to be safe by others. It is also inexpensive and readily available. The pilot data are promising. This project will provide the pathophysiologic basis for the use of L-glutamine and will evaluate the efficacy of L-glutamine in the therapy of sickle cell anemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ORAL THERAPEUTIC FOR INDUCING FETAL HEMOGLOBIN Principal Investigator & Institution: Faller, Douglas V.; Professor and Director; Gene Regulation Laboratories 45 Beaver Rd Weston, Ma 02493 Timing: Fiscal Year 2002; Project Start 01-JUN-1999; Project End 31-AUG-2004 Summary: (provided by applicant): Sickle cell disease (SCD) and beta-thalassemia are genetic disorders caused by molecular mutations affecting the genes for adult hemoglobin. With a world-wide birth prevalence of 2/1,000, hemoglobin disorders are the most common genetic diseases in the world (360,000 patients/year - 250,000 with sickling disorders and 110,000 with thalassemias. These conditions can be ameliorated by reactivating production of fetal hemoglobin (Hb F) in the patient?s blood. Pharmacologic re-induction of fetal hemoglobin has been achieved in these diseases using a first generation intravenous therapeutic, a short-chain fatty acid (SCFA) salt, and these treated patients experienced both biochemical and clinical improvement in their diseases, with excellent safety profiles. During the Phase I STTR, the applicant organization developed third-generation SCFAs with substantial advantages over the first generation agent, including enhanced Hb F-and cellular growth stimulatory activity, oral-bioavailability, and prolonged biological half-lives. These agents have proven effective and safe in a baboon model for Hb F induction. In this Phase II application, we propose to conduct the preclinical development studies necessary to obtain Investigational New Drug status for a new lead compound (ST-20) for human clinical trials. The goals of this proposal are: I) To prepare a stable medicinal formulation of a sodium salt of ST20, a synthetic SCFAD which stimulates Hb F production; ii) To refine oral dosing-regimens for ST20 for application to patients; iii) To prepare an IND Application for ST20; iv) To evaluate additional SCFADs for activity in induction of Hb F expression, as back-up compounds. PROPOSED COMMERCIAL APPLICATION: Sickle cell disease and thalassemia are the two most common genetic diseases in the world, killing millions of people. No safe definitive therapy exists for these diseases. The applicant organization has developed an oral version of a first-generation therapeutic, which must be given intravenously. Upon completion of preclinical studies, Investigational New Drug status will be obtained and the new therapeutic agent will be tested in human clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OXYGEN SATURATION MONITORING IN NEONATES Principal Investigator & Institution: Shiao, Shyang-Yun P.; None; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225

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Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-JAN-2004 Summary: (Adapted from the Investigator's Abstract): Maintaining adequate oxygenation for neonates who need ventilatory support is essential for optimal health outcomes in this vulnerable group. To avoid oxygen toxicity, neonates are aggressively weaned from the ventilator. Neonates on ventilators are more sensitive to stimuli and frequently develop desaturation episodes, apnea, and bradycardia. They are at greater risk of hypoxemia, in part because of their high fetal hemoglobin level. Accurate and continuous oxygen saturation (SO2) status is crucial. The aims of this study are: 1. to examine the effects of using fiberoptic umbilical catheters to monitor arterial and venous SO2 (SaO2 and SvO2) on ventilatory weaning and oxygenation complications including hyperoxemia and hypoxemia; 2. to validate bedside monitoring of SaO2, SvO2, and pulse oximetry (SpO2) by examining: a.) the effect of fetal hemoglobin on the accuracy of SO2 monitoring, using a gold standard co-oximeter, and b.) the association between SO2 and oxygen tension values in neonates; 3. to examine the effects of ventilatory weaning on SO2 readings and vagal tone as measured by ECG R-R intervals. Neonates who need an umbilical arterial catheter (UAC) and an umbilical venous catheter (UVC) will be randomly assigned to the fiberoptic group (n=120) or the control group (n=120) based on five prenatal and five birth characteristics using the minimization method. Ventilatory support and oxygenation complications will be followed. The fiberoptic group will be monitored on SaO2 and SvO2 through fiberoptic catheters, in addition to SpO2. These measurements will be validated at 4-hour intervals against a co-oximeter, taking into account the effects of fetal hemoglobin on SO2. A bedside computer will be used to continuously record SaO2, SvO2, SpO2, and ECG R-R intervals. Using a computerized coding system, a data collector along with a video camera will continuously record bedside care events including each ventilatory weaning attempt. This study will determine whether SaO2 and SvO2 monitoring will improve the success of ventilatory weaning and reduce oxygenation complications. In addition, the study will examine oxygen utilization and hemodynamic function when neonates adapt to extrauterine life during ventilatory support. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENESIS OF FALCIPARUM MALARIA IN INFANCY Principal Investigator & Institution: Duffy, Patrick E.; Director; Seattle Biomedical Research Institute 4 Nickerson St, Ste 200 Seattle, Wa 98109 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by the applicant): Malaria kills 1 million African children each year. However, although all infants in holoendemic areas develop parasitemia frequently, only 10 percent develop severe anemia, the commonest cause of death. We previously showed that parasite adhesion and anti-adhesion antibodies explain susceptibility and resistance to pregnancy malaria. Because the parasites infecting children have binding phenotypes distinct from those infecting adults, we hypothesize that a similar paradigm explains the pathogenesis of infancy malaria. We propose a longitudinal study of infants from birth through age 3. We will examine samples for: 1) P. falciparum adhesion phenotype; 2) anti-adhesion antibodies; 3) presence of parasites in hemoglobin (Hb)Fvs HbA-containing (i.e., fetal vs. maternal) red cells; 4) levels of pamino benzoic acid (PABA), HbF, and antibodies. We will test our primary hypothesis that parasite binding and anti-adhesion antibodies predict severe infancy malaria. In addition, we will examine a secondary hypothesis that neonates are resistant to malaria because their vasculature does not support parasite binding. Based on our hypotheses, we expect the following results: 1) parasite adhesion phenotypes change with host age;

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2) anti-adhesion antibodies protect infants from parasites with the corresponding adhesion phenotype; 3) parasite binding patterns and specific anti-adhesion antibodies predict protection from severe anemia; 4) cord blood parasites will bind CSA, and parasites will appear exclusively in HbA-containing red cells of neonates; 5) the genotype and binding phenotype will differ between cord blood isolates and isolates obtained at the time of an infant's first infection. We will examine other factors for their effect on malaria, including transpiacentally transferred maternal antibodies, HbF, and PABA levels, and we will determine HIV status as a potential confounder in these studies. If breastfeeding confers resistance to malaria by limiting PABA intake, this will influence the debate on whether HIV-infected women in tropical areas should breastteed. These studies will establish the roles of parasite adhesion and anti-adhesion antibodies in the pathogenesis of infancy malaria, and may identify new targets for antimalarial therapies in children. Identifying new therapies for children is an urgent public health goal, but is not a funding priority for the United States Department of Defense. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOPHYSIOLOGY OF CHRONIC CEREBRAL VASOSPASM Principal Investigator & Institution: Macdonald, R Loch.; Associate Professor; Surgery; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-APR-1988; Project End 31-MAY-2006 Summary: (provided by applicant): We are investigating cerebral vasospasm which is an important cause of cerebral ischemia after subarachnoid hemorrhage (SAH). The longterm objective of this grant is to determine the mechanism of vasospasm after SAH and to thereby develop treatments that will prevent and/or reverse it. We have shown that hemoglobin causes vasospasm and that vasospasm is associated with impaired arterial relaxation. One mechanism of hemoglobin-induced vasospasm may be the binding and removal of nitric oxide (NO). We have used electron paramagnetic resonance (EPR) spectroscopy to detect nitrosyl hemoglobin in the subarachnoid space after SAH, proving that this mechanism occurs. We will therefore test the hypothesis that there is an NO-reversible component of vasospasm by: 1) defining the extent to which vasospasm is reversible with NO donors in a monkey model of SAH; 2) measuring heme-NO adducts (nitrosyl hemoglobin) by EPR spectroscopy in clots removed from the subarachnoid space of monkeys at different times after SAH; 3) quantifying NO in the perivascular space at different times after SAH in monkeys; and 4) defining the time course of changes in and the immunohistochemical locations of the 3 isoforms of NOS in cerebral arteries and perivascular blood clot after SAH in monkeys. Second, because vasospasm does not seem to be completely preventable by NO donors, we will investigate mechanisms of NO-independent vasospasm by: 1) measuring protein kinase G messenger ribonucleic acid, protein and activity during the time course of vasospasm in monkeys; and 2) assessing calcium sensitivity of monkey cerebral arteries during the time course of vasospasm. In a rat model, we will assess the contribution of other downstream effectors of NO-induced relaxation by: 1) assessing potassium channel function during vasospasm (calcium-activated potassium channel density, single channel conductance, and open probability will be assessed using whole cell and single channel patch clamp recordings of isolated vasospastic rat cerebrovascular smooth muscle cells); and 2) measuring whole cell calcium currents during vasospasm in rats because assessment of potassium channel function requires knowledge of intracellular calcium and because smooth muscle calcium homeostasis may be altered during vasospasm after SAH.

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

Project Title: PILOT STUDY OF VEDIC MEDICINE FOR TYPE 2 DIABETES Principal Investigator & Institution: Elder, Charles R.; Kaiser Foundation Research Institute 1800 Harrison St, 16Th Fl Oakland, Ca 94612 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 30-NOV-2004 Summary: (provided by applicant): Diabetes mellitus is a condition that is extremely serious from both clinical and public health standpoints. While standard allopathic modalities alone are often effective in managing diabetes, a compelling case can be made for supplementing conventional management with complementary approaches. Maharishi Vedic Medicine (MVM) represents a synthesis of Vedic sciences, including Ayur-Veda, into a single, comprehensive, natural approach to health care. The objectives of this phase II pilot trial are to determine the feasibility, acceptability, and safety of implementing a multi-modality MVM intervention for newly diagnosed type 2 diabetics, and to measure the impact of such a protocol on overall glycemic control. Newly diagnosed type 2 diabetics will be recruited through the Kaiser Permanente Diabetes Registry and those meeting eligibility criteria will be contacted and invited to participate in the study. A total of sixty patients will be recruited and randomized to either a whole practice MVM intervention or to usual care. Patients in the MVM group will receive instruction in Transcendental Meditation, an appropriate herbal supplement, and advice regarding diet, exercise, and daily routine. Patients in the usual care group will attend a series of four classes on diabetes care, along with usual primary care physician follow-up. Outcome measures will include glycosylated hemoglobin levels, assessed at baseline, 6 weeks, 3 months, and 6 months, as well as fasting glucose and serum lipids. Patients in the MVM group will additionally undergo periodic serologic assessment of hepatic, renal, and hematologic function to monitor for potential toxicities related to the herb supplement. For all patients, self-report questionnaires will be used to evaluate outcomes of compliance and quality of life. Compliance will be measured by questions asking participants to rank their adherence to individual components of the treatment protocol. Responses will be measured on a 5-point scale ranging from 'all the time' to 'none of the time'. Changes in quality of life and health status will be evaluated via the SF-12 and a current symptom checklist. This study is significant in being the first randomized controlled trial to evaluate a multi-modality MVM protocol for the management of type 2 diabetes Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PILOT STUDY--CV DYNAMICS IN FRAGILITY/DISABILITY OF ELDE Principal Investigator & Institution: Chaves, Paulo; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Healthy physiologic function is characterized by the complex interaction of multiple control systems and feedback loops that enable a subject to rapidly adapt to the internal and external stresses of everyday life. This dynamic interplay of multiple regulatory mechanisms is key to the ability to maintain internal equilibrium and good health in older adults. Cumulative declines across multiple physiologic systems and regulatory mechanisms have been hypothesized to be a major pathway to frailty in older adults. The overall goal of this project is to investigate the role of dysregulation of cardiovascular dynamics, as assessed by measures of heart rate

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(HR) variability and complexity, in frailty and disability, and to explore how such dysregulation may interact with other physiologically-related systems to exacerbate the risk for adverse outcomes. Specifically, we will conduct secondary data analyses using data from 525 women 3 age 65 from the Women's Health and Aging Study I, to test the following hypotheses: (1) Cross-sectionally, reduction in HR variability and complexity are independently associated with: (a) decreased exercise-tolerance, (b) impaired cardioacceleration in response to isometric and isokinetic stressors (c) frailty status, (d) and severity of disability; (2) Longitudinally, reduction in HR variability and complexity are predictive, independent of chronic diseases, of onset and progression of frailty and disability, and mortality; and (3) There are interactions between reduction in HR variability and complexity and impairment in other physiologic parameters of the cardiopulmonary system, particularly hemoglobin, FEV1, and atherosclerosis (measured by the ankle-arm index), vis-a-vis risk of frailty, disability, and mortality. Inferences will ultimately be based on regression models within the generalized linear model framework. Proportional hazards models will be used for time-to-event analysis. Interactions will be assessed through standard regression techniques, and by sequence analysis using "logic regression". Potential practical implications of this study include: (a) the identification of clinically relevant interactions between physiologic systems and threshold associations, which might lead to the development of methods to identify those at risk of frailty, and (b) development of multifactorial interventions targeting simultaneous impairments in multiple physiologic systems for prevention of frailty and disability in older adults. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PLANT-BASED DIETRY INTERVENTION IN TYPE 2 DIABETES Principal Investigator & Institution: Barnard, Neal D.; Physicians Committee for Responsible Med Responsible Medicine Washington, Dc 20016 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Diabetes often leads to serious complications, including coronary heart disease, kidney disease, and blindness, among others. Previous studies have suggested that low-fat, plant-based diets can have a strongly favorable effect on the management of type 2 diabetes mellitus, as well as on the elevations of body weight and serum cholesterol that often accompany it, reducing the risk of complications, and raising the possibility of reducing or even eliminating medication use for many individuals. Evidence suggests that the dietary recommendations that are most effective in diabetes management may be similar to the low-fat, vegetarian diets that have demonstrated utility in reversing coronary artery blockages. However, no study to date has examined the effect of a low-fat, vegetarian diet as an intervention for diabetes in a substantial number of participants, and most studies using plant-based (near-vegetarian) diets have also included exercise as a major intervention component, making it impossible to separate the effects of physical activity from those of diet or to reach any definitive conclusion as to which type of dietary intervention is best. This study, which follows an encouraging preliminary trial reported in Preventive Medicine in 1999, will test the hypothesis that a low-fat, vegetarian diet yields significant improvements in key indices of diabetic control, including glycosylated hemoglobin, fasting serum glucose and insulin concentrations, microalbuminuria, and medication requirements, as well as in cardiovascular risk factors, such as body weight, serum lipids, and blood pressure, in a 22-week intervention controlled throughout for exercise, with a 1-year follow-up. Sixty-eight volunteers with type 2 diabetes will be randomly assigned to a low-fat, vegan (intervention) diet or a control diet deriving 15-20percent of

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energy from protein and < 7percent of energy from saturated fats, with carbohydrate and monounsaturated fats together providing 60-70percent of energy intake, based on current American Diabetes Association guidelines. Participants in both groups will be asked to attend weekly meetings for nutrition and cooking instruction and group support, and will be asked not to alter their exercise patterns. Physical activity will be monitored by use of the Bouchard 3-Day Physical Activity Record. (Bouchard 1983) Diets will be assessed at baseline and 11, 22, and 74 weeks, using a 3-day dietary record. Fasting serum glucose will be monitored for the study duration and will be used to adjust medications according to a set protocol. Glycosylated hemoglobin, insulin concentrations, 24-hour urinary albumin, body weight, blood pressure, serum lipids, and related cardiovascular risk factors will be measured at baseline, 22 weeks, and 74 weeks. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTEIN DYNAMICS AND INTERACTIONS: VIBRATIONAL ECHOES Principal Investigator & Institution: Fayer, Michael D.; Chemistry; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: Research is proposed to study protein dynamics and intraprotein interactions using an entirely new approach, ultrafast infrared vibrational echo experiments, stimulated vibrational echoes, chemically written stimulated vibrational echoes, and two dimensional vibrational echo spectroscopies. The vibrational echo, which operates on picosecond and femtosecond time scales, is the infrared vibrational equivalent of the NMR spin echo, but it directly examines dynamics and interactions among mechanical degrees of freedom rather than spins. The stimulated vibrational echo experiments extend the time scales that can be investigated, permitting the spectrum of structural fluctuation dynamics to be mapped out over a broad range of time scales. The vibrational echo experiments will initially be applied to the study myoglobin-CO (MbCO), hemoglobin-CO (Hb-CO), Mb-NO, lysozyme, Amide I bands and model structures. The time dependent vibrational echo studies of the heme proteins will examine protein dynamics that are felt by a ligand bound at the active site and provide information on how structure, temperature, and viscosity influence protein dynamics. The role played by the protein/solvent boundary in protein dynamics will be studied at room temperature, and the nature of glass like protein dynamics at low temperatures will be investigated. Experiments on intact proteins will be compared to experiments on denatured proteins to examine changes in structural dynamics caused by denaturing. Small molecules will be used as Structural Dynamics Labels that will permit examination of structural fluctuations occurring in different regions of a protein. Vibrational Echo Spectroscopy, a 2D method in which frequency and time are varied, will be used to obtain background suppression and peak enhancement in vibrational spectra of proteins that are not resolvable with conventional IR spectroscopy, e. g., MbNO. Two time 2D vibrational echo spectroscopy will be developed and applied to the study of the mechanical coupling between different structural units in proteins. The vibrational echo experiments are the first to use IR coherence experiments on biological systems, moving vibrational spectroscopy along the path that has been so fruitful in the study of biological systems and processes with of magnetic resonance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PULSE CO-OXIMETER FOR MULTIPLE HEMOGLOBIN SPECIES Principal Investigator & Institution: Pologe, Jonas A.; Kestrel Labs, Inc. 515 Hartford Dr Boulder, Co 80305 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 30-SEP-2003 Summary: (provided by applicant): Conventional pulse oximetry has significant limitations because it works on the assumption that there are only two species of hemoglobin present: oxygenated hemoglobin (O2Hb) and reduced hemoglobin (RHb). In reality, two other hemoglobin species -- carboxyhemoglobin (COHb) and methemoglobin (metHb), collectively termed dyshemoglobins -- are present at all times. These two species of hemoglobin are formed endogenously at very low levels, but their quantities can increase to dangerous levels when carbon monoxide is present in inspired air or as a reaction to certain drugs or chemicals in the environment. All pulse oximeters used in medicine today, representing over 1,000,000 units worldwide, read oxygenation levels that are too high when there are elevated levels of dyshemoglobins in the blood. The alternative to pulse oximetry is to analyze arterial blood with a laboratory COoximeter. This procedure involves several different health care workers, potentially exposes personnel to blood borne pathogens, takes minutes or even hours to get results, and provides only a single data point in time. All of this adds cost, increases risks to health care workers, and delays appropriate treatment. Previous attempts by various companies to develop a noninvasive method of CO-oximetry have not succeeded. The limiting factors have been the correct selection of optical emitter wavelengths, spectral bandwith of the emitters, and troublesome power instabilities of the requisite laser light sources. Kestrel Labs has recently developed a new Optical Stabilization Method that will make possible the use of laser light for accurate photoplethysmographic measurements, and thus make possible the world's first, commercially-viable, noninvasive CO-oximeter. This new type of medical monitor, termed a Pulse COOximeter, will provide clinicians with a powerful, cost saving new tool for patient diagnosis and care. This SBIR Phase I effort focuses on computer simulations and empirical validation of this new Optical Stabilization Method Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RATIONAL DESIGN OF ANTISICKLING AGENTS Principal Investigator & Institution: Safo, Martin K.; Assistant Professor; Medicinal Chemistry; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2003 Summary: (Adapted from applicant's abstract) The applicant's career goal is to seek a research position in a reputable Institution. His primary goal would be to establish rigorous research programs involving structure-based drug design to find the origin, causes, treatment and prevention of tropical diseases, such as sickle cell anemia, malaria, and sleeping sickness. Furthermore, it is anticipated that molecular modeling techniques unique to the problems to be encountered will be developed to improve the efficiency of the drug development process. To reach these goals, would require considerable experience and skills in drug designing process. Therefore, under the direction of his mentor, he intends to initiate a career development research program involving rational development of compounds to treat sickle cell anemia. This would help him gain the necessary skills and experience to develop his career as an independent researcher. Below is a brief description of the proposal research. A group of halogenated aromatic compounds are known to bind to hemoglobin and show potential as antisickling agents. These compounds bind to the surface of the protein and may explain the

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antisickling properties. The long term-goal of this research project is to utilize the above information to design and develop stereospecific agents to bind with high affinity to the surface of the hemoglobin for more potent antisickling agents. In addition, both the T and R-state hemoglobins will be used to study structure-function activities. Therefore, the specific aims are: 1) determine and refine the crystal structures of the deoxygenated hemoglobin co-crystallized with halogenated aromatic acids; 2) determine and refine the crystal structures of carbonmonoxy hemoglobin bound with halogenated aromatic acid; 3) rational design of new stereospecific compounds to bind to known binding sites at the surface of the hemoglobin, and other newly identified binding sites; and 4) biological evaluation of the designed compounds for antisickling, antigelling and allosteric activities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REACTIONS HEMOGLOBIN

OF

HYDROXYUREA

WITH

SICKLE

CELL

Principal Investigator & Institution: King, S B.; Associate Professor of Chemistry; Chemistry; Wake Forest University 2240 Reynolda Rd Winston-Salem, Nc 27106 Timing: Fiscal Year 2001; Project Start 10-SEP-2000; Project End 31-AUG-2003 Summary: Hydroxyurea represents anew treatment for sickle cell disease, a condition that affects 1 in 600 Americans of African descent. While the molecular mechanisms of how hydroxyurea beneficially affect sickle cell disease patients remain unknown, hydroxyurea reacts with sickle cell hemoglobin. The long-- term goal of the proposed research is to thoroughly and clearly understand the contribution the reaction of hydroxyurea and sickle cell hemoglobin provides towards the beneficial effects observed with sickle cell disease patients undergoing hydroxyurea therapy. This goal is based upon the hypotheses that 1) the reaction of hydroxyurea with sickle cell hemoglobin forms sickle cell S-nitroso hemoglobin, 2) the formation of sickle cell Snitroso hemoglobin contributes a portion of the beneficial consequences of hydroxyurea therapy in sickle cell disease, 3) nitric oxide (NO) or nitroxyl (HNO/NO') produced during the reaction of hydroxyurea and sickle cell hemoglobin represent the ultimate source of the nitroso group of sickle cell S-nitroso hemoglobin, and 4) nitric oxide or nitroxyl donors capable of producing sickle cell S-nitroso hemoglobin will demonstrate beneficial effects similar to hydroxyurea. To study this reaction, the kinetics and product distribution of the reaction of hydroxyurea and oxy, deoxy, and met sickle cell hemoglobin and sickle red blood cells will be determined. The effects of nitric oxide and nitroxyl donors on sickle red blood cells will also be determined and a new watersoluble nitroxyl donor will be developed and evaluated with sickle red blood cells. Biophysical measurements regarding the delay time and percent sickle hemoglobin and the rheological properties of purified hemoglobins and red cells will determine the consequences of these reactions. These results will provide important information regarding the mechanism of hydroxyurea action in sickle cell disease that would be significant in the design and application of superior treatments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REACTIVE OXYGEN SPECIES AND HEMOGLOBIN-INDUCED INJURY Principal Investigator & Institution: Baldwin, Ann L.; Professor; Physiology; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2001; Project Start 01-AUG-1994; Project End 30-SEP-2003

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Summary: Many diseases and clinical procedures produce lysis of red blood cells that results in release of free hemoglobin in the circulation, which is often fatal. The longterm aim of the proposed research is to determine the mechanisms by which free Hb in the circulation causes intestinal tissue damage and increases microvascular permeability. The immediate goal of this proposal is to determine the roles that reactive oxygen species (ROS), produced by hemoglobin, play in causing tissue damage and disturbing macromolecular exchange in an intravital in situ preparation of the rat intestinal mucosa and mesentery. The intestine is one of the principal sites of transvascular exchange in the body, and if the selectivity of the exchange pathways is compromised, then undesirable products from the intestinal lumen will gain access to the bloodstream, possibly leading to sepsis. In this study a number of different modifications of Hb will be used, some of which produce ROS, and others which do not. The following hypothesis will be tested: The loss of selectivity of transvascular exchange barriers in the intestine and mesentery following intravascular injection of Hb, is due to the production of ROS and is catalysed by free iron, and amplified by mast cell degranulation. The role of nitric oxide in this process will also be investigated. Formation of ROS in the intestinal mucosa and mesentery, following injection of Hb, will be detected using a probe which fluoresces on contact with ROS. The effects of pretreatment with ROS scavengers, mast cell stabilizers, iron chelators and nitric oxide donors on intestinal endothelial and epithelial cell damage, and on formation of products of lipid peroxidation will be evaluated using electron microscopy and spectrophotometry, respectively. Presence or absence of endothelial junctional proteins will be evaluated using immunofluorescence microscopy. The effects of Hb on transvascular passage of bovine serum albumin (BSA) will be measured using epifluorescence microscopy and computer analysis of video images. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REFERENCE LABORATORY TO EVALUATE THERAPIES FOR SCD Principal Investigator & Institution: Asakura, Toshio; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-AUG-2005 Summary: The Sickle Cell Disease (SCD) Reference Laboratory (SCD-RL) was established to perform efficient, accurate and cost-effective evaluation of candidate agents for the treatment of SCD. Since its inception in 1997, the SCD-RL has validated seven new potential therapeutic agents including three agents that prolong the survival time of transgenic sickle mice under hypoxic conditions and four agents that promote the production of fetal hemoglobin (Hb F) in K562 cells. These promising results validate the approach taken by the SCD-RL, which is based on a comprehensive approach to the characterization of potential antisickling agents. The SCD-RL utilizes a standard in vitro protocol including more than 10 procedures to determine whether a candidate agent has beneficial and/or adverse effects. In addition to assessing antisickling effects in vitro, other parameters such as prolongation of the delay time prior to the polymerization of deoxygenated sickle hemoglobin, shift of the oxygen equilibrium curve to the left, induction of Hb F synthesis, hydration or reduction of dehydration of red blood cells (RBCs), and adhesiveness of RBCs to endothelial cells, are examined. The SCD-RL also studies the adverse effects of potential drugs such as formation of methemoglobin, hemolysis, and/or increase in the amount of denatured hemoglobin inside RBCs. Results of the in vitro evaluation of candidate drugs are then presented to the Ad Hoc Committee. This Committee reviews results and recommends which drugs should be evaluated by in vivo evaluation protocols utilizing transgenic mice. The SCD-

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RL found a particular transgenic mouse line that exclusively develops acute chest syndrome (ACS) upon exposure to hypoxia. The availability of a NIH-funded Reference Laboratory has facilitated and promoted the interest of outside commercial and academic entities. We received a much higher volume of requests for drug evaluation than originally expected. Based on the experience of the last 3 years, we believe that the SCD-RL plays a major role in assessing compounds which have already received an initial screen by other investigators. This enhances the likelihood of finding potentially clinically useful compounds. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION AND FUNCTION OF MACROPHAGE CD163 Principal Investigator & Institution: Guyre, Paul M.; Professor; Physiology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Recent key observations suggest that CD163 plays an important role in the regulation of inflammation. Expressed only on monocytes (Mo) and macrophages (MO), CD163 was shown last year to be an endocytic scavenger receptor for hemoglobin-haptoglobin (Hb/Hp) complexes. It is notable that haptoglobin has two allelic forms with different affinities for CD163, and haptoglobin phenotype is a predictor of diabetic nephropathy and of restenosis after coronary angioplasty. Moreover, CD163 expression on monocytes is markedly increased by glucocorticoids and IL-10--two mediators that increase rapidly in response to trauma or infection and are well characterized for reducing lipopolysaccharide (LPS) toxicity. Using a newly developed ELISA we show (i) that the extracellular domain of CD163 is rapidly shed from the monocyte after exposure to as little as 50 pg/ml of lipopolysaccharide (LPS) and (ii) that soluble CD163 (sCD163) in plasma rises rapidly and markedly during cardiac surgery with cardiopulmonary bypass, as well as following a bolus injection of LPS into experimental human subjects. A better understanding of the production and function of CD163 is therefore warranted. The goal of this RO3 application is the generation of reagents and pilot data that will enable the PI to establish a new research program focused on understanding the role that CD163 plays in regulating inflammation. The Specific Aims are designed to elucidate the molecular mechanisms of glucocorticoid, cytokine and LPS effects on CD163 expression and shedding. In addition, the newly sequenced murine CD163 will be compared to the human CD163 in terms of synthesis, shedding and Hb/Hp uptake in order to establish an appropriate murine model for future studies. New monoclonal antibodies (mAbs), soluble CD163 fusion proteins, and transfectants expressing both human and murine CD163 will also be developed. Fusion proteins and mAbs will be tested for inhibition of uptake of Hb/Hp complexes via CD163 using primary Mo cultures, Mo cell lines and transfectants. These reagents will also be used in pilot experiments to probe the effect of surface and soluble CD163 on immunological functions. The development of mechanistic and functional information, the generation of human and mouse reagents, and the potential validation of a mouse model should lay the foundation for an expanded application to determine more precisely the role of CD163 in the control of inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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

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Project Title: REGULATION OF PROTEIN SYNTHESIS AND ERYTHROPOIESIS Principal Investigator & Institution: Chen, Jane-Jane; Principal Research Scientist; None; Massachusetts Institute of Technology Cambridge, Ma 02139 Timing: Fiscal Year 2001; Project Start 01-JAN-1979; Project End 31-DEC-2002 Summary: (Adapted from investigator's abstract) The overall objective of this proposal is to more clearly define the regulation of hemoglobin synthesis and erythropoiesis in normal and abnormal hematologic conditions. In particular, the role of the hemeregulated translational inhibitor (HRI) on protein synthesis in immature erythroid cells, especially reticulocytes, and the regulation of HRI by heme will be studied. HRI is a heme regulated protein kinase that phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF-2-alpha). The phosphorylation of the alpha subunit of eIF-2 substantially inhibits the recycling of translational initiation and thereby results in the cessation of protein synthesis. This proposal therefore seeks to clarify the physiologic function of HRI by studying the consequences of the ablation of this expression or in its activity both in cell culture and in transgenic animals. Three specific aims are listed: 1) to

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study the regulation of hemoglobin synthesis and late erythroid differentiation by HRI in murine erythroleukemia cells; 2) to study the role of HRI in the regulation of erythroid differentiation and HRI in the regulation of erythroid differentiation and hemoglobin synthesis in bone marrow stem cells in culture and in whole animals; and 3) to study the erythroid development and hemoglobin synthesis during embryonic development in adult mice by knock-out of the HRI gene. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REVERSAL OF EPIGENETIC SILENCING OF THE G-GLOBIN GENE Principal Investigator & Institution: Atweh, George F.; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): The discovery that fetal hemoglobin can ameliorate the clinical severity of sickle cell disease generated considerable interest in the reactivation of the silenced gamma-globin genes in adult life as a potential therapeutic approach in patients with this disease. Intensive investigation of the molecular bases of the genetic disorders that are characterized by the persistence of fetal hemoglobin production in adult life has not translated into effective therapies. In contrast, the study of epigenetic modifications (e.g. DNA methylation and histone acetylation) in the developmental silencing of the gamma-globin genes spurred the development of a number of therapeutic agents that can induce fetal hemoglobin and ameliorate the severity of sickle cell disease. For the past 8 years, we have been conducting clinical trials of butyrate and hydroxyurea in sickle cell disease. In the course of these studies, we made a number of important and at times unexpected clinical observations that raised new questions about the mechanism(s) of induction of fetal hemoglobin by these agents. The major aim of this application is to study the potential role of the epigenetic state of the beta-globin gene cluster in the variable silencing of the gamma-globin genes and in the reactivation of fetal hemoglobin by butyrate and hydroxyurea. The specific aims are to: 1) Compare the state of histone acetylation and DNA methylation in the gamma-globin gene cluster of patients with variable silencing (i.e. either complete or partial silencing) of the beta-globin genes; 2) Investigate the effects of butyrate and hydroxyurea on histone acetylation and DNA methylation in the beta-globin gene cluster; 3) Investigate the potential roles of histone acetylation and DNA methylation in butyrate resistance and the reversal of this resistance by pre-treatment with hydroxyurea; 4) Investigate the heritability of the induction of gamma-globin gene expression by butyrate and nonbutyrate inhibitors of histone deacetylases; 5) Investigate the effects of butyrate and other inhibitors of histone deacetylase on the translational efficiency of gamma-globin mRNA. We believe these studies will shed important light on the normal mechanisms of silencing of the gamma-globin genes and their reversal by pharmacological therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF LBP-1A AND P14 NF-E4 IN GAMMA GLOBIN GENE EXPRE* Principal Investigator & Institution: Jane, Stephen M.; Royal Melbourne Hospital Melbourne 3050, Australia Melbourne, Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2005 Summary: (provided by applicant): Elevated levels of fetal hemoglobin lead to a significant amelioration of symptoms in patients with sickle cell disease and beta-

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thalassemia. This observation suggests that treatment strategies capable of re-activating fetal hemoglobin expression after birth should be explored. To achieve this goal we must first understand the mechanisms underlying the developmental regulation of the beta-globin locus, particularly the factors that can modulate gamma- globin expression. We have previously identified a candidate factor for this aim, the stage selector protein (SSP). The SSP is an erythroid-specific protein complex consisting of the ubiquitously expressed transcription factor CP2, and a tissue-restricted partner, p22 NF-E4. We have recently identified a second CP2-like gene, LBP-1a that also can form an SSP complex with NF-E4. We have also identified a 14 kD isoform of NF-E4 which acts in direct contrast to p22 NF-E4 and represses gamma-gene expression in a fetal/erythroid cell line. We have coupled these recent observations to our pre-existing knowledge of the SSP to develop three aims that will enhance our understanding of the mechanisms of action of this complex. The first specific aim focuses on the mechanistic roles of LBP-1a and p14 NF-E4 in regulating gamma-globin gene expression in the fetal erythroid environment and in hemoglobin switching models. These experiments will employ gene-targeting and transgenic strategies to elucidate the role of LBP-1a and p14 NF-E4 in vitro and in vivo. Specific aim 2 will expand on our observation that p14 NF-E4 fails to bind CP2/LBP-1a, full length NF-E4 or DNA and thus appears to exert is dominant negative effect through sequestration of a protein associating with the SSP. We will define the protein partners of both isoforms of NF-E4 using molecular and biochemical approaches. The work described in specific aim 3 will focus on the identification and characterisation of the core regions of the NF-E4 promoter using transcription assays in cell lines and transgenic mice. Taken together, these aims address many of the issues raised in the RFA. In particular, they seek to validate an existing trans-activator by direct function analysis and by investigation of mechanism of action. They also examine induction of the structural gene of such an activator with the emphasis on developing an assay system for high throughput drug screening. Finally, through protein interaction studies they may identify additional novel factors important in the activation (or repression) of gamma-globin gene expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SEVERE MALARIAL ANEMIA AND ALTERED IMMUNE FUNCTION Principal Investigator & Institution: Gordeuk, Victor R.; Professor of Medicine; Medicine; Howard University 2400 6Th St Nw Washington, Dc 20059 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: (Adapted from the Applicant's Abstract): The proposed research is designed to determine if excessive activity of the T helper lymphocyte type 1 (Th-1) immune response and decreased activity of the Th-2 immune response are involved in the pathogenesis of severe anemia in children with Plasmodium falciparum malaria. Severe malarial anemia (hemoglobin <5g/dL in a patient with a positive malaria smear) accounts for almost 10 percent of pediatric hospital admissions in southern Zambia and has a mortality of 9 percent despite aggressive therapy with blood transfusion and antimalaria therapy. Th-1 cytokines suppress erythroid precursors, divert iron from hemoglobin synthesis to stores, and lead to moderate to severe anemia. MIF, produces by macrophages upon ingestion of P. falciparum-infected erythrocytes, is an immune modulator hat has a suppressive effect on erythropoiesis. This study hypothesizes that severe malarial anemia develops in a patient with an abnormal immune response pattern characterized by 1) the persistence or resurgence of a prominent Th-1 response in the presence of chronic malaria and 2) 2xcessive release of MIF. The proposed research will examine the Th-1 and Th-2 responses and MIF production in Zambian

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children with uncomplicated malaria. The nutritional status, underlying parasitic infections, and genotypes and numbers of infecting P. falciparum strains will also be characterized. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SICKLE RBC, INTERMITTENT HYPOXIA AND VASCULAR PATHOLOGY Principal Investigator & Institution: Kuypers, Frans A.; Children's Hospital & Res Ctr at Oakland Research Center at Oakland Oakland, Ca 94609 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2004 Summary: The unique oxygen sensing capacity of the sickle red cell defines sickle cell disease (SCD) pathology resulting from the polymerization of sickle hemoglobin under low partial oxygen pressure (PO2). Our long term goal is to understand how intermittent hypoxia changes the red cell membrane and its interactions with vascular endothelium (E.C.). We hypothesize a novel chain of events in which intermittent hypoxia will generate lysophosphatidic acid (LPA), a powerful lipid mediator, exposes phosphatidyl serine (PS) on the red surface, and depletes plasma gelsolin levels, the buffer protein for LPA. We pose that nitric oxide (NO) and related compounds, generated by E.C. under hypoxia will affect this process depending on the hemoglobin concentration and type (HbS, or HbF). Increased levels of the inflammatory mediator secretory phospholipase A2 (sPLA2) in SCD will further exacerbate this process which will ultimately lead to vascular drainage. To address these aspects of RBC-E.C. interaction, we have developed the following specific aims: I. To investigate the effect of intermittent hypoxia on sickle red cells. II. To investigate intermittent hypoxia on red cell-endothelial interaction, and III. To evaluate factors of intermittent hypoxia in sickle cell patients and murine models of sickle cell disease. To accomplish these goals, we will use a multidisciplinary approach using biochemistry and cell biology techniques to study RBC and E.C. under well-defined conditions of intermittent hypoxia in vitro, in a unique incubation system, separately or together. We will measure the generation of LPA in vitro and define its role, determine the LPA buffering capacity of the plasma actin-binding protein gelsolin, and define the role for E.C. derived NO and its derivatives. We will relate the data of in vitro studies to in vivo findings of LPA, gelsolin and NO footprints in SCD patients with vasoocclusive crisis, stroke and acute chest syndrome as well as our murine model for SCD. Together, our results may indicate novel treatment regiments in the management of SCD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: S-NITROSOTHIOL BREAKDOWN BY AIRWAY EPITHELIAL CELLS Principal Investigator & Institution: Gaston, Benjamin M.; Associate Professor; Pediatrics; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 31-DEC-2002 Summary: S-Nitrosothiols (SNOs) in general - and S-nitrosoglutathione (GSNO) in particular - are stable, potent bronchodilators which also have immune regulatory functions and are present in the normal human airway. Asthmatic bronchospasm is associated with paradoxically low airway SNO levels - and undetectable GSNO levels despite relatively high concentrations of nitric oxide ( NO) in expired air and upregulation of inducible-nitric oxide synthase. This paradox may be best explained by considering GSNO to be a reservoir of bioactive nitrogen oxides in the airway - as it is in brain and other tissues - the breakdown of which is accelerated in asthma. In this sense,

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airway SNO catabolism may contribute both to high expired NO concentrations and to bronchospasm in asthmatic patients. This project will test the hypotheses that 1) airway epithelial cells catabolize SNO; 2) the SNO catabolic activity of airway epithelial cells is altered by stimulants relevant to asthma pathophysiology; and 3) airway epithelial cellmediated SNO catabolism inhibits airway smooth muscle relaxation. A new methodology will be used to study the conversion of SNO to NO in the presence of airway cells. Preliminary data using this system suggest that there are epithelial cell proteins which catalyze GSNO breakdown. These proteins will be characterized with regard to size, sequence, reactant and product stoichiometry and kinetics. Further, the effects of interleukin 4, vasoactive intestinal peptide, dexamethasone, acivicin, aurothioglucose and hemoglobin on epithelial GSNO catabolism and nitrogen oxide transport will be investigated. Finally, the relevance of epithelial GSNO breakdown will be studied in a bioassay of guinea-pig airway smooth muscle relaxation. In summary, this project will test the overall hypothesis that GSNO-mediated relaxation of airway smooth muscle is inhibited in the presence of airway epithelial cells by a regulated protein which catalyzes GSNO catabolism. If this hypothesis is proven, prevention of GSNO catabolism may define new asthma therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURAL BASIS FOR ASSEMBLY OF COOPERATIVE HEMOGLOBINS Principal Investigator & Institution: Royer, William E.; Associate Professor; Program in Molecular Medicine; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2002; Project Start 01-JAN-1991; Project End 31-DEC-2005 Summary: Much of biology is regulated by macromolecular interactions. Understanding the principles that govern the regulation of macromolecular interactions is critical for the rational manipulation of biological processes such as the immune response, gene expression and cellular growth. Allosteric proteins, which alter the interactions between subunits in response to environmental conditions, provide ideal systems for exploring the regulation of macromolecular interactions. We will be using three disparate invertebrate and primitive vertebrate hemoglobins as model systems for investigating atomic-level principles of allosteric protein function. Despite the similar tertiary structure of these hemoglobins, the extent of assembly into cooperative complexes is very different. The goal of this project is to elucidate the structural diversity and common themes that operate to regulate function in this family of proteins. Scapharca dimeric hemoglobin represents the simplest possible model system for cooperative protein function. Our powerful combination of structural, functional and mutational approaches for exploring the cooperative mechanism has revealed a number of important aspects of its function, including the central role of water molecules as sensors of ligation state. We are continuing our approaches to learn how assembly alters ligand pathways and to dissect the coupling between alternate pathways for communication between subunits. A much more complex system is Lumbricus erythrocruorin, which is assembled from 144 hemoglobin subunits and 36 non-hemoglobin (linker) subunits. Our structural results reveal that this molecule is assembled using an intricate hierarchy of symmetry. Our investigation of this molecule is designed to determine the role of two important domains, coiled coils and the cysteine-rich LDL-A module, for formation of this gigantic complex. In addition, we will determine the structural basis for the high cooperativity of this complex. A third system under investigation is the hemoglobin from lamprey, a primitive vertebrate. Unlike other hemoglobins, this hemoglobin gains

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cooperativity as a result of the concentration dependent equilibrium between different oligomeric states. Our structural analysis suggests a number of hypotheses for the regulation of function, which we will be testing by mutagenesis, kinetic and structural experiments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURAL ENERGETICS OF HEMOGLOBIN INTERMEDIATES Principal Investigator & Institution: Ackers, Gary K.; Professor; Biochem & Molecular Biophysics; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-SEP-1989; Project End 30-NOV-2005 Summary: (provided by applicant): The goal of this research is to determine the molecular mechanism and driving forces that regulate communication between the oxygen binding sites of human hemoglobin. The overall oxygen binding properties of hemoglobin are well-documented, however, the molecular basis of positive cooperativity, which is crucial to physiological efficacy, is not understood. The primary functional units within the hemoglobin tetramer have only recently been identified as its alphabeta dimer components, as shown by the distribution of structural energetics among intermediate states. The order of oxygen binding, as well as its release, follows specific combinatorial rules, binding preferentially to both sites on one dimer within the tetramer, then binding to the sites on the remaining dimer. This functional asymmetry within the hemoglobin tetramer is also observed in initial studies on hybrid tetramers, where one alphabeta dimer is normal but the other dimer contains a single amino acid in the cross-dimer interface. The effect of the modification on the cooperative free energy of oxygen binding is felt only on the modified dimer, while the normal dimer is not significantly affected. Dr. Ackers plans to extend these studies for the 02 intermediates using recombinant hemoglobins with designed sets of altered residue sites. Subunit interactions of the recombinant systems will be studied by techniques of kinetics, analytical gel chromatography, cryogenic isoelectric focusing, as well as by direct 02 binding. As the Hb regulatory system is an important prototype for a large family of cooperative multi-site regulatory assemblies, the methods developed by this program should have wide applicability. Deeper understanding of human Hb mechanisms is also of current interest to the potential design of red cell substitute oxygen carriers and hemoglobin-based drug delivery systems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRUCTURE FUNCTION RELATIONSHIP IN HEMEPROTEINS Principal Investigator & Institution: Yeh, Syun-Ru; Physiology and Biophysics; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2005 Summary: The objective of this proposal is to elucidate the protein-ligand interactions and structure/function relationships in three new bacterial hemoglobins (Hb) and two mammalian prostaglandin H synthases (PGHS-1 and PGHS-2). The two bacterial hemoglobins from Mycobacterium tuberculosis (HbN and HbO) belong to a newly discovered truncated hemoglobin family, which are characterized by a novel two-overtwo alpha-helical sandwich motif, the absence of the A- helix and the presence of an extended loop substituting for most of the F-helix. The physiological functions of HbN and HbO are not established but because O2 delivery in unicellular organisms is a diffusion-controlled process, functions other than oxygen transport have been put forth. The bacterial hemoglobin from E. coli (Hmp) is a flavohemoglobin consisting of a heme-

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containing globin-like domain and a FAD-containing reductase domain. It is believed that the function of Hmp is to detoxify NO and other reactive nitrogen species. The structural properties of the three bacterial hemoglobins will be fully characterized. Based on our preliminary resonance Raman studies, we postulate that the heme pockets of these bacterial hemoglobins are tailored to perform chemistry, such as oxygen activation, and that they may share structural and functional similarities to peroxidases. This hypothesis will be tested by studies of the reactions of these hemoglobins with NO, hydrogen peroxide and peroxynitrite. The possible role of these hemoglobins in protecting the microorganisms against attack by reactive nitrogen intermediates will be explored by monitoring NO and O2 consumption in wild-type and hemoglobin knockout cells. Related reactions will be studied in the peroxidase sites of two PGHS isoforms, which play an essential role in the synthesis of prostaglandins. Preliminary data suggests that the proximal bond that coordinates the heme to the polypeptide is quite weak in PGHS's, which is very unusual for peroxidases. Experiments are proposed to test the functional consequences of this finding. These hemeprotein systems provide an excellent model for investigating fundamental structural properties that underlie biological reactivity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TARGETED ACTIVATION OF FETAL HEMOGLOBIN Principal Investigator & Institution: Barbas, Carlos F.; Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): This project seeks to clarify molecular pathways that activate fetal hemoglobin or prevent its silencing as well as to define or develop novel transactivators of fetal hemoglobin. The net result of this study will be an increased understanding of globin regulation and novel molecular targets and therapeutic strategies to treat b-chain hemoglobinopathies. The ability to selectively manipulate the transcription of genes controlling the -globin locus is anticipated to have a significant impact on both our understanding of this locus as well as the treatment of diseases associated with mutations in this locus. The study proposed here capitalizes on our development of designed transcription factors that enable the transcription of endogenous genes to be either activated or repressed. Currently no other gene therapy strategy provides the means of effectively knocking out the expression of an endogenous gene- for example knocking out a silencer of g-globin expression. Polydactyl zinc finger proteins can now be prepared that recognize 18 bp DNA target sequences with high affinity and specificity. When fused to activation or repression domains, these proteins become potent regulators of the transcriptional activity of the target gene. This proposal focuses on the use of our transcriptional regulators to specifically modulate transcription of the b-globin locus with the aim of up-regulating fetal hemoglobin. We aim to explore the potential of targeted gene modulation as a gene-based therapeutic strategy for the treatment of b-hemoglobinopathies as well as a unique gene discovery tool for the identification of novel transcriptional modifiers of this locus and the validation of existing ones. A novel genome-wide transcriptional modulation strategy will be applied to the search for new targets for therapeutic intervention. With selective and potent transcriptional regulators we will address the therapeutic potential of controlling the globin locus in animal models. It is anticipated that the results of this work will provide a novel approach to study the molecular mechanisms of hemoglobinopathies as well as new strategies to treat them. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE GLYCOSYLATION GAP AND DIABETIC COMPLICATIONS Principal Investigator & Institution: Cohen, Robert M.; Associate Professor of Medicine; Internal Medicine; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Hemoglobin A1c (Hb1c) is the gold standard for assessing diabetes control yet some patients have HbA1c discordant from plasma glucose. We developed a measure of the discordance between Hb1c and a plasma test of glycemic control, the "Glycosylation Gap" (GG). The GG is highly reproducible, correlates with an important clinical outcome, diabetic nephropathy, and appears genetically linked. A parallel measure of variance between HbA1c and glucose monitoring (Hb glycosylation index), has been shown to predict retinopathy and nephropathy in the DCCT. These data suggest that variation in HbA1c, expressed as the GG, arises from biological mechanism(s) that contribute to diabetic complications in here-to-fore unrecognized ways. Since HbA1c is determined by red blood cell (RBC) glucose concentration, the rate of Hb glycosylation and RBC lifespan, this proposal examines the variability of these factors in diabetic and non-diabetic populations. We found substantial variation in RBC glucose relative to extracellular glucose. This in vitro erythrocyte membrane glucose gradient (EMGG) correlated with GG and by inference with a higher risk of complications. The fact that the RBC and the endothelial cell - the major cell type in which diabetic complications occur - share the same glucose transporter, GLUT1, raises the question whether this finding is mediated by shared GLUT1 variation in the two tissues. These studies will seek to determine: (1) whether variation in GLUT1 function contributes to variation in HbA1c; (2) how variation in RBC lifespan or HbA1c formation rate contributes to HbA1c variability; (3) how long-term glycemic control affects the EMGG and the GG, and whether they represent reproducible phenotypes for genetic studies. These studies provide a comprehensive approach to understanding important sources of variation in HbA1c. The variation in EMGG could account for 11% of total variation in >30 million HbA1c measurements yearly in the United States. This proposal extends the consideration of complications risk from the glucose concentration in the plasma to the glucose concentration inside the cell. The proposal therefore has potentially important basic science, clinical and population implications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TRANS-ACTING FACTORS IN FETAL HEMOGLOBIN SILENCING Principal Investigator & Institution: Crossley, P Merlin.; University of Sydney Main Quadrangle, Bld A14 Sydney, 2006 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): The symptoms of Sickle Cell Disease and Cooley's Anemia can be ameliorated by reactivating the fetal globin genes. Although fetal globin is not normally expressed at high level in adults, significant expression is observed when erythroid cells or patients are treated with certain chemicals, which are believed to act by inhibiting transcriptional repression. Fetal globin expression also occurs when the fetal globin promoters are altered by point mutations, as seen in some cases of heriditary persistence of fetal hemoglobin (HPFH). We have focused on point mutations in the fetal globin promoters that are associated with HPFH and examined the roles of DNAbinding proteins that recognize the elements implicated by these mutations. We have shown that Basic Kruppel-like Factor (BKLF) binds together with GATA-1 over one site and the orphan receptor COUP-TF2 recognizes a separate site. In the case of BKLF

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experiments involving breeding BKLF knockout mice to transgenic mice carrying the entire human beta globin locus have confirmed that BKLF is required for fetal globin silencing in vivo. In vitro experiments also argue in favor of a role for BKLF. We now wish to carry out further in vivo and in vitro work to verify that BKLF is directly involved, to identify other components of the silencing complex and to investigate the mechanism of silencing. We will use chromatin immunoprecipitation assays to confirm the presence of the silencing complex, biochemical fractionation to identify additional components, and experiments with cells immortalized from BKLF knockout mice to test the direct functional relevance of these proteins. We will also use a dominant negative strategy in cell lines and primary cells to assess the role of COUP-TF2. It has previously been reported that Ikaros plays a role in fetal globin silencing and we will also analyze a novel Ikaros mutant mouse bred to globin transgenic mice to test the effect of Ikaros in vivo. These experiments are aimed at confirming the in vivo relevance of BKLF, GATA1, COUP-TF2 and Ikaros and may ultimately lead to the development of inhibitors that mimic the effect of specific HPHF point mutations and allow reactivation of fetal globin gene expression as a treatment for Sickle Cell Disease and Cooley's anemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSACTIVATORS VALIDATION

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F:

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Principal Investigator & Institution: Surrey, Saul; 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): Sickle cell disease (SCD) and Cooley's anemia (CA) are disorders ameliorated by continued expression of fetal hemoglobin; first shown in patients with continued expression of fetal globin due to deletional or nondeletional hereditary persistence of fetal hemoglobin (HFPH). However, others express high fetal globin in the absence of mutation, and therapeutic agents, such as hydroxyurea, induce expression of Hb F. If the rate-limiting factors involved in the regulation of fetal hemoglobin were elucidated, targeted drug discovery could succeed in developing agents with this specific effect. Our proposal focuses on three areas: 1) identify new candidate modifiers using unbiased, genome-wide microarray-based expression profiling to define genes critical to induction of Hb F in cultured human erythroid progenitors. The candidates will be assessed for identification of genes that fall into several categories, including transcription factors, signaling and chromatin remodeling molecules. 2) examine suspected regulators of Hb F expression as well as a subset of differentially-expressed transcripts comparing cord to adult erythroid cultures for functionally relevant genetic variation associated with elevated Hb F levels. Known regulators (KLFs, NFE-4 and soluble guanylate cyclase) and the most promising of the candidate transactivators identified by expression profiling will be explored to identify putative coding region and proximal promoter sequence allelic variants using both public databases and SNP discovery methods. Those with allele frequencies of 10% or more in a small group of SCD patients, will be tested in sequential cohorts of adult and pediatric patients with SCD with and without elevated Hb F. Significant QTL loci will then be examined in a group of parent-child trios and followed with a third population of SCD patients. 3) functional validation of candidate modifiers will be accomplished by knockdown technology employing morpholino antisense oligos and/or interference RNA (iRNA) using K562 cells containing a fetal globin promoter-driven GFP readout from a beta-like globin gene cluster BAC. We are confident that our strategy to identify critical regulatory molecules for Hb F regulation and our ability to quickly and reliably

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screen for candidate gene variants will have significant impact on the development of therapeutic intervention strategies for patients with SCD and CA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRAUMA PRIMES CELLS Principal Investigator & Institution: Harken, Alden H.; Professor and Chairman; Surgery; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-MAR-2004 Summary: This current application is conceived as an extension of our funded 1998 Trauma Center application. Our GLOBAL HYPOTHESIS is that we can devise THERAPY FOR TRAUMA PRIMES CELLS. During the past two years, we have enjoyed gratifying recruitment of patients into our Trauma/MOF Registries (ADULTS-Project IA and Children-Project 1C) and we postulate that polymorphisms in the promoter region of stress- response genes influence the susceptibility to post-injury MOF (Project 1B). Activated neutrophils have traditionally been linked to post-injury systemic inflammation and we postulate an exacerbation of this injury due to delayed neutrophil apoptosis (Project II). Cells/organs/patient ischemia is the hallmark of any major injury and we wish to explore this altered cellular bioenergic profile as signal dictating posttraumatic events (Project III). We expand our previous interrogation of signaling mechanisms to an examination of mechanisms of hyperosmolar therapy (Project IV). Liposomal delivery of HSP72 inhibits Mphi TNF production. We further propose that HSP72 suppresses TNF receptor mediated amplification of Mphi inflammatory response and that targeted deliver of HSP72 controls post-injury myocardial inflammation (Project V). Lung dysfunction is acknowledged by an early victim in the sequential cascade of post-injury organ failure. We propose pulmonary vasomotor dysfunction to be the origin of this clinically frightening problem (Project VI). TNF (although immunologically healthy) is now recognized for its post-injury depressive potential. We propose both mechanisms of and therapy against interleukin-18 as an even more proximal "out of control" cytokine (Project VII). Two years ago, we proposed kinase/phosphatase signaling as the backbone of post-injury cellular message transmission. We now postulate that sarcolemmal signal endocytosis onto a cytoskeletal scaffolding regulates the sequence and magnitude of post-injury information transfer (Project VIII). To our surprise, blood transfusion (which we had happily translated as a surrogate for shock) proved to be an independent predictor of post- traumatic MOF. We now postulate that the oxygen carrying hemoglobin is good; but, the red cell membrane lipid bits are bad. We propose to decipher which membrane lipid parts cause trouble (Project IX) and further we will conduct clinical anti-cytokine trials (Projects VI and VII) (no funding requested) and a resuscitative trial with a hemoglobin based oxygen carrier (no funding requested) which we hope will bypass a problem (blood transfusion) that we identified in our early Trauma Registry (Project IA). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: USE OF MODIFIED EKLF FOR GAMMA GLOBIN AUGMENTATION Principal Investigator & Institution: Manwani, Deepa G.; Pediatrics; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2005 Summary: (adapted from the application) Sickle cell anemia and related hemoglobinopathies are among the most common genetic disorders in this country.

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Reactivation of fetal globin by pharmacologic agents provides therapeutic benefits in these patients by interfering with the polymerization of the mutant hemoglobin. This proposal outlines an alternative approach for augmentation of fetal hemoglobin. All vertebrate animals switch hemoglobins during development from fetal to adult type. The molecular mechanisms that mediate this process are complex. Erythroid Kruppel like factor (EKLF) is an erythroid specific transcription factor that plays a crucial role in activating beta globin expression and in consolidating the switch from fetal to adult globin. In its absence not only is adult beta globin expression abolished, but there is a competitive increase in gamma globin expression. This has led us to consider whether manipulating EKLF's molecular properties so that it acts as a transcriptional repressor might further augment and stabilize gamma globin gene expression. The above hypothesis will be tested by: (1) Constructing repressor EKLF constructs and testing them by transient transfection assays in cell lines. (2) Monitoring the functional importance of repressor constructs in differentiating embryonic stem cells and transgenic mice.(3) Analyzing the effect of repressor constructs on sickle erythropoiesis in liquid cultures. The end result of these aims will be to provide a transcriptional reagent for gene therapy approaches that will augment fetal hemoglobin levels in patients with sickle cell disease. Amelioration of the debilitating effects of this disease provides a considerable clinical rationale for pursuing this goal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VACCINE STUDIES OF THE HEMOGLOBIN RECEPTOR OF H. DUCREYI Principal Investigator & Institution: Elkins, Christopher; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2006 Summary: (provided by applicant): Haemophilus ducreyi, the etiologic agent of the genital ulcer disease chancroid, is a significant public health problem in several regions worldwide. In Africa, Asia and other developing countries, it is an important cofactor for the heterosexual transmission of HIV. Control of chancroid, using an effective vaccine that is properly administered, would likely reduce HIV transmission. It is the goal of my laboratory to develop such a vaccine. We propose studies on the immunobiology and structure of the hemoglobin receptor (HgbA) of H. ducreyi. Several attributes of HgbA make it an attractive vaccine candidate. HgbA is required to establish human experimental infection. HgbA is conserved immunologically and functionally and all H. ducreyi express it. Unlike hemoglobin receptors from other bacteria, HgbA does not undergo phase or antigenic variation. Studies in the chilled rabbit model of chancroid infection, suggest purified native HgbA or recombinantly expressed HgbA are partially effective vaccines. Further vaccine studies utilizing the Swine model of H.ducreyi infection, that more closely resembles natural human infection. Experimental vaccines will consist of purified native HgbA from H. ducreyi type strain 35000, or possibly synthetic peptides derived from HgbA. We will test the ability of native HgbA to protect against a homologous and heterologous challenge infection. Detailed studies will be undertaken on HgbA including understanding its structure and regions/residues of HgbA that are surface-exposed. We will determine the variability of the HgbA protein from geographically diverse isolates. These studies are important for better understanding of chancroid pathogenesis and will facilitate vaccine development in several aspects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

104 Hemoglobin

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 “hemoglobin” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for hemoglobin in the PubMed Central database: •

A Brief History of Hemoglobins: Plant, Animal, Protist, and Bacteria. by Hardison RC.; 1996 Jun 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=39118

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A cooperative oxygen-binding hemoglobin from Mycobacterium tuberculosis. by Couture M, Yeh SR, Wittenberg BA, Wittenberg JB, Ouellet Y, Rousseau DL, Guertin M.; 1999 Sep 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18015

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A hemoglobin from plants homologous to truncated hemoglobins of microorganisms. by Watts RA, Hunt PW, Hvitved AN, Hargrove MS, Peacock WJ, Dennis ES.; 2001 Aug 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=56925

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A hemoglobin-binding outer membrane protein is involved in virulence expression by Haemophilus ducreyi in an animal model. by Stevens MK, Porcella S, Klesney-Tait J, Lumbley S, Thomas SE, Norgard MV, Radolf JD, Hansen EJ.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173985

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A human embryonic hemoglobin inhibits Hb S polymerization in vitro and restores a normal phenotype to mouse models of sickle cell disease. by He Z, Russell JE.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124997

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A Mutation That Improves Soluble Recombinant Hemoglobin Accumulation in Escherichia coli in Heme Excess. by Weickert MJ, Pagratis M, Glascock CB, Blackmore R.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=91073

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A New Hemoglobin Gene from Soybean: A Role for Hemoglobin in All Plants. by Andersson CR, Jensen EO, Llewellyn DJ, Dennis ES, Peacock WJ.; 1996 Jun 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39120

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A role for nitric oxide in hydroxyurea-mediated fetal hemoglobin induction. by King SB.; 2003 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151883

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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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A signature of the T [right arrow] R transition in human hemoglobin. by Mihailescu MR, Russu IM.; 2001 Mar 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31128

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A TyrCD1 /TrpG8 hydrogen bond network and a TyrB10[bond]TyrCD1 covalent link shape the heme distal site of Mycobacterium tuberculosis hemoglobin O. by Milani M, Savard PY, Ouellet H, Ascenzi P, Guertin M, Bolognesi M.; 2003 May 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156275

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Adaptation of Bird Hemoglobins to High Altitudes: Demonstration of Molecular Mechanism by Protein Engineering. by Jessen T, Weber RE, Fermi G, Tame J, Braunitzer G.; 1991 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52117

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Allosteric intermediates indicate R2 is the liganded hemoglobin end state. by Schumacher MA, Zheleznova EE, Poundstone KS, Kluger R, Jones RT, Brennan RG.; 1997 Jul 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21516

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Analysis of the mechanism of action of non-deletion hereditary persistence of fetal hemoglobin mutants in transgenic mice. by Li Q, Duan ZJ, Stamatoyannopoulos G.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140187

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Antarctic fish hemoglobins: Evidence for adaptive evolution at subzero temperature. by Bargelloni L, Marcato S, Patarnello T.; 1998 Jul 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21134

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Bacterial Hemoglobins and Flavohemoglobins for Alleviation of Nitrosative Stress in Escherichia coli. by Frey AD, Farres J, Bollinger CJ, Kallio PT.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=126413

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Binding of hemoglobin to the envelope of Porphyromonas gingivalis and isolation of the hemoglobin-binding protein. by Fujimura S, Shibata Y, Hirai K, Nakamura T.; 1996 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174076

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Binding Specificity of the Porphyromonas gingivalis Heme and Hemoglobin Receptor HmuR, Gingipain K, and Gingipain R1 for Heme, Porphyrins, and Metalloporphyrins. by Olczak T, Dixon DW, Genco CA.; 2001 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95451

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Carbohydrate Gluing, an Architectural Mechanism in the Supramolecular Structure of an Annelid Giant Hemoglobin. by Ebina S, Matsubara K, Nagayama K, Yamaki M, Gotoh T.; 1995 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41340

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Cell-specific expression of the promoters of two nonlegume hemoglobin genes in a transgenic legume, Lotus corniculatus. by Andersson CR, Llewellyn DJ, Peacock WJ, Dennis ES.; 1997 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=158114

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Central Role of Hemoglobin Degradation in Mechanisms of Action of 4Aminoquinolines, Quinoline Methanols, and Phenanthrene Methanols. by Mungthin M, Bray PG, Ridley RG, Ward SA.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105975

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Characterization and Expression of HmuR, a TonB-Dependent Hemoglobin Receptor of Porphyromonas gingivalis. by Simpson W, Olczak T, Genco CA.; 2000 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=94695

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Characterization of the hgbA locus encoding a hemoglobin receptor from Haemophilus ducreyi. by Elkins C, Chen CJ, Thomas CE.; 1995 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173285

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Characterization of the Pasteurella multocida hgbA Gene Encoding a HemoglobinBinding Protein. by Bosch M, Garrido ME, Llagostera M, Perez de Rozas AM, Badiola I, Barbe J.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130319

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Chimeric Vitreoscilla Hemoglobin (VHb) Carrying a Flavoreductase Domain Relieves Nitrosative Stress in Escherichia coli: New Insight into the Functional Role of VHb. by Kaur R, Pathania R, Sharma V, Mande SC, Dikshit KL.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=126558

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Cloning of a DNA fragment encoding a heme-repressible hemoglobin-binding outer membrane protein from Haemophilus influenzae. by Jin H, Ren Z, Pozsgay JM, Elkins C, Whitby PW, Morton DJ, Stull TL.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174198

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Debate: Transfusing to normal hemoglobin levels improves outcome. by Haupt MT.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137268

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Detection of Phase Variation in Expression of Proteins Involved in Hemoglobin and Hemoglobin-Haptoglobin Binding by Nontypeable Haemophilus influenzae. by Cope LD, Hrkal Z, Hansen EJ.; 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101702

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Dissection of Central Carbon Metabolism of Hemoglobin-Expressing Escherichia coli by 13C Nuclear Magnetic Resonance Flux Distribution Analysis in Microaerobic Bioprocesses. by Frey AD, Fiaux J, Szyperski T, Wuthrich K, Bailey JE, Kallio PT.; 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=92635

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Enhanced Polymerization of Recombinant Human Deoxyhemoglobin [beta]6 Glu [right arrow] Ile. by Baudin-Chich V, Pagnier J, Marden M, Bohn B, Lacaze N, Kister J, Schaad O, Edelstein SJ, Poyart C.; 1990 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53580

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Expression of Alcaligenes eutrophus Flavohemoprotein and Engineered Vitreoscilla Hemoglobin-Reductase Fusion Protein for Improved Hypoxic Growth of Escherichia coli. by Frey AD, Bailey JE, Kallio PT.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=91791

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Expression of Fully Functional Tetrameric Human Hemoglobin in Escherichia coli. by Hoffman SJ, Looker DL, Roehrich JM, Cozart PE, Durfee SL, Tedesco JL, Stetler GL.; 1990 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54988

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Extension of transverse relaxation-optimized spectroscopy techniques to allosteric proteins: CO- and paramagnetic fluoromet-hemoglobin [[beta](15N-valine)]. by Nocek JM, Huang K, Hoffman BM.; 2000 Mar 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15964

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Flavohemoglobin denitrosylase catalyzes the reaction of a nitroxyl equivalent with molecular oxygen. by Hausladen A, Gow A, Stamler JS.; 2001 Aug 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=56923

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Formation of Two Hydrogen Bonds from the Globin to the Heme-Linked Oxygen Molecule in Ascaris Hemoglobin. by De Baere I, Perutz MF, Kiger L, Marden MC, Poyart C.; 1994 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43206

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Functional expression of falcipain, a Plasmodium falciparum cysteine proteinase, supports its role as a malarial hemoglobinase. by Salas F, Fichmann J, Lee GK, Scott MD, Rosenthal PJ.; 1995 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173275

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Gene therapy for the hemoglobin disorders: Past, present, and future. by Persons DA, Nienhuis AW.; 2000 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33980

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Hemoglobin Biosynthesis in Vitreoscilla stercoraria DW: Cloning, Expression, and Characterization of a New Homolog of a Bacterial Globin Gene. by Joshi M, Mande S, Dikshit KL.; 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=106302

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Hemoglobin in Frankia, a Nitrogen-Fixing Actinomycete. by Tjepkema JD, Cashon RE, Beckwith J, Schwintzer CR.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127563

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Hemoglobin increases mortality from bacterial endotoxin. by Su D, Roth RI, Yoshida M, Levin J.; 1997 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175126

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Hemoglobin induction in mouse macrophages. by Liu L, Zeng M, Stamler JS.; 1999 Jun 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21968

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Hemoglobin Toxicity in Experimental Bacterial Peritonitis Is Due to Production of Reactive Oxygen Species. by Yoo YM, Kim KM, Kim SS, Han JA, Lea HZ, Kim YM.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95802

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Hemoglobinase Activity of the Lysine Gingipain Protease (Kgp) of Porphyromonas gingivalis W83. by Lewis JP, Dawson JA, Hannis JC, Muddiman D, Macrina FL.; 1999 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93978

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Hemoglobin-Induced Binding of Candida albicans to the Cell-Binding Domain of Fibronectin Is Independent of the Arg-Gly-Asp Sequence. by Yan S, Rodrigues RG, Roberts DD.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108142

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Heterometallic Hybrids of Homometallic Human Hemoglobins. by Huang Y, Yonetani T, Tsuneshige A, Hoffman BM, Ackers GK.; 1996 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39554

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hgpB, a Gene Encoding a Second Haemophilus influenzae Hemoglobin- and Hemoglobin-Haptoglobin-Binding Protein. by Ren Z, Jin H, Morton DJ, Stull TL.; 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108583

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High Expression of Human [beta]S- and [alpha]-Globins in Transgenic Mice: Hemoglobin Composition and Hematological Consequences. by Fabry ME, Nagel RL, Pachnis A, Suzuka SM, Costantini F.; 1992 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50716

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High levels of human gamma-globin gene expression in adult mice carrying a transgene of deletion-type hereditary persistence of fetal hemoglobin. by Arcasoy MO, Romana M, Fabry ME, Skarpidi E, Nagel RL, Forget BG.; 1997 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232055

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High-Fidelity Translation of Recombinant Human Hemoglobin in Escherichia coli. by Weickert MJ, Apostol I.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=106200

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HmbR outer membrane receptors of pathogenic Neisseria spp.: iron-regulated, hemoglobin-binding proteins with a high level of primary structure conservation. by Stojiljkovic I, Larson J, Hwa V, Anic S, So M.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=178238

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HmbR, a Hemoglobin-Binding Outer Membrane Protein of Neisseria meningitidis, Undergoes Phase Variation. by Richardson AR, Stojiljkovic I.; 1999 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93618

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Hydroxyurea induces fetal hemoglobin by the nitric oxide --dependent activation of soluble guanylyl cyclase. by Cokic VP, Smith RD, Beleslin-Cokic BB, Njoroge JM, Miller JL, Gladwin MT, Schechter AN.; 2003 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151872

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Identification and purification of a conserved heme-regulated hemoglobin-binding outer membrane protein from Haemophilus ducreyi. by Elkins C.; 1995 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173141

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Identification and purification of a hemoglobin-binding outer membrane protein from Neisseria gonorrhoeae. by Chen CJ, Sparling PF, Lewis LA, Dyer DW, Elkins C.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174481

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Identification of a Two-Component Signal Transduction System from Corynebacterium diphtheriae That Activates Gene Expression in Response to the Presence of Heme and Hemoglobin. by Schmitt MP.; 1999 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=94039

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Identification of an iron-regulated outer membrane protein of Neisseria meningitidis involved in the utilization of hemoglobin complexed to haptoglobin. by Lewis LA, Dyer DW.; 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=176737

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Identification of an outer membrane protein involved in utilization of hemoglobinhaptoglobin complexes by nontypeable Haemophilus influenzae. by Maciver I, Latimer JL, Liem HH, Muller-Eberhard U, Hrkal Z, Hansen EJ.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174284

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Identification of the Intermediate Allosteric Species in Human Hemoglobin Reveals a Molecular Code for Cooperative Switching. by Daugherty MA, Shea MA, Johnson JA, LiCata VJ, Turner GJ, Ackers GK.; 1991 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50966

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Induction of protective immunity in cattle against infection with Fasciola hepatica by vaccination with cathepsin L proteinases and with hemoglobin. by Dalton JP, McGonigle S, Rolph TP, Andrews SJ.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174490

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Involvement of HxuC Outer Membrane Protein in Utilization of Hemoglobin by Haemophilus influenzae. by Cope LD, Love RP, Guinn SE, Gilep A, Usanov S, Estabrook RW, Hrkal Z, Hansen EJ.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98165

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Isolation and Sequencing of a cDNA for an Unusual Hemoglobin from the Parasitic Nematode Pseudoterranova decipiens. by Dixon B, Walker B, Kimmins W, Pohajdak B.; 1991 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51936

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Lipopolysaccharides of Actinobacillus pleuropneumoniae bind pig hemoglobin. by Belanger M, Begin C, Jacques M.; 1995 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173045

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Liquid --liquid separation in solutions of normal and sickle cell hemoglobin. by Galkin O, Chen K, Nagel RL, Hirsch RE, Vekilov PG.; 2002 Jun 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124280

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Modifications of RNA Processing Modulate the Expression of Hemoglobin Genes. by Kollia P, Fibach E, Najjar SM, Schechter AN, Noguchi CT.; 1996 Jun 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39122

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Mycobacterium tuberculosis hemoglobinN displays a protein tunnel suited for O2 diffusion to the heme. by Milani M, Pesce A, Ouellet Y, Ascenzi P, Guertin M, Bolognesi M.; 2001 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149180

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Neisseria gonorrhoeae Heme Biosynthetic Mutants Utilize Heme and Hemoglobin as a Heme Source but Fail To Grow within Epithelial Cells. by Turner PC, Thomas CE, Elkins C, Clary S, Sparling PF.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108651

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Nitric oxide is consumed, rather than conserved, by reaction with oxyhemoglobin under physiological conditions. by Joshi MS, Ferguson TB Jr, Han TH, Hyduke DR, Liao JC, Rassaf T, Bryan N, Feelisch M, Lancaster JR Jr.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124916

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Nitric oxide reaction with red blood cells and hemoglobin under heterogeneous conditions. by Han TH, Hyduke DR, Vaughn MW, Fukuto JM, Liao JC.; 2002 May 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124345

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NMR reveals hydrogen bonds between oxygen and distal histidines oxyhemoglobin. by Lukin JA, Simplaceanu V, Zou M, Ho NT, Ho C.; 2000 Sep 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27028

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Ordered water molecules as key allosteric mediators in a cooperative dimeric hemoglobin. by Royer WE Jr, Pardanani A, Gibson QH, Peterson ES, Friedman JM.; 1996 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26166

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Pathogenic Neisseriae Can Use Hemoglobin, Transferrin, and Lactoferrin Independently of the tonB Locus. by Desai PJ, Garges E, Genco CA.; 2000 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111005

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Phase Variation of Hemoglobin Utilization in Neisseria gonorrhoeae. by Chen CJ, Elkins C, Sparling PF.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108006

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Physiological reactions of nitric oxide and hemoglobin: A radical rethink. by Gross SS, Lane P.; 1999 Aug 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33713

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Point Mutations in HpuB Enable Gonococcal HpuA Deletion Mutants To Grow on Hemoglobin. by Chen CJ, Mclean D, Thomas CE, Anderson JE, Sparling PF.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139576

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Polar Zipper Sequence in the High-Affinity Hemoglobin of Ascaris suum: Amino Acid Sequence and Structural Interpretation. by Baere ID, Liu L, Moens L, Beeumen JV, Gielens C, Richelle J, Trotman C, Finch J, Gerstein M, Perutz M.; 1992 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49138

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Porphyrin-Mediated Binding to Hemoglobin by the HA2 Domain of Cysteine Proteinases (Gingipains) and Hemagglutinins from the Periodontal Pathogen Porphyromonas gingivalis. by DeCarlo AA, Paramaesvaran M, Yun PL, Collyer C, Hunter N.; 1999 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93857

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Porphyrin-Mediated Cell Surface Heme Capture from Hemoglobin by Porphyromonas gingivalis. by Paramaesvaran M, Nguyen KA, Caldon E, McDonald

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JA, Najdi S, Gonzaga G, Langley DB, DeCarlo A, Crossley MJ, Hunter N, Collyer CA.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152631 •

Preparation, Properties, and Plasma Retention of Human Hemoglobin Derivatives: Comparison of Uncrosslinked Carboxymethylated Hemoglobin with Crosslinked Tetrameric Hemoglobin. by Manning LR, Morgan S, Beavis RC, Chait BT, Manning JM, Hess JR, Cross M, Currell DL, Marini MA, Winslow RM.; 1991 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51440

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Production of Unmodified Human Adult Hemoglobin in Escherichia coli. by Shen T, Ho NT, Simplaceanu V, Zou M, Green BN, Tam MF, Ho C.; 1993 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47297

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Quaternary structure of hemoglobin in solution. by Lukin JA, Kontaxis G, Simplaceanu V, Yuan Y, Bax A, Ho C.; 2003 Jan 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=141027

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Recombinant Expression and Localization of Schistosoma mansoni Cathepsin L1 Support Its Role in the Degradation of Host Hemoglobin. by Brady CP, Dowd AJ, Brindley PJ, Ryan T, Day SR, Dalton JP.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96319

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Recombinant Human Hemoglobins Designed for Gene Therapy of Sickle Cell Disease. by McCune SL, Reilly MP, Chomo MJ, Asakura T, Townes TM.; 1994 Oct 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44915

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Recombinant Human Sickle Hemoglobin Expressed in Yeast. by de Llano JJ, Schneewind O, Stetler G, Manning JM.; 1993 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45781

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Reevaluation of Chloride's Regulation of Hemoglobin Oxygen Uptake: The Neglected Contribution of Protein Hydration in Allosterism. by Colombo MF, Rau DC, Parsegian VA.; 1994 Oct 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45052

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Relative role of heme nitrosylation and [beta]-cysteine 93 nitrosation in the transport and metabolism of nitric oxide by hemoglobin in the human circulation. by Gladwin MT, Ognibene FP, Pannell LK, Nichols JS, Pease-Fye ME, Shelhamer JH, Schechter AN.; 2000 Aug 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27634

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Restoration of hemoglobin A synthesis in erythroid cells from peripheral blood of thalassemic patients. by Lacerra G, Sierakowska H, Carestia C, Fucharoen S, Summerton J, Weller D, Kole R.; 2000 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16909

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Restoring Allosterism with Compensatory Mutations in Hemoglobin. by Kim H, Shen T, Sun DP, Ho NT, Madrid M, Tam MF, Zou M, Cottam PF, Ho C.; 1994 Nov 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45268

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Rice hemoglobins. Gene cloning, analysis, and O2-binding kinetics of a recombinant protein synthesized in Escherichia coli. by Arrendondo-Peter R, Hargrove MS, Sarath G, Moran JF, Lohrman J, Olson JS, Klucas RV.; 1997 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=158590

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Role of CCAA Nucleotide Repeats in Regulation of Hemoglobin and HemoglobinHaptoglobin Binding Protein Genes of Haemophilus influenzae. by Ren Z, Jin H, Whitby PW, Morton DJ, Stull TL.; 1999 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=94113

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Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans. by Gladwin MT, Shelhamer JH, Schechter AN, Pease-Fye ME, Waclawiw MA, Panza JA, Ognibene FP, Cannon RO III.; 2000 Oct 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17226

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Role of the Haemophilus ducreyi Ton System in Internalization of Heme from Hemoglobin. by Elkins C, Totten PA, Olsen B, Thomas CE.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107871

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Routes to S-nitroso-hemoglobin formation with heme redox and preferential reactivity in the [beta] subunits. by Luchsinger BP, Rich EN, Gow AJ, Williams EM, Stamler JS, Singel DJ.; 2003 Jan 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=141017

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Simultaneous observation of the O[bond]O and Fe[bond]O2 stretching modes in oxyhemoglobins. by Das TK, Couture M, Ouellet Y, Guertin M, Rousseau DL.; 2001 Jan 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14612

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Single residue modification of only one dimer within the hemoglobin tetramer reveals autonomous dimer function. by Ackers GK, Dalessio PM, Lew GH, Daugherty MA, Holt JM.; 2002 Jul 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125012

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Sparing Effect of Hemoglobin F and Hemoglobin A2 on the Polymerization of Hemoglobin S at Physiologic Ligand Saturations. by Poillon WN, Kim BC, Rodgers GP, Noguchi CT, Schechter AN.; 1993 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46649

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Specific Antibodies to Porphyromonas gingivalis Lys-Gingipain by DNA Vaccination Inhibit Bacterial Binding to Hemoglobin and Protect Mice from Infection. by Kuboniwa M, Amano A, Shizukuishi S, Nakagawa I, Hamada S.; 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98250

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Specific induction of fibronectin binding activity by hemoglobin in Candida albicans grown in defined media. by Yan S, Negre E, Cashel JA, Guo N, Lyman CA, Walsh TJ, Roberts DD.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174169

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S-Sulfohemoglobin and disulfide exchange: The mechanisms of sulfide binding by Riftia pachyptila hemoglobins. by Zal F, Leize E, Lallier FH, Toulmond A, Van Dorsselaer A, Childress JJ.; 1998 Jul 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21191

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Stabilization of apoglobin by low temperature increases yield of soluble recombinant hemoglobin in Escherichia coli. by Weickert MJ, Pagratis M, Curry SR, Blackmore R.; 1997 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=168751

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Structural changes in hemoglobin during adsorption to solid surfaces: Effects of pH, ionic strength, and ligand binding. by Hook F, Rodahl M, Kasemo B, Brzezinski P.; 1998 Oct 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22821

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Structure and Inhibition of Plasmepsin II, a Hemoglobin-Degrading Enzyme from Plasmodium falciparum. by Silva AM, Lee AY, Gulnik SV, Majer P, Collins J, Bhat TN, Collins PJ, Cachau RE, Luker KE, Gluzman IY, Francis SE, Oksman A, Goldberg DE, Erickson JW.; 1996 Sep 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38331

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Symbiotic and nonsymbiotic hemoglobin genes of Casuarina glauca. by JacobsenLyon K, Jensen EO, Jorgensen JE, Marcker KA, Peacock WJ, Dennis ES.; 1995 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=160777

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The crystal structure of a tetrameric hemoglobin in a partial hemichrome state. by Riccio A, Vitagliano L, di Prisco G, Zagari A, Mazzarella L.; 2002 Jul 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125021

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The loss of the hemoglobin H2S-binding function in annelids from sulfide-free habitats reveals molecular adaptation driven by Darwinian positive selection. by Bailly X, Leroy R, Carney S, Collin O, Zal F, Toulmond A, Jollivet D.; 2003 May 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156296

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The oxyhemoglobin reaction of nitric oxide. by Gow AJ, Luchsinger BP, Pawloski JR, Singel DJ, Stamler JS.; 1999 Aug 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17726

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The Structure of Ascaris Hemoglobin Domain I at 2.2 A Resolution: Molecular Features of Oxygen Avidity. by Yang J, Kolek AP, Goldberg DE, Mathews FS.; 1995 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41916

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The T-to-R Transformation in Hemoglobin: A Reevaluation. by Srinivasan R, Rose GD.; 1994 Nov 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45177

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Transfection of the Human Heme Oxygenase Gene Into Rabbit Coronary Microvessel Endothelial Cells: Protective Effect Against Heme and Hemoglobin Toxicity. by Abraham NG, Lavrovsky Y, Schwartzman ML, Stoltz RA, Levere RD, Gerritsen ME.; 1995 Jul 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41416

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Transgenic knockout mice exclusively expressing human hemoglobin S after transfer of a 240-kb [beta]s-globin yeast artificial chromosome: A mouse model of sickle cell

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anemia. by Chang JC, Lu R, Lin C, Xu SM, Kan YW, Porcu S, Carlson E, Kitamura M, Yang S, Flebbe-Rehwaldt L, Gaensler KM.; 1998 Dec 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24545 •

Transport of Intact Porphyrin by HpuAB, the Hemoglobin-Haptoglobin Utilization System of Neisseria meningitidis. by Lewis LA, Sung MH, Gipson M, Hartman K, Dyer DW.; 1998 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107682

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Truncated hemoglobin HbN protects Mycobacterium bovis from nitric oxide. by Ouellet H, Ouellet Y, Richard C, Labarre M, Wittenberg B, Wittenberg J, Guertin M.; 2002 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122874

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Two hemoglobin genes in Arabidopsis thaliana: The evolutionary origins of leghemoglobins. by Trevaskis B, Watts RA, Andersson CR, Llewellyn DJ, Hargrove MS, Olson JS, Dennis ES, Peacock WJ.; 1997 Oct 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23758

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Use of a rapid arterial blood gas analyzer to estimate blood hemoglobin concentration among critically ill adults. by Ray JG, Post JR, Hamielec C.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=83849

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Use of heme and hemoglobin by Escherichia coli O157 and other Shiga-like-toxinproducing E. coli serogroups. by Law D, Kelly J.; 1995 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173054

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Utilization of hemin and hemoglobin by Vibrio vulnificus biotype 2. by Fouz B, Mazoy R, Lemos ML, del Olmo MJ, Amaro C.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=168066

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Utilization of host iron sources by Corynebacterium diphtheriae: identification of a gene whose product is homologous to eukaryotic heme oxygenases and is required for acquisition of iron from heme and hemoglobin. by Schmitt MP.; 1997 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=178768

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Variable expression of myoglobin among the hemoglobinless Antarctic icefishes. by Sidell BD, Vayda ME, Small DJ, Moylan TJ, Londraville RL, Yuan ML, Rodnick KJ, Eppley ZA, Costello L.; 1997 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20385

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X-Ray Diffraction Study of the Binding of the Antisickling Agent 12C79 to Human Hemoglobin. by Wireko FC, Abraham DJ.; 1991 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51199

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 6

PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction

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

A 74-year-old woman with desaturation following surgery. Co-oximetry is the first step in making the diagnosis of dyshemoglobinemia. Author(s): Konig MW, Dolinski SY. Source: Chest. 2003 February; 123(2): 613-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12576388&dopt=Abstract

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A micronutrient-fortified beverage prevents iron deficiency, reduces anemia and improves the hemoglobin concentration of pregnant Tanzanian women. Author(s): Makola D, Ash DM, Tatala SR, Latham MC, Ndossi G, Mehansho H. Source: The Journal of Nutrition. 2003 May; 133(5): 1339-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12730420&dopt=Abstract

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A novel blood transfusant candidate: intact human erythrocytes containing hemoglobin exclusively nitrosylated in the alpha-subunits. Author(s): Tsuneshige A, Yonetani T. Source: Advances in Experimental Medicine and Biology. 2003; 510: 93-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12580411&dopt=Abstract

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A recombinant polymeric hemoglobin with conformational, functional, and physiological characteristics of an in vivo O2 transporter. Author(s): Bobofchak KM, Mito T, Texel SJ, Bellelli A, Nemoto M, Traystman RJ, Koehler RC, Brinigar WS, Fronticelli C. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2003 August; 285(2): H549-61. Epub 2003 April 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12689854&dopt=Abstract

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Abnormal hemoglobins found in Hunan. Author(s): Lu Y, Liu J. Source: Chinese Medical Journal. 2003 April; 116(4): 483-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875707&dopt=Abstract

with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

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Accurate mass measurement by electrospray ionization quadrupole mass spectrometry: detection of variants differing by <6 Da from normal in human hemoglobin heterozygotes. Author(s): Rai DK, Griffiths WJ, Landin B, Wild BJ, Alvelius G, Green BN. Source: Analytical Chemistry. 2003 May 1; 75(9): 1978-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12720330&dopt=Abstract

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Alarming levels of carboxyhemoglobin in a unit of banked blood. Author(s): Ehlers M, McCloskey D, Devejian NS. Source: Anesthesia and Analgesia. 2003 July; 97(1): 289-90, Table of Contents. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818984&dopt=Abstract

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Allosteric changes in protein structure computed by a simple mechanical model: hemoglobin T<-->R2 transition. Author(s): Xu C, Tobi D, Bahar I. Source: Journal of Molecular Biology. 2003 October 10; 333(1): 153-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14516750&dopt=Abstract

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Analysis of hemoglobins and globin chains by high-performance liquid chromatography. Author(s): Wajcman H. Source: Methods in Molecular Medicine. 2003; 82: 21-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669635&dopt=Abstract

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Anesthetic management of a patient with methemoglobinemia. Author(s): Groeper K, Katcher K, Tobias JD. Source: Southern Medical Journal. 2003 May; 96(5): 504-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12911193&dopt=Abstract

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Antioxidant vitamins improves hemoglobin level in children with group a beta hemolytic streptococcal infection. Author(s): Ahmed J, Zaman MM, Ali K. Source: Mymensingh Med J. 2003 July; 12(2): 120-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894046&dopt=Abstract

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Application of a gold electrode, modified by a self-assembled monolayer of 2mercaptodecylhydroquinone, to the electroanalysis of hemoglobin. Author(s): Zhang J, Seo K, Jeon IC. Source: Analytical and Bioanalytical Chemistry. 2003 February; 375(4): 539-43. Epub 2003 January 29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12610707&dopt=Abstract

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Association of interferon-gamma responses to pre-erythrocytic stage vaccine candidate antigens of Plasmodium falciparum in young Kenyan children with improved hemoglobin levels: XV. Asembo Bay Cohort Project. Author(s): Ong'echa JM, Lal AA, Terlouw DJ, Ter Kuile FO, Kariuki SK, Udhayakumar V, Orago AS, Hightower AW, Nahlen BL, Shi YP. Source: The American Journal of Tropical Medicine and Hygiene. 2003 May; 68(5): 590-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12812352&dopt=Abstract

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Beta-globin-like gene cluster haplotypes in hemoglobinopathies. Author(s): Muralitharan S, Krishnamoorthy R, Nagel RL. Source: Methods in Molecular Medicine. 2003; 82: 195-211. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669645&dopt=Abstract

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Binding of polychlorinated biphenyls/metabolites to hemoglobin. Author(s): Tampal N, Myers S, Robertson LW. Source: Toxicology Letters. 2003 April 30; 142(1-2): 53-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765239&dopt=Abstract

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Blood storage for forensic hemoglobin analysis using CO-oximeter. Author(s): Watanabe N, Terazawa K, Sakaihara M. Source: Hokkaido Igaku Zasshi. 2003 July; 78(4): 289-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12911004&dopt=Abstract

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Carbon monoxide exposure and carboxyhemoglobin. Author(s): Donnay A. Source: Environmental Health Perspectives. 2003 August; 111(10): A511-2; Author Reply A512. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12896866&dopt=Abstract

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Carbon monoxide hemoglobin and bilirubin metabolism in small-for-size graft in adult living-related liver transplantation. Author(s): Hirano K, Sato Y, Kobayashi T, Yamamoto S, Nakatsuka H, Oya H, Kato T, Watanabe T, Kameyama H, Hatakeyama K. Source: Transplantation Proceedings. 2003 February; 35(1): 410-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591464&dopt=Abstract

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Cerebrovascular response to decreased hematocrit: effect of cell-free hemoglobin, plasma viscosity, and CO2. Author(s): Rebel A, Ulatowski JA, Kwansa H, Bucci E, Koehler RC. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2003 October; 285(4): H1600-8. Epub 2003 June 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816746&dopt=Abstract

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Chemoradiation of unresectable pancreatic carcinoma: impact of pretreatment hemoglobin level on patterns of failure. Author(s): Morganti AG, Forni F, Macchia G, Valentini V, Smaniotto D, Trodella L, Balducci M, Cellini N. Source: Strahlentherapie Und Onkologie : Organ Der Deutschen Rontgengesellschaft. [et Al]. 2003 February; 179(2): 87-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12590318&dopt=Abstract

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Cognitive impairment in children with hemoglobin SS sickle cell disease: relationship to MR imaging findings and hematocrit. Author(s): Steen RG, Miles MA, Helton KJ, Strawn S, Wang W, Xiong X, Mulhern RK. Source: Ajnr. American Journal of Neuroradiology. 2003 March; 24(3): 382-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12637286&dopt=Abstract

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Coliforms in the water and hemoglobin concentration are predictors of gastrointestinal morbidity of Bangladeshi children ages 1-10 years. Author(s): Bhargava A, Bouis HE, Hallman K, Hoque BA. Source: American Journal of Human Biology : the Official Journal of the Human Biology Council. 2003 March-April; 15(2): 209-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12621609&dopt=Abstract

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Comparison of HemoCue method with the cyanmethemoglobin method for estimation of hemoglobin. Author(s): Saxena R, Malik R. Source: Indian Pediatrics. 2003 September; 40(9): 917. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14530566&dopt=Abstract

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Comparison of hemoglobin values obtained by HaemoCue and Sahli's methods. Author(s): Kapil U, Tandon M, Pathak P, Dwivedi SN. Source: Indian J Public Health. 2002 January-March; 46(1): 28-30. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12652997&dopt=Abstract

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Comparison of lactate, bilirubin and hemoglobin F concentrations obtained by the ABL 700 series blood gas analyzers with laboratory methods. Author(s): Suen WW, Ridley B, Blakney G, Higgins TN. Source: Clinical Biochemistry. 2003 March; 36(2): 103-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12633758&dopt=Abstract

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Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease. Author(s): Steinberg MH, Voskaridou E, Kutlar A, Loukopoulos D, Koshy M, Ballas SK, Castro O, Barton F. Source: American Journal of Hematology. 2003 February; 72(2): 121-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12555216&dopt=Abstract

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Congenital methemoglobinemia due to NADH-methemoglobin reductase deficiency in three Indian families. Author(s): Kedar PS, Colah RB, Ghosh K, Mohanty D. Source: Haematologia. 2002; 32(4): 543-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12803131&dopt=Abstract

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Congenital methemoglobinemia: a rare cause of cyanosis in the newborn--a case report. Author(s): Da-Silva SS, Sajan IS, Underwood JP 3rd. Source: Pediatrics. 2003 August; 112(2): E158-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12897322&dopt=Abstract

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Content of reticulocyte hemoglobin is a reliable tool for determining iron deficiency in dialysis patients. Author(s): Tsuchiya K, Okano H, Teramura M, Iwamoto Y, Yamashita N, Suda A, Shimada K, Nihei H, Ando M. Source: Clinical Nephrology. 2003 February; 59(2): 115-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12608554&dopt=Abstract

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Correspondence re: Czene et al., Analysis of DNA and hemoglobin adducts and sister chromatid exchanges in a human population occupationally exposed to propylene oxide: a pilot study. Cancer Epidemiol. Biomark. Prev., 11: 315-318, 2002. Author(s): Albertini RJ. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2003 April; 12(4): 388; Author Reply 388-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12692119&dopt=Abstract

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Crystallization and preliminary X-ray structural studies of hemoglobin A2 and hemoglobin E, isolated from the blood samples of beta-thalassemic patients. Author(s): Dasgupta J, Sen U, Choudhury D, Datta P, Chakrabarti A, Chakrabarty SB, Chakrabarty A, Dattagupta JK. Source: Biochemical and Biophysical Research Communications. 2003 April 4; 303(2): 619-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12659864&dopt=Abstract

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Dehydroepiandrosterone sulfate levels associated with decreased malaria parasite density and increased hemoglobin concentration in pubertal girls from western Kenya. Author(s): Leenstra T, ter Kuile FO, Kariuki SK, Nixon CP, Oloo AJ, Kager PA, Kurtis JD. Source: The Journal of Infectious Diseases. 2003 July 15; 188(2): 297-304. Epub 2003 Jul 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12854087&dopt=Abstract

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Development of gene therapy for hemoglobin disorders. Author(s): Nienhuis AW, Hanawa H, Sawai N, Sorrentino BP, Persons DA. Source: Annals of the New York Academy of Sciences. 2003 May; 996: 101-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799288&dopt=Abstract

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Diagnostic value of serum transferrin receptor and glycosylated hemoglobin on hemolytic anemia. Author(s): Ho CH, You JY, Chau WK, Hsu HC, Gau JP, Chen CC, Yu TJ. Source: Annals of Hematology. 2003 April; 82(4): 228-30. Epub 2003 March 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12707725&dopt=Abstract

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Diaspirin-crosslinked hemoglobin reduces blood transfusion in noncardiac surgery: a multicenter, randomized, controlled, double-blinded trial. Author(s): Schubert A, Przybelski RJ, Eidt JF, Lasky LC, Marks KE, Karafa M, Novick AC, O'Hara JF Jr, Saunders ME, Blue JW, Tetzlaff JE, Mascha E; Perioperative Avoidance or Reduction of Transfusion Trial (PARTT) Study Group. Source: Anesthesia and Analgesia. 2003 August; 97(2): 323-32, Table of Contents. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873912&dopt=Abstract

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Direct observation of photolysis-induced tertiary structural changes in hemoglobin. Author(s): Adachi S, Park SY, Tame JR, Shiro Y, Shibayama N. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 June 10; 100(12): 7039-44. Epub 2003 May 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12773618&dopt=Abstract

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DNA diagnosis confirms hemoglobin deletion in newborn screen follow-up. Author(s): Bhardwaj U, Zhang YH, Jackson DS, Buchanan GR, Therrell BL Jr, McCabe LL, McCabe ER. Source: The Journal of Pediatrics. 2003 March; 142(3): 346-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640388&dopt=Abstract

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DNA diagnosis of hemoglobin mutations. Author(s): Old JM. Source: Methods in Molecular Medicine. 2003; 82: 101-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669640&dopt=Abstract

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Do hemoglobin and hemocyanin impair schistosoma killing by no? Author(s): Ascenzi P, Fasano M, Gradoni L. Source: Iubmb Life. 2002 June; 53(6): 287-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12625366&dopt=Abstract

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Does daily monitoring of blood glucose predict hemoglobin A1c levels? Author(s): Rose E, Ketchell D. Source: The Journal of Family Practice. 2003 June; 52(6): 485-90; Discussion 490. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791231&dopt=Abstract

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Effect of higher hemoglobin levels on health-related quality of life parameters. Author(s): Gregory N. Source: Nephrology Nursing Journal : Journal of the American Nephrology Nurses' Association. 2003 February; 30(1): 75-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12674955&dopt=Abstract

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Effects of heme addition on formation of stable human globin chains and hemoglobin subunit assembly in a cell-free system. Author(s): Adachi K, Zhao Y, Surrey S. Source: Archives of Biochemistry and Biophysics. 2003 May 1; 413(1): 99-106. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12706346&dopt=Abstract

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Effects of weaning cereals with different phytate contents on hemoglobin, iron stores, and serum zinc: a randomized intervention in infants from 6 to 12 mo of age. Author(s): Lind T, Lonnerdal B, Persson LA, Stenlund H, Tennefors C, Hernell O. Source: The American Journal of Clinical Nutrition. 2003 July; 78(1): 168-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816787&dopt=Abstract

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Elderly patients on chronic hemodialysis: effect of the secondary hyperparathyroidism on the hemoglobin level. Author(s): Neves PL, Trivino J, Casaubon F, Romao P, Mendes P, Bexiga I, Pinto I, Santos V, Bernardo I. Source: International Urology and Nephrology. 2002; 34(1): 147-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12549658&dopt=Abstract

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Electrophoretic methods for study of hemoglobins. Author(s): Wajcman H. Source: Methods in Molecular Medicine. 2003; 82: 93-100. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669639&dopt=Abstract

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Erythrocyte protoporphyrin or hemoglobin: which is a better screening test for iron deficiency in children and women? Author(s): Mei Z, Parvanta I, Cogswell ME, Gunter EW, Grummer-Strawn LM. Source: The American Journal of Clinical Nutrition. 2003 May; 77(5): 1229-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12716676&dopt=Abstract

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Evaluation of autofluorescent property of hemoglobin-advanced glycation end product as a long-term glycemic index of diabetes. Author(s): Gopalkrishnapillai B, Nadanathangam V, Karmakar N, Anand S, Misra A. Source: Diabetes. 2003 April; 52(4): 1041-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12663478&dopt=Abstract

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Evaluation of the HB-Quick: a portable hemoglobinometer. Author(s): Gong AK, Backenstose B. Source: Journal of Clinical Monitoring and Computing. 1999 May; 15(3-4): 171-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12568168&dopt=Abstract

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Expression of the hemoglobin scavenger receptor (CD163/HbSR) as immunophenotypic marker of monocytic lineage in acute myeloid leukemia. Author(s): Walter RB, Bachli EB, Schaer DJ, Ruegg R, Schoedon G. Source: Blood. 2003 May 1; 101(9): 3755-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12707228&dopt=Abstract

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FDA clears home glycated hemoglobin test for diabetics. Author(s): Walczak IM. Source: Diabetes Technology & Therapeutics. 2003; 5(1): 124. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12733538&dopt=Abstract

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Fetal hemoglobin synthesis determined by gamma-mRNA/gamma-mRNA + betamRNA quantitation in infants at risk for sudden infant death syndrome being monitored at home for apnea. Author(s): Bard H, Cote A, Praud JP, Infante-Rivard C, Gagnon C. Source: Pediatrics. 2003 October; 112(4): E285. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14523213&dopt=Abstract

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Functional and spectroscopic characterization of half-liganded iron-zinc hybrid hemoglobin: evidence for conformational plasticity within the T state. Author(s): Samuni U, Juszczak L, Dantsker D, Khan I, Friedman AJ, Perez-Gonzalez-deApodaca J, Bruno S, Hui HL, Colby JE, Karasik E, Kwiatkowski LD, Mozzarelli A, Noble R, Friedman JM. Source: Biochemistry. 2003 July 15; 42(27): 8272-88. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846576&dopt=Abstract

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Gene therapy for the hemoglobin disorders. Author(s): Persons DA, Nienhuis AW. Source: Curr Hematol Rep. 2003 July; 2(4): 348-55. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901333&dopt=Abstract

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Generation of a haptoglobin-hemoglobin complex-specific Fab antibody blocking the binding of the complex to CD163. Author(s): Horn IR, Nielsen MJ, Madsen M, Jacobsen C, Graversen JH, Moestrup SK, Jacobsen C. Source: European Journal of Haematology. 2003 October; 71(4): 289-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12950239&dopt=Abstract

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Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease. Author(s): Asleh R, Marsh S, Shilkrut M, Binah O, Guetta J, Lejbkowicz F, Enav B, Shehadeh N, Kanter Y, Lache O, Cohen O, Levy NS, Levy AP. Source: Circulation Research. 2003 June 13; 92(11): 1193-200. Epub 2003 May 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12750308&dopt=Abstract

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Heme and lipid peroxides in hemoglobin-modified low-density lipoprotein mediate cell survival and adaptation to oxidative stress. Author(s): Asatryan L, Ziouzenkova O, Duncan R, Sevanian A. Source: Blood. 2003 September 1; 102(5): 1732-9. Epub 2003 May 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12750169&dopt=Abstract

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Hemin: a possible cause of oxidative stress in blood circulation of betathalassemia/hemoglobin E disease. Author(s): Phumala N, Porasuphatana S, Unchern S, Pootrakul P, Fucharoen S, Chantharaksri U. Source: Free Radical Research. 2003 February; 37(2): 129-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12653201&dopt=Abstract

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Hemoglobin A1c is not the only issue. Author(s): Colwell JA. Source: Curr Diab Rep. 2002 August; 2(4): 295-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12643188&dopt=Abstract

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Hemoglobin adducts from glycidamide: acetonization of hydrophilic groups for reproducible gas chromatography/tandem mass spectrometric analysis. Author(s): Paulsson B, Athanassiadis I, Rydberg P, Tornqvist M. Source: Rapid Communications in Mass Spectrometry : Rcm. 2003; 17(16): 1859-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876686&dopt=Abstract

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Hemoglobin and hemoglobinologists. Preface. Author(s): Nagel RL. Source: Methods in Molecular Medicine. 2003; 82: V-Xvi. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669633&dopt=Abstract

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Hemoglobin and nitric oxide. Author(s): Gaston BM, Hare JM. Source: The New England Journal of Medicine. 2003 July 24; 349(4): 402-5; Author Reply 402-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879897&dopt=Abstract

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Hemoglobin and nitric oxide. Author(s): McMahon TJ. Source: The New England Journal of Medicine. 2003 July 24; 349(4): 402-5; Author Reply 402-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879896&dopt=Abstract

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Hemoglobin and nitric oxide. Author(s): Pawloski JR. Source: The New England Journal of Medicine. 2003 July 24; 349(4): 402-5; Author Reply 402-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879895&dopt=Abstract

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Hemoglobin and nitric oxide. Author(s): Singel DJ. Source: The New England Journal of Medicine. 2003 July 24; 349(4): 402-5; Author Reply 402-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879894&dopt=Abstract

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Hemoglobin and nitric oxide. Author(s): Stamler JS. Source: The New England Journal of Medicine. 2003 July 24; 349(4): 402-5; Author Reply 402-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12878751&dopt=Abstract

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Hemoglobin and platelet count effect on platelet yields in plateletpheresis. Author(s): Guerrero-Rivera S, Gutierrez-Espindola G, Talavera JO, Meillon-Garcia LA, Pedraza-Echevarria M, Pizzuto-Chavez J. Source: Archives of Medical Research. 2003 March-April; 34(2): 120-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700007&dopt=Abstract

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Hemoglobin and the paracrine and endocrine functions of nitric oxide. Author(s): Schechter AN, Gladwin MT. Source: The New England Journal of Medicine. 2003 April 10; 348(15): 1483-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12686706&dopt=Abstract

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Hemoglobin as an independent prognostic factor in the radiotherapy of head and neck tumors. Author(s): Schafer U, Micke O, Muller SB, Schuller P, Willich N. Source: Strahlentherapie Und Onkologie : Organ Der Deutschen Rontgengesellschaft. [et Al]. 2003 August; 179(8): 527-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14509951&dopt=Abstract

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Hemoglobin concentrations influence birth outcomes in pregnant African-American adolescents. Author(s): Chang SC, O'Brien KO, Nathanson MS, Mancini J, Witter FR. Source: The Journal of Nutrition. 2003 July; 133(7): 2348-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12840205&dopt=Abstract

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Hemoglobin dendrimers: functional protein clusters. Author(s): Kluger R, Zhang J. Source: Journal of the American Chemical Society. 2003 May 21; 125(20): 6070-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12785833&dopt=Abstract

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Hemoglobin estimation method. Author(s): Satyanarayana L. Source: Indian Pediatrics. 2003 August; 40(8): 798. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12951392&dopt=Abstract

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Hemoglobin fluorescence. Author(s): Hirsch RE. Source: Methods in Molecular Medicine. 2003; 82: 133-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669642&dopt=Abstract

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Hemoglobin metabolites mimic benzodiazepines and are possible mediators of hepatic encephalopathy. Author(s): Ruscito BJ, Harrison NL. Source: Blood. 2003 August 15; 102(4): 1525-8. Epub 2003 April 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12714506&dopt=Abstract

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Hemoglobin switching: new insights. Author(s): Peterson KR. Source: Current Opinion in Hematology. 2003 March; 10(2): 123-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12579037&dopt=Abstract

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Hemoglobin variants and hemoglobin A1c analysis: problem solved? Author(s): Sacks DB. Source: Clinical Chemistry. 2003 August; 49(8): 1245-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12881436&dopt=Abstract

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Hemoglobin, iron, nutrition and life-style among adolescents in a coastal and an inland community in northern Norway. Author(s): Brox J, Bjornstad E, Olaussen K. Source: Int J Circumpolar Health. 2003 May; 62(2): 130-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12862177&dopt=Abstract

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Hemoglobinopathies among five major ethnic groups in Karachi, Pakistan. Author(s): Ghani R, Manji MA, Ahmed N. Source: Southeast Asian J Trop Med Public Health. 2002 December; 33(4): 855-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757239&dopt=Abstract

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Hemoglobinopathy case finding by pulse oximetry. Author(s): Bruns CM, Thet LA, Woodson RD, Schultz J, Hla KM. Source: American Journal of Hematology. 2003 October; 74(2): 142-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14508804&dopt=Abstract

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Hemoglobinuria with ribavirin treatment. Author(s): Massoud OI, Yousef WI, Mullen KD. Source: Journal of Clinical Gastroenterology. 2003 April; 36(4): 367-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12642748&dopt=Abstract

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Homozygous hemoglobin Tak causes symptomatic secondary polycythemia in a Thai boy. Author(s): Tanphaichitr VS, Viprakasit V, Veerakul G, Sanpakit K, Tientadakul P. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 March; 25(3): 261-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12621249&dopt=Abstract

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Hookworm aspartic protease, Na-APR-2, cleaves human hemoglobin and serum proteins in a host-specific fashion. Author(s): Williamson AL, Brindley PJ, Abbenante G, Datu BJ, Prociv P, Berry C, Girdwood K, Pritchard DI, Fairlie DP, Hotez PJ, Zhan B, Loukas A. Source: The Journal of Infectious Diseases. 2003 February 1; 187(3): 484-94. Epub 2003 January 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12552433&dopt=Abstract

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Hydroxyurea-induced splenic regrowth in an adult patient with severe hemoglobin SC disease. Author(s): Huang Y, Ananthakrishnan T, Eid JE. Source: American Journal of Hematology. 2003 October; 74(2): 125-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14508799&dopt=Abstract

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Imaging hemoglobin oxygen saturation in sickle cell disease patients using noninvasive visible reflectance hyperspectral techniques: effects of nitric oxide. Author(s): Zuzak KJ, Gladwin MT, Cannon RO 3rd, Levin IW. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2003 September; 285(3): H1183-9. Epub 2003 June 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791593&dopt=Abstract

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In vitro induction of fetal hemoglobin in human erythroid progenitor cells. Author(s): Ho JA, Pickens CV, Gamcsik MP, Colvin OM, Ware RE, Gamscik MP. Source: Experimental Hematology. 2003 July; 31(7): 586-91. Erratum In: Exp Hematol. 2003 August; 31(8): 741. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12842703&dopt=Abstract

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Inaccurate glycosylated hemoglobin A1C measurements in human immunodeficiency virus-positive patients with diabetes mellitus. Author(s): Polgreen PM, Putz D, Stapleton JT. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 August 15; 37(4): E53-6. Epub 2003 July 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12905153&dopt=Abstract

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Increase of fetal hemoglobin synthesis indicating differentiation induction in children receiving valproic acid. Author(s): Kieslich M, Schwabe D, Cinatl J Jr, Driever PH. Source: Pediatric Hematology and Oncology. 2003 January-February; 20(1): 15-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687749&dopt=Abstract

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Interactions between sickle hemoglobin fibers. Author(s): Jones CW, Wang JC, Ferrone FA, Briehl RW, Turner MS. Source: Faraday Discuss. 2003; 123: 221-36; Discussion 303-22, 419-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12638863&dopt=Abstract

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Is glycosylated hemoglobin A1c a surrogate for metabolic syndrome in nondiabetic, first-degree relatives of African-American patients with type 2 diabetes? Author(s): Osei K, Rhinesmith S, Gaillard T, Schuster D. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4596-601. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557428&dopt=Abstract

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Kinetics of the reactions of nitrogen monoxide and nitrite with ferryl hemoglobin. Author(s): Herold S, Rehmann FJ. Source: Free Radical Biology & Medicine. 2003 March 1; 34(5): 531-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614842&dopt=Abstract

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Laboratory testing for glycated hemoglobin in the general community: are we following the clinical recommendations? Author(s): Harwell TS, Little RR, McDowall JM, Helgerson SD, Gohdes D. Source: Diabetes Technology & Therapeutics. 2002; 4(6): 859-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614489&dopt=Abstract

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Lactic response in sickle cell trait carriers in comparison with subjects with normal hemoglobin. Author(s): Sara F, Hardy-Dessources MD, Voltaire B, Etienne-Julan M, Hue O. Source: Clinical Journal of Sport Medicine : Official Journal of the Canadian Academy of Sport Medicine. 2003 March; 13(2): 96-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12629427&dopt=Abstract

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Localized irregularities in hemoglobin flow and oxygenation in calf muscle in patients with peripheral vascular disease detected with near-infrared spectrophotometry. Author(s): Wolf U, Wolf M, Choi JH, Levi M, Choudhury D, Hull S, Coussirat D, Paunescu LA, Safonova LP, Michalos A, Mantulin WW, Gratton E. Source: Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. 2003 May; 37(5): 1017-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12756348&dopt=Abstract

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Longitudinal trends of hemoglobin levels in a Japanese population--RERF's Adult Health Study subjects. Author(s): Yamada M, Wong FL, Suzuki G; RERF's (Radiation Effects Research Foundation) Adult Health Study. Source: European Journal of Haematology. 2003 March; 70(3): 129-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12605656&dopt=Abstract

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Long-term exposure to intermittent hypoxia results in increased hemoglobin mass, reduced plasma volume, and elevated erythropoietin plasma levels in man. Author(s): Heinicke K, Prommer N, Cajigal J, Viola T, Behn C, Schmidt W. Source: European Journal of Applied Physiology. 2003 February; 88(6): 535-43. Epub 2002 December 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12560952&dopt=Abstract

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Measurement of mucosal capillary hemoglobin oxygen saturation in the colon by reflectance spectrophotometry. Author(s): Friedland S, Benaron D, Parachikov I, Soetikno R. Source: Gastrointestinal Endoscopy. 2003 April; 57(4): 492-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12665758&dopt=Abstract

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Measurement of rate constants for reactions of O2, CO, and NO with hemoglobin. Author(s): Olson JS, Foley EW, Maillett DH, Paster EV. Source: Methods in Molecular Medicine. 2003; 82: 65-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669638&dopt=Abstract

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Mechanism of low-density lipoprotein oxidation by hemoglobin-derived iron. Author(s): Grinshtein N, Bamm VV, Tsemakhovich VA, Shaklai N. Source: Biochemistry. 2003 June 17; 42(23): 6977-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12795592&dopt=Abstract

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Method for hemoglobin A(1c) measurement based on peptide analysis by electrospray ionization mass spectrometry with deuterium-labeled synthetic peptides as internal standards. Author(s): Nakanishi T, Iguchi K, Shimizu A. Source: Clinical Chemistry. 2003 May; 49(5): 829-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12709383&dopt=Abstract

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Mithramycin induces fetal hemoglobin production in normal and thalassemic human erythroid precursor cells. Author(s): Fibach E, Bianchi N, Borgatti M, Prus E, Gambari R. Source: Blood. 2003 August 15; 102(4): 1276-81. Epub 2003 May 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738678&dopt=Abstract

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Mixed chimerism following in utero hematopoietic stem cell transplantation in murine models of hemoglobinopathy. Author(s): Hayashi S, Abdulmalik O, Peranteau WH, Ashizuka S, Campagnoli C, Chen Q, Horiuchi K, Asakura T, Flake AW. Source: Experimental Hematology. 2003 February; 31(2): 176-84. Erratum In: Exp Hematol. 2003 April; 31(4): 348. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591283&dopt=Abstract

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Molecular characterization of hemoglobin alpha-D chains from Geochelone carbonaria and Geochelone denticulata land turtles. Author(s): Melo MB, Bordin S, Duarte AS, Ogo SH, Torsoni MA, Saad ST, Costa FF. Source: Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology. 2003 February; 134(2): 389-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12568815&dopt=Abstract

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Naringin and naringenin inhibit nitrite-induced methemoglobin formation. Author(s): Kumar MS, Unnikrishnan MK, Patra S, Murthy K, Srinivasan KK. Source: Pharmazie. 2003 August; 58(8): 564-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12967034&dopt=Abstract

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New enzymatic assay for glycohemoglobin. Author(s): Sakurabayashi I, Watano T, Yonehara S, Ishimaru K, Hirai K, Komori T, Yagi M. Source: Clinical Chemistry. 2003 February; 49(2): 269-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12560350&dopt=Abstract

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Nitric oxide's reactions with hemoglobin: a view through the SNO-storm. Author(s): Gladwin MT, Lancaster JR Jr, Freeman BA, Schechter AN. Source: Nature Medicine. 2003 May; 9(5): 496-500. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12724752&dopt=Abstract

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Notable diversity in hemoglobin expression patterns among species of the deep-sea clam, Calyptogena. Author(s): Kawano K, Iwasaki N, Suzuki T. Source: Cellular and Molecular Life Sciences : Cmls. 2003 September; 60(9): 1952-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14523555&dopt=Abstract

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Novel approach for the analysis of glycated hemoglobin using capillary isoelectric focusing with chemical mobilization. Author(s): Vincenzi Jager A, Franco Maggi Tavares M. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 March 5; 785(2): 285-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554141&dopt=Abstract

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Nuclear magnetic resonance of hemoglobins. Author(s): Lukin JA, Ho C. Source: Methods in Molecular Medicine. 2003; 82: 251-69. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669648&dopt=Abstract

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Nucleation and crystal growth of hemoglobins. The case of HbC. Author(s): Vekilov PG, Feeling-Taylor A, Hirsch RE. Source: Methods in Molecular Medicine. 2003; 82: 155-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669643&dopt=Abstract

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Once-weekly dosing of epoetin-alpha increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concomitantly or sequentially with chemotherapy. Author(s): Shasha D, George MJ, Harrison LB. Source: Cancer. 2003 September 1; 98(5): 1072-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12942577&dopt=Abstract

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Optimization of low pre-operative hemoglobin reduces transfusion requirement in patients undergoing transurethral resection of prostate. Author(s): Ather MH, Faruqui N, Abid F. Source: J Pak Med Assoc. 2003 March; 53(3): 104-6. Erratum In: J Pak Med Assoc. 2003 April; 53(4): 170. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12779024&dopt=Abstract

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Oral amino acid load mimicking hemoglobin results in reduced regional cerebral perfusion and deterioration in memory tests in patients with cirrhosis of the liver. Author(s): Jalan R, Olde Damink SW, Lui HF, Glabus M, Deutz NE, Hayes PC, Ebmeier K. Source: Metabolic Brain Disease. 2003 March; 18(1): 37-49. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603081&dopt=Abstract

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Orthopedic Surgery Transfusion Hemoglobin European Overview (OSTHEO) study: blood management in elective knee and hip arthroplasty in Europe. Author(s): Rosencher N, Kerkkamp HE, Macheras G, Munuera LM, Menichella G, Barton DM, Cremers S, Abraham IL; OSTHEO Investigation. Source: Transfusion. 2003 April; 43(4): 459-69. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12662278&dopt=Abstract

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Oxidation of hemoglobin to methemoglobin in intact erythrocyte by a hydroperoxide induces formation of glutathionyl hemoglobin and binding of alpha-hemoglobin to membrane. Author(s): Murakami K, Mawatari S. Source: Archives of Biochemistry and Biophysics. 2003 September 15; 417(2): 244-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941307&dopt=Abstract

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Pharmacist-led, primary care-based disease management improves hemoglobin A1c in high-risk patients with diabetes. Author(s): Rothman R, Malone R, Bryant B, Horlen C, Pignone M. Source: American Journal of Medical Quality : the Official Journal of the American College of Medical Quality. 2003 March-April; 18(2): 51-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12710553&dopt=Abstract

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Pharmacologic induction of fetal hemoglobin synthesis: cellular and molecular mechanisms. Author(s): Yang YM, Pace B. Source: Pediatric Pathology & Molecular Medicine. 2001 January-February; 20(1): 87-106. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12673846&dopt=Abstract

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Phosphatidylserine externalization in sickle red blood cells: associations with cell age, density, and hemoglobin F. Author(s): Yasin Z, Witting S, Palascak MB, Joiner CH, Rucknagel DL, Franco RS. Source: Blood. 2003 July 1; 102(1): 365-70. Epub 2003 February 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12609840&dopt=Abstract

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Plants, humans and hemoglobins. Author(s): Kundu S, Trent JT 3rd, Hargrove MS. Source: Trends in Plant Science. 2003 August; 8(8): 387-93. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12927972&dopt=Abstract

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Postpartum maternal levels of hemoglobin A1c and cord C-peptide in macrosomic infants of non-diabetic mothers. Author(s): Akin M, Ceran O, Atay E, Atay Z, Akin F, Akturk Z. Source: J Matern Fetal Neonatal Med. 2002 October;12(4):274-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12572597&dopt=Abstract

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Predictors of hemoglobin A1c in a national sample of nondiabetic children: the Third National Health and Nutrition Examination Survey, 1988-1994. Author(s): Eldeirawi K, Lipton RB. Source: American Journal of Epidemiology. 2003 April 1; 157(7): 624-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12672682&dopt=Abstract

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Prenatal detection of fetal hemoglobin E gene from maternal plasma. Author(s): Fucharoen G, Tungwiwat W, Ratanasiri T, Sanchaisuriya K, Fucharoen S. Source: Prenatal Diagnosis. 2003 May; 23(5): 393-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12749037&dopt=Abstract

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Priapism in a patient with unstable hemoglobin: hemoglobin Koln. Author(s): Andrieu V, Dumonceau O, Grange MJ. Source: American Journal of Hematology. 2003 September; 74(1): 73-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12949895&dopt=Abstract

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Prognostic implications of hemoglobin levels before and after surgery as well as before and after radiochemotherapy for head and neck tumors. Author(s): Reichel O, Panzer M, Wimmer C, Duhmke E, Kastenbauer E, Suckfull M. Source: Eur Arch Otorhinolaryngol. 2003 May;260(5):248-53. Epub 2002 December 04. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12750913&dopt=Abstract

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Purification and molecular analysis of hemoglobin by high-performance liquid chromatography. Author(s): Manjula BN, Acharya SA. Source: Methods in Molecular Medicine. 2003; 82: 31-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669636&dopt=Abstract

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Quaternary structure dependence of kinetic hole burning and conformational substates interconversion in hemoglobin. Author(s): Levantino M, Cupane A, Zimanyi L. Source: Biochemistry. 2003 April 22; 42(15): 4499-505. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12693946&dopt=Abstract

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Rapid determination of carboxyhemoglobin in blood by Oximeter. Author(s): Brehmer C, Iten PX. Source: Forensic Science International. 2003 April 23; 133(1-2): 179-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12742708&dopt=Abstract

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Regioselective covalent modification of hemoglobin in search of antisickling agents. Author(s): Park S, Hayes BL, Marankan F, Mulhearn DC, Wanna L, Mesecar AD, Santarsiero BD, Johnson ME, Venton DL. Source: Journal of Medicinal Chemistry. 2003 March 13; 46(6): 936-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12620071&dopt=Abstract

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Relation of hemoglobin A1c to left ventricular relaxation in patients with type 1 diabetes mellitus and without overt heart disease. Author(s): Shishehbor MH, Hoogwerf BJ, Schoenhagen P, Marso SP, Sun JP, Li J, Klein AL, Thomas JD, Garcia MJ. Source: The American Journal of Cardiology. 2003 June 15; 91(12): 1514-7, A9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804750&dopt=Abstract

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Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Author(s): Osterborg A, Brandberg Y. Source: Cancer. 2003 June 15; 97(12): 3125-6; Author Reply 3126-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12784351&dopt=Abstract

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Reticulocyte parameters and hemoglobin F production in sickle cell disease patients undergoing hydroxyurea therapy. Author(s): Borba R, Lima CS, Grotto HZ. Source: Journal of Clinical Laboratory Analysis. 2003; 17(2): 66-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640630&dopt=Abstract

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Role of phlebotomy in the management of hemoglobin SC disease: case report and review of the literature. Author(s): Markham MJ, Lottenberg R, Zumberg M. Source: American Journal of Hematology. 2003 June; 73(2): 121-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12749014&dopt=Abstract

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Saturation transfer in human red blood cells with normal and unstable hemoglobin. Author(s): Sogami M, Uyesaka N, Era S, Kato K. Source: Nmr in Biomedicine. 2003 February; 16(1): 19-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12577294&dopt=Abstract

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Screening for the carriers of thalassemias and abnormal hemoglobins at the community level. Author(s): Winichagoon P, Thitivichianlert A, Lebnak T, Piankijagum A, Fucharoen S. Source: Southeast Asian J Trop Med Public Health. 2002; 33 Suppl 2: 145-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12755285&dopt=Abstract

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Semisynthesis of hemoglobin. Author(s): Acharya SA, Srinivasulu S. Source: Methods in Molecular Medicine. 2003; 82: 177-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669644&dopt=Abstract

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Severe methemoglobinemia after transesophageal echocardiography. Author(s): Vidyarthi V, Manda R, Ahmed A, Khosla S, Lubell DL. Source: American Journal of Therapeutics. 2003 May-June; 10(3): 225-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12756430&dopt=Abstract

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Significance of beta116 His (G18) at alpha1beta1 contact sites for alphabeta assembly and autoxidation of hemoglobin. Author(s): Adachi K, Yang Y, Lakka V, Wehrli S, Reddy KS, Surrey S. Source: Biochemistry. 2003 September 2; 42(34): 10252-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939154&dopt=Abstract

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Significant decrease in hemoglobin and hematocrit levels in a virologically controlled HIV-infected patient. Pure red cell aplasia (PRCA) caused by human parvovirus B19. Author(s): Naval-Srinivas RM, Church LW. Source: Aids Read. 2003 April; 13(4): 189. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12741369&dopt=Abstract

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S-nitrosohemoglobin is distinguished from other nitrosovasodilators by unique oxygen-dependent responses that support an allosteric mechanism of action. Author(s): McMahon TJ, Pawloski JR, Hess DT, Piantadosi CA, Luchsinger BP, Singel DJ, Stamler JS. Source: Blood. 2003 July 1; 102(1): 410-1; Author Reply 412-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814919&dopt=Abstract

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S-nitrosylated polyethylene glycol-conjugated hemoglobin derivative as a candidate material for oxygen therapeutics. Author(s): Nakai K, Sakuma I, Togashi H, Yoshioka M, Sugawara T, Satoh H, Kitabatake A. Source: Advances in Experimental Medicine and Biology. 2003; 519: 207-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12675217&dopt=Abstract

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Sodium thiosulfate fails to reduce nitrite-induced methemoglobinemia in vitro. Author(s): Matteucci MJ, Reed WJ, Tanen DA. Source: Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine. 2003 April; 10(4): 299-302. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12670840&dopt=Abstract

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Solution 1H NMR study of the active site molecular structure and magnetic properties of the cyanomet complex of the isolated alpha-chain from human hemoglobin A. Author(s): Tran AT, Kolczak U, La Mar GN. Source: Biochimica Et Biophysica Acta. 2003 August 21; 1650(1-2): 59-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12922170&dopt=Abstract

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Stable octameric structure of recombinant hemoglobin alpha(2)beta(2)83 Gly-->Cys. Author(s): Fablet C, Marden MC, Green BN, Ho C, Pagnier J, Baudin-Creuza V. Source: Protein Science : a Publication of the Protein Society. 2003 April; 12(4): 690-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12649426&dopt=Abstract

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Studies of cisplatin and hemoglobin interactions using nanospray mass spectrometry and liquid chromatography with inductively-coupled plasma mass spectrometry. Author(s): Mandal R, Teixeira C, Li XF. Source: The Analyst. 2003 June; 128(6): 629-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12866879&dopt=Abstract

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Suspected methemoglobinemia following awake intubation: one possible effect of benzocaine topical anesthesia--a case report. Author(s): Rinehart RS, Norman D. Source: Aana Journal. 2003 April; 71(2): 117-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12776639&dopt=Abstract

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The clinical trials of diaspirin cross-linked hemoglobin (DCLHb) in severe traumatic hemorrhagic shock: the tale of two continents. Author(s): Sloan EP. Source: Intensive Care Medicine. 2003 March; 29(3): 347-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12710459&dopt=Abstract

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The cooperativity of human fetal and adult hemoglobins is optimized: a consideration based on the effectiveness of the Bohr shift. Author(s): Zhang Y, Miki M, Sasagawa K, Kobayashi M, Imai K, Kobayashi M. Source: Zoological Science. 2003 January; 20(1): 23-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12560597&dopt=Abstract

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The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Author(s): Scroggie DA, Albright A, Harris MD. Source: Archives of Internal Medicine. 2003 July 14; 163(13): 1587-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860582&dopt=Abstract

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The effects of health state, hemoglobin, global symptom distress, mood disturbance, and treatment site on fatigue onset, duration, and distress in patients receiving radiation therapy. Author(s): Magnan MA, Mood DW. Source: Oncology Nursing Forum. 2003 March-April; 30(2): E33-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12692668&dopt=Abstract

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The inhibitory action of protamine on human internal thoracic artery contractions: the effect of free hemoglobin. Author(s): Golbasi I, Nacitarhan C, Ozdem S, Turkay C, Karakaya H, Sadan G, Bayezid O. Source: European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery. 2003 June; 23(6): 962-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829073&dopt=Abstract

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The mysteries of hemoglobin degradation in Plasmodium falciparum-infected erythrocytes. Author(s): Ginsburg H. Source: Trends in Parasitology. 2003 May; 19(5): 198-9; Author Reply 199-200. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12763422&dopt=Abstract

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The roles of changes in deoxyhemoglobin concentration and regional cerebral blood volume in the fMRI BOLD signal. Author(s): Toronov V, Walker S, Gupta R, Choi JH, Gratton E, Hueber D, Webb A. Source: Neuroimage. 2003 August; 19(4): 1521-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12948708&dopt=Abstract

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The validation of an automated liquid chromatography system for the diagnosis of thalassemias and hemoglobinopathies. Author(s): Sangkitporn S, Pung-amritt P, Sangkitporn SK, Sangnoi A, Tanphaichitr VS. Source: Southeast Asian J Trop Med Public Health. 2002 December; 33(4): 862-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757240&dopt=Abstract

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Therapies to increase fetal hemoglobin in sickle cell disease. Author(s): Steinberg MH. Source: Curr Hematol Rep. 2003 March; 2(2): 95-101. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901139&dopt=Abstract

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Time course of hemoglobin concentrations in nonbleeding intensive care unit patients. Author(s): Nguyen BV, Bota DP, Melot C, Vincent JL. Source: Critical Care Medicine. 2003 February; 31(2): 406-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12576944&dopt=Abstract

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Tobacco smoke and formation of N-(2-hydroxyethyl)valine in human hemoglobin. Author(s): Bono R, Vincenti M, Saglia U, Pignata C, Russo R, Gilli G. Source: Archives of Environmental Health. 2002 September-October; 57(5): 416-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12641182&dopt=Abstract

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Total lymphocyte count and hemoglobin combined in an algorithm to initiate the use of highly active antiretroviral therapy in resource-limited settings. Author(s): Spacek LA, Griswold M, Quinn TC, Moore RD. Source: Aids (London, England). 2003 June 13; 17(9): 1311-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799552&dopt=Abstract

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Transgenic mice and hemoglobinopathies. Author(s): Fabry ME, Bouhassira EE, Suzuka SM, Nagel RL. Source: Methods in Molecular Medicine. 2003; 82: 213-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669646&dopt=Abstract

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Twisted protein aggregates and disease: the stability of sickle hemoglobin fibers. Author(s): Turner MS, Briehl RW, Ferrone FA, Josephs R. Source: Physical Review Letters. 2003 March 28; 90(12): 128103. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12688906&dopt=Abstract

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Two cases in which an abnormal hemoglobin (Hb Kamakura) was identified on the basis of an abnormally low glycohemoglobin levels. Author(s): Saisho Y, Saitoh F, Tabata M, Imafuku T, Ogihara T, Issiki I, Hattori Y, Yamashiro Y. Source: Intern Med. 2003 July; 42(7): 595-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879953&dopt=Abstract

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Use of a human polymerized hemoglobin solution as an adjunct to acute normovolemic hemodilution during complex abdominal aortic reconstruction. Author(s): Norris EJ, Ness PM, Williams GM. Source: Journal of Clinical Anesthesia. 2003 May; 15(3): 220-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12770661&dopt=Abstract

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Using a “non uniform pulse sequence” can improve selective coagulation with a Nd:YAG laser (1.06 microm) thanks to Met-hemoglobin absorption: a clinical study on blue leg veins. Author(s): Mordon S, Brisot D, Fournier N. Source: Lasers in Surgery and Medicine. 2003; 32(2): 160-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12561051&dopt=Abstract

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Validation of hemoglobin estimation using Hemocue. Author(s): Bhaskaram P, Balakrishna N, Radhakrishna KV, Krishnaswamy K. Source: Indian J Pediatr. 2003 January; 70(1): 25-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12619948&dopt=Abstract

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Vasoactivity of S-nitrosohemoglobin: role of oxygen, heme, and NO oxidation states. Author(s): Crawford JH, White CR, Patel RP. Source: Blood. 2003 June 1; 101(11): 4408-15. Epub 2003 January 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12560216&dopt=Abstract

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Whether an increase in hemoglobin above 12 g/dL is of clinical benefit. Author(s): Ng T. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 June 1; 21(11): 2223-4; Author Reply 2224-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12775753&dopt=Abstract

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X-ray crystallography of hemoglobins. Author(s): Safo MK, Abraham DJ. Source: Methods in Molecular Medicine. 2003; 82: 1-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669634&dopt=Abstract

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

Finding Nutrition Studies on Hemoglobin 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 “hemoglobin” (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 information is typical of that found when using the “Full IBIDS Database” to search for “hemoglobin” (or a synonym): •

Diabetic patients on peritoneal dialysis need less erythropoietin to maintain adequate hemoglobin. Author(s): Division of Nephrology, University of Ottawa and Ottawa Hospital, Ottawa, Ontario, Canada. Source: Page, D E Cheung, V Poirier, F Adv-Perit-Dial. 2001; 17: 130-1 1197-8554

•

Effects of lead on 4-aminobiphenyl pharmacokinetics in liver, kidney, spleen, testes, heart, lung and hemoglobin adduct for rat model. Author(s): Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing. Source: Chen, H M Qin, T Zhao, L X Xu, X B Ecotoxicology. 2002 August; 11(4): 255-64 0963-9292

•

Electron transfer of hemoglobin at electrodes modified with colloidal clay nanoparticles. Author(s): Department of Analytical Biochemistry, University of Potsdam, Golm, Germany. Source: Lei, C Wollenberger, U Bistolas, N Guiseppi Elie, A Scheller, F W Anal-BioanalChem. 2002 January; 372(2): 235-9 1618-2642

•

Endotoxin induces rapid metalloproteinase-mediated shedding followed by upregulation of the monocyte hemoglobin scavenger receptor CD163. Author(s): Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire, USA. Source: Hintz, K A Rassias, A J Wardwell, K Moss, M L Morganelli, P M Pioli, P A Givan, A L Wallace, P K Yeager, M P Guyre, P M J-Leukoc-Biol. 2002 October; 72(4): 7117 0741-5400

•

Hemoglobin binds melanoma cell tissue factor and enhances its procoagulant activity. Author(s): Center for Hemostasis and Thrombosis, Clinical and Research Laboratories, Florida Hospital Cancer Institute, Orlando, Florida 32804, USA. [email protected] Source: Siddiqui, F A Francis, J L Blood-Coagul-Fibrinolysis. 2002 April; 13(3): 173-80 0957-5235

•

Methemoglobinemia following unintentional ingestion of sodium nitrite--New York, 2002. Source: Anonymous MMWR-Morb-Mortal-Wkly-Repage 2002 July 26; 51(29): 639-42 0149-2195

•

N-terminal contributions of the gamma-subunit of fetal hemoglobin to its tetramer strength: remote effects at subunit contacts. Author(s): Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA. Source: Yagami, Takeshi Ballard, Barry T Padovan, Julio Cesar Chait, Brian T Popowicz, Anthony M Manning, James M Protein-Sci. 2002 January; 11(1): 27-35 0961-8368

•

Reducing requirements for hemoglobin hydrolysis by Plasmodium falciparum cysteine proteases. Author(s): Department of Medicine, San Francisco General Hospital, Box 0811 University of California, San Francisco, CA 94143-0811, USA.

Nutrition

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Source: Shenai, B R Rosenthal, P J Mol-Biochem-Parasitol. 2002 June; 122(1): 99-104 01666851

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

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

144 Hemoglobin

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

Vitamins Pyridoxine Source: Integrative Medicine Communications; www.drkoop.com Vitamin B6 (Pyridoxine) Source: Integrative Medicine Communications; www.drkoop.com Vitamin C Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,904,00.html

•

Minerals Boron Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,909,00.html Copper Source: Integrative Medicine Communications; www.drkoop.com Copper Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,886,00.html Iron Source: Healthnotes, Inc.; www.healthnotes.com Iron Alternative names: Ferrous Sulfate Source: Integrative Medicine Communications; www.drkoop.com Iron Source: Prima Communications, Inc.www.personalhealthzone.com

•

Food and Diet Diabetes Source: Healthnotes, Inc.; www.healthnotes.com Ferrous Sulfate Source: Integrative Medicine Communications; www.drkoop.com

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

Accuracy of point-of-care-testing (POCT) for determining hemoglobin concentrations. Author(s): Gehring H, Hornberger C, Dibbelt L, Rothsigkeit A, Gerlach K, Schumacher J, Schmucker P. Source: Acta Anaesthesiologica Scandinavica. 2002 September; 46(8): 980-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12190799&dopt=Abstract

•

Combined one-tube osmotic fragility (OF) test and dichlorophenol-indolphenol (DCIP) test screening for hemoglobin disorders, an experience in 213 Thai pregnant women. Author(s): Wiwanitkit V, Suwansaksri J, Paritpokee N. Source: Clin Lab. 2002; 48(9-10): 525-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12389713&dopt=Abstract

•

Comparative structural and functional studies of avian and mammalian hemoglobins. Author(s): Ajloo D, Moosavi-Movahedi AA, Sadeghi M, Gharibi H.

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Source: Acta Biochimica Polonica. 2002; 49(2): 459-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12362988&dopt=Abstract •

Consequence of beta 16 and beta 112 replacements on the kinetics of hemoglobin assembly. Author(s): Adachi K, Yang Y, Joshi AA, Vasudevan G, Morris A, McDonald MJ. Source: Biochemical and Biophysical Research Communications. 2001 November 23; 289(1): 75-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11708779&dopt=Abstract

•

Declining hemoglobin during chemoradiotherapy for locally advanced non-small cell lung cancer is significant. Author(s): MacRae R, Shyr Y, Johnson D, Choy H. Source: Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. 2002 July; 64(1): 37-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12208573&dopt=Abstract

•

Evidence of a threshold value of glycated hemoglobin to improve the course of renal function in type 2 diabetes with typical diabetic glomerulopathy. Author(s): Brocco E, Velussi M, Cernigoi AM, Abaterusso C, Bruseghin M, Carraro A, Sambataro M, Piarulli F, Sfriso A, Nosadini R. Source: Journal of Nephrology. 2001 November-December; 14(6): 461-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11783602&dopt=Abstract

•

Glycosal: the first rapid, point-of-care test for the determination of hemoglobin A1c in patients with diabetes. Author(s): Stevenson T. Source: Diabetes Technology & Therapeutics. 1999 Winter; 1(4): 425-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11474827&dopt=Abstract

•

Hemoglobin adducts of ethylene oxide, propylene oxide, acrylonitrile and acrylamide-biomarkers in occupational and environmental medicine. Author(s): Schettgen T, Broding HC, Angerer J, Drexler H. Source: Toxicology Letters. 2002 August 5; 134(1-3): 65-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12191862&dopt=Abstract

•

Hemoglobin induces the expression and secretion of vascular endothelial growth factor from human malignant cells. Author(s): Siddiqui FA, Desai H, Siddiqui TF, Francis JL. Source: The Hematology Journal : the Official Journal of the European Haematology Association / Eha. 2002; 3(5): 264-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12391545&dopt=Abstract

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•

Hemoglobin induces the production and release of matrix metalloproteinase-9 from human malignant cells. Author(s): Siddiqui FA, Siddiqui TF, Francis JL. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. 2003 July; 14(5): 449-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12851530&dopt=Abstract

•

Inhibition of nitrobenzene-induced DNA and hemoglobin adductions by dietary constituents. Author(s): Li H, Cheng Y, Wang H, Sun H, Liu Y, Liu K, Peng S. Source: Applied Radiation and Isotopes : Including Data, Instrumentation and Methods for Use in Agriculture, Industry and Medicine. 2003 March; 58(3): 291-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12595006&dopt=Abstract

•

Iron in nutrition. VII. Copper as a supplement to iron for hemoglobin building in the rat. 1928. Author(s): Hart EB, Steenbock H, Waddell J, Elvehjem CA. Source: The Journal of Biological Chemistry. 2002 August 23; 277(34): E22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12243126&dopt=Abstract

•

Methemoglobin is a supplement for in vitro culture of human nasopharyngeal epithelial cells transformed by human papillomavirus type 16 DNA. Author(s): Wen WN. Source: In Vitro Cellular & Developmental Biology. Animal. 2001 November-December; 37(10): 668-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11776972&dopt=Abstract

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Postcollection rise in methemoglobin level in frozen blood specimens. Author(s): Wallace KL, Curry SC. Source: Journal of Toxicology. Clinical Toxicology. 2002; 40(1): 91-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11990209&dopt=Abstract

•

Protective effect of heme oxygenase-1 gene transfer against oxyhemoglobin-induced endothelial dysfunction. Author(s): Eguchi D, Weiler D, Alam J, Nath K, Katusic ZS. Source: Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2001 October; 21(10): 1215-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11598499&dopt=Abstract

•

School-administered weekly iron supplementation--effect on the growth and hemoglobin status of non-anemic Bolivian school-age children. A randomized placebo-controlled trial. Author(s): Aguayo VM.

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Source: European Journal of Nutrition. 2000 December; 39(6): 263-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11395986&dopt=Abstract •

Screening for hemoglobin disorders in Thai pregnant women by England and Frazer's calculation method. Author(s): Suwansaksri J, Wiwanitkit V, Paritpokee N. Source: Archives of Gynecology and Obstetrics. 2003 September 9 [epub Ahead of Print] http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13680265&dopt=Abstract

•

Simplified flow cytometric method for fetal hemoglobin containing red blood cells. Author(s): Mundee Y, Bigelow NC, Davis BH, Porter JB. Source: Cytometry : the Journal of the Society for Analytical Cytology. 2000 December 15; 42(6): 389-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11135294&dopt=Abstract

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The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Author(s): Scroggie DA, Albright A, Harris MD. Source: Archives of Internal Medicine. 2003 July 14; 163(13): 1587-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860582&dopt=Abstract

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The effects of hemoglobin glutamer-200 (bovine) on the microcirculation in a canine hypovolemia model: a noninvasive computer-assisted intravital microscopy study. Author(s): Cheung AT, Jahr JS, Driessen B, Duong PL, Chan MS, Lurie F, Golkaryeh MS, Kullar RK, Gunther RA. Source: Anesthesia and Analgesia. 2001 October; 93(4): 832-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11574342&dopt=Abstract

•

The influence of l-carnitine supplementation on hematocrit and hemoglobin levels in patients with end stage renal failure on CAPD. Author(s): Sotirakopoulos N, Athanasiou G, Tsitsios T, Mavromatidis K. Source: Renal Failure. 2002 July; 24(4): 505-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12212830&dopt=Abstract

•

The oxidative effect of bacterial lipopolysaccharide on native and cross-linked human hemoglobin as a function of the structure of the lipopolysaccharide. Author(s): Currell DL, Levin J. Source: European Journal of Biochemistry / Febs. 2002 September; 269(18): 4635-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12230576&dopt=Abstract

•

Weekly supplementation with iron and vitamin A during pregnancy increases hemoglobin concentration but decreases serum ferritin concentration in Indonesian

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11303488&dopt=Abstract

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/

•

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

•

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/

•

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

•

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/

•

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

•

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

•

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

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

General Overview Anemia Source: Integrative Medicine Communications; www.drkoop.com Diabetes Source: Prima Communications, Inc.www.personalhealthzone.com Iron-Deficiency Anemia Source: Healthnotes, Inc.; www.healthnotes.com

150 Hemoglobin

Sickle Cell Anemia Source: Healthnotes, Inc.; www.healthnotes.com •

Alternative Therapy Color Projection Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/c.html

•

Herbs and Supplements Ashwagandha Source: Prima Communications, Inc.www.personalhealthzone.com Athletic Performance Source: Healthnotes, Inc.; www.healthnotes.com Eleuthero Alternative names: Siberian Ginseng, Eleuthero; Acanthopanax/Eleutherococcus senticosus Rupr. & Maxim. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Metoclopramide Source: Healthnotes, Inc.; www.healthnotes.com Phosphatidylserine Source: Prima Communications, Inc.www.personalhealthzone.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 HEMOGLOBIN Overview In this chapter, we will give you a bibliography on recent dissertations relating to hemoglobin. 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 “hemoglobin” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on hemoglobin, we have not necessarily excluded nonmedical dissertations in this bibliography.

Dissertations on Hemoglobin 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 hemoglobin. 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: •

Analysis of a Novel Polymerized Hemoglobin Based Oxygen Carrier by Haney, Chadentree Roland; PhD from University of Illinois at Chicago, 2002, 122 pages http://wwwlib.umi.com/dissertations/fullcit/3047894

•

Changes in the Stages of Concern and the Glycosylated Hemoglobin: the Effects of Two Methods of Diabetes Education by Carpentier, Wilma Sloan, PhD from The University of Texas at Austin, 1989, 193 pages http://wwwlib.umi.com/dissertations/fullcit/8920673

•

Chronic Exercise, 2,3-diphosphoglycerate Concentration and Hemoglobin Electrophoretic Patterns in Laboratory Rats. by Baer, Clarence Linden Hutchins, Jr., PhD from University of Oregon, 1975, 85 pages http://wwwlib.umi.com/dissertations/fullcit/7615022

152 Hemoglobin

•

Conformational and Functional Changes of Hemoglobin and Myosin Induced by Ph: Functional Role in Fish Quality by Kristinsson, Hordur Gudjon; PhD from University of Massachusetts Amherst, 2002, 241 pages http://wwwlib.umi.com/dissertations/fullcit/3039370

•

Cross-linked Superoxide Dismutase and Cross-linked Hemoglobin: an Active Conjugate by Koprianiuk, Agnieszka Malgorzata; MSC from University of Toronto (Canada), 2002, 51 pages http://wwwlib.umi.com/dissertations/fullcit/MQ73848

•

Effects of Moderate Altitude and Weight Loss on Exercise Performance and Hemoglobin Concentration in Adult Males. by Pavlisko, Jon Joseph, PhD from the University of Utah, 1974, 124 pages http://wwwlib.umi.com/dissertations/fullcit/7421244

•

Effects of the Vitreoscilla Hemoglobin Gene on the Production of Biosurfactant in Gordonia Amarae by Dogan, Ilhan; PhD from Illinois Institute of Technology, 2002, 107 pages http://wwwlib.umi.com/dissertations/fullcit/3074339

•

Evaluation of Genetic Engineering with Mutant Bacterial Hemoglobin Genes As a Method to Enhance Bioremediation of Aromatic Compounds and Survival of Pucbased Plasmids in Pseudomonas Aeruginosa by Kim, Yongsoon; PhD from Illinois Institute of Technology, 2002, 141 pages http://wwwlib.umi.com/dissertations/fullcit/3074346

•

Factors That Affect Goal Setting in Diabetes Self-management Education and Changes in Hemoglobin A1c Values in Participants with Diabetes by Staton, Lesli Lyn; MS from Texas A&M University - Kingsville, 2002, 66 pages http://wwwlib.umi.com/dissertations/fullcit/1411886

•

Fourier Transform Infrared Spectroscopy Studies of Ferrous and Ferric Hemoglobin I Cyanide Complexes from Lucina Pectinata by Oritz Pijuan, Yohmary; MS from University of Puerto Rico, Mayaguez (Puerto Rico), 2002, 43 pages http://wwwlib.umi.com/dissertations/fullcit/1406821

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Glycosylated Hemoglobin and the Oxygen Kinetics in Individuals with Type Ii Diabetes (diabetes Mellitus, Ventilatory Threshold) by Dwyer, Gregory Byron, PhD from Indiana University, 1992, 152 pages http://wwwlib.umi.com/dissertations/fullcit/9310326

•

Haptoglobins and Hemoglobin-haptoglobin Complexes by Malchy, Barry L; Advdeg from the University of British Columbia (Canada), 1970 http://wwwlib.umi.com/dissertations/fullcit/NK06918

•

Hematological Changes in Response to Exposure to Moderate Altitudes (hemoglobin, Red Blood Cells, Systemic Blood Pressure) by Berry, Michael Joseph, PhD from Texas A&M University, 1983, 119 pages http://wwwlib.umi.com/dissertations/fullcit/8408403

•

Hemoglobin Genotype and Fertility in a Malarial Environment: Limon, Costa Rica by Madrigal-Diaz, Lorena, PhD from University of Kansas, 1988, 132 pages http://wwwlib.umi.com/dissertations/fullcit/8918393

•

Hemoglobin Oxygenation of a Two-layer Tissue-simulating Phantom from Timeresolved Reflectance by Hunter, Robert John; PhD from McMaster University (Canada), 2002, 122 pages http://wwwlib.umi.com/dissertations/fullcit/NQ80712

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•

Hemoglobin Switching by Narayan, Angelina Daisy; PhD from University of Nevada, Reno, 2002, 73 pages http://wwwlib.umi.com/dissertations/fullcit/3060396

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Hemoglobin Switching during Murine Embryonic Development by Wong, Peter Man Chun; PhD from McMaster University (Canada), 1983 http://wwwlib.umi.com/dissertations/fullcit/NK65459

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Kinetic and Spectroscopic Studies of Hemoglobin and Myoglobin in Porous Sol-gels by Khan, Imran; PhD from Yeshiva University, 2002, 207 pages http://wwwlib.umi.com/dissertations/fullcit/3069382

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Mate Choice and Sickle Cell Hemoglobin by Metcalfe, Duncan Wain, PhD from The University of Utah, 1987, 108 pages http://wwwlib.umi.com/dissertations/fullcit/8802708

•

Matrix Laser Desorption Ionization (MALDI) Time-of-flight Mass Spectrometry (TOFMS) Studies of Arylamine Dna Adducts and Cross-linked Hemoglobin by Wu, Huaping; PhD from Loyola University of Chicago, 2002, 117 pages http://wwwlib.umi.com/dissertations/fullcit/3039312

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Mechanism for Nitric Oxide Release from S-nitrosylated Hemoglobin by an Internal Electron Transfer and Development of Nitrosylated Hemoglobin-based Blood Substitutes by Ship, Noam Jonathan; MSC from University of Toronto (Canada), 2002, 34 pages http://wwwlib.umi.com/dissertations/fullcit/MQ68682

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Mutants of Vitreoscilla Hemoglobin: Comparison of Site-directed Mutants with Wild Type Vhb Regarding Functional Characteristics and Dnt Degradation by Lee, Sang, Yeol; PhD from Illinois Institute of Technology, 2002, 82 pages http://wwwlib.umi.com/dissertations/fullcit/3051391

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New Hemoglobin Cross-linking Reagents and Physical Properties of Bis-tetramers by Gourianov, Nikolai N.; MSC from University of Toronto (Canada), 2002, 57 pages http://wwwlib.umi.com/dissertations/fullcit/MQ68675

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Nitroxylation of Chemically Modified Hemoglobins As Potential Resuscitative Fluids by Buehler, Paul Werner; PhD from University of Illinois at Chicago, Health Sciences Center, 2002, 141 pages http://wwwlib.umi.com/dissertations/fullcit/3074211

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Plant Nonsymbiotic Hemoglobins: Hexacoordinated Hemoglobins Involved in Hormonally-regulated Cell Differentiation by Ross, Emily Jane Hume; PhD from The University of Nebraska - Lincoln, 2002, 198 pages http://wwwlib.umi.com/dissertations/fullcit/3059968

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Plasma Volume, Metabolic, and Cardiorespiratory Responses to Various Intensities of Weight Lifting (blood Volume, Hemoglobin, Hematocrit, Dynamic Exercise) by Collins, Mitchell Allen, EDD from University of Georgia, 1985, 147 pages http://wwwlib.umi.com/dissertations/fullcit/8524326

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Plasmepsins I, Ii, Iv, and Hap Comprise a Novel Family of Hemoglobin-degrading Proteases in the Malaria Parasite, Plasmodium Falciparum by Banerjee, Ritu; PhD from Washington University, 2003, 139 pages http://wwwlib.umi.com/dissertations/fullcit/3095499

154 Hemoglobin

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Polyhemoglobin-superoxide Dismutase-catalase Blood Substitute for Ichemiareperfusion in Brain by Powanda, Doi Douglas; MSC from McGill University (Canada), 2002, 60 pages http://wwwlib.umi.com/dissertations/fullcit/MQ78943

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Regulation of the Haptoglobin-hemoglobin Scavenger Receptor Cd163 in the Inflammatory Response to Endotoxin by Goldstein, Katharine Ann; PhD from Dartmouth College, 2003, 138 pages http://wwwlib.umi.com/dissertations/fullcit/3084572

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Separation of Hemoglobin-albumin System by Gradient Ionic Strength: Operating Conditions by Mui, Kenneth; Me from The Cooper Union for the Advancement of Science and Art, 2003, 123 pages http://wwwlib.umi.com/dissertations/fullcit/1413936

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Solution Proton NMR Studies on Structural and Dynamic Properties of the R-state Cyanomet Human Adult Hemoglobin by Tran, Anh-Tuyet Thi; PhD from University of California, Davis, 2002, 394 pages http://wwwlib.umi.com/dissertations/fullcit/3065313

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Spectroelectrochemical and Functional Studies of Hemoglobin and Diaspirin Crosslinked Hemoglobins by Dragan, Simona Adriana; PhD from Loyola University of Chicago, 2002, 139 pages http://wwwlib.umi.com/dissertations/fullcit/3039279

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Steady-rate Exercise Cardiac Output: Influence of Hemoglobin by Freedson, Patty Susan, PhD from the University of Michigan, 1980, 166 pages http://wwwlib.umi.com/dissertations/fullcit/8017263

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Structural Studies of Mutant and Wild Type Vitreoscilla Hemoglobins Using X-ray Absorbtion Fine Structure Spectroscopy by Golbahar-Agun, Aysel; PhD from Illinois Institute of Technology, 2003, 86 pages http://wwwlib.umi.com/dissertations/fullcit/3087838

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Structure-function Studies of Native and Mutant Vitreoscilla Hemoglobins by Ahuja, Sandhya; PhD from Illinois Institute of Technology, 2002, 89 pages http://wwwlib.umi.com/dissertations/fullcit/3074332

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Studies of Some Mutants of Human Hemoglobin Including a New Alpha-variant Hb Mahidol by Pootrakul, Sa-Nga; ADVDEG from the University of British Columbia (Canada), 1970 http://wwwlib.umi.com/dissertations/fullcit/NK06936

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Studies on Subunit Interrelations in the Hemoglobin-haptoglobin Complex by Lockhart, Wallace Lyle; ADVDEG from The University of Western Ontario (Canada), 1971 http://wwwlib.umi.com/dissertations/fullcit/NK09873

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Studies on the Combination of Haptoglobin with Hemoglobin by Chan, Gwendolyn Faye Quen, 1933-; ADVDEG from The University of British Columbia (Canada), 1968 http://wwwlib.umi.com/dissertations/fullcit/NK02357

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Studies on the Complex of Haptoglobin and Hemoglobin by Oda, George; PhD from The University of Western Ontario (Canada), 1973 http://wwwlib.umi.com/dissertations/fullcit/NK14047

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Studies on the Hemoglobin Alpha-subunit and Its Interaction with Haptoglobin by Terpstra, Frank Alexander; PhD from The University of Western Ontario (Canada), 1975 http://wwwlib.umi.com/dissertations/fullcit/NK24681

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Study of Soluble Dextran-hemoglobin Complexes As Potential Blood Substitutes by Tam, Siu-Cheung; PhD from University of Toronto (Canada), 1978 http://wwwlib.umi.com/dissertations/fullcit/NK38854

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The Effects of Hemoglobin Supplements upon Maximal Oxygen Uptake in Females. by Miller, Ernest Albert, Jr., EDD from University of Arkansas, 1978, 122 pages http://wwwlib.umi.com/dissertations/fullcit/7823243

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The Effects of Hemoglobin Supplements upon Maximal Oxygen Uptake. by Batesky, James Anthony, EDD from University of Arkansas, 1977, 103 pages http://wwwlib.umi.com/dissertations/fullcit/7723381

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The Effects of Reduced Hemoglobin-oxygen Affinity on the Normoxic and Ischemic Canine Myocardium by Robertson, Murray Alexander; PhD from McMaster University (Canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK52290

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The Interaction of Haptoglobin with Hemoglobin and Hemoglobin Subunits by Boyd, Nigel David; ADVDEG from The University of Western Ontario (Canada), 1971 http://wwwlib.umi.com/dissertations/fullcit/NK08600

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The Pharmacogenetics of Fetal Hemoglobin and F-cell Variation by Schneidereith, Tonya Andrade; PhD from The Johns Hopkins University, 2003, 98 pages http://wwwlib.umi.com/dissertations/fullcit/3080760

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The Relationship of Cognitive Development on Assuming Self-management in Juvenile Diabetes Mellitus: an Application of Piagetian Theory in Assessing Readiness for Self-care in a Chronic Illness (glycohemoglobin, Locus of Control, Information) by Diamond, Kenneth, PhD from State University of New York at Buffalo, 1984, 104 pages http://wwwlib.umi.com/dissertations/fullcit/8410540

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Tonb-dependent Ligand Interactins of the Neisseria Meningitidis Receptor Hpuab Involved in Heme-iron Uptake from Hemoglobin and Hemoglobin-haptoglobin by Rohde, Kyle Herman; PhD from the University of Oklahoma Health Sciences Center, 2003, 244 pages http://wwwlib.umi.com/dissertations/fullcit/3094431

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Ultrafast Time-resolved Absorption Study of Hemoglobin I-ligand Complexes from Lucina Pectinata by Ramos-Alvarez, Cacimar Antonio; MS from University of Puerto Rico, Mayaguez (Puerto Rico), 2002, 57 pages http://wwwlib.umi.com/dissertations/fullcit/1411314

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. CLINICAL TRIALS AND HEMOGLOBIN Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning hemoglobin.

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

Bone marrow transplant from donor using less toxic conditioning for patient with high risk hemoglobinopathies Condition(s): Sickle Cell Anemia; Hemoglobinopathy; Thalassemia Study Status: This study is currently recruiting patients. Sponsor(s): Baylor College of Medicine; Texas Children's Hospital; The Methodist Hospital Purpose - Excerpt: The major goal of this study is to determine the risks and benefits of stem cell transplants in combination with a newer, less toxic conditioning chemotherapy treatment in patients with severe sickle cell disease (SCD) or sickle hemoglobin variants (hemoglobin SC or hemoglobin SB0/+), or homozygous b0/+ thalassemia or severe B0/+ thalassemia variants. Participation in this project will be for one year, with follow up evaluations done every 6 months thereafter for 10 years or until participants are 18 years old. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00040417

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These are listed at www.ClinicalTrials.gov.

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Bone Marrow transplant from related donor for patients with high risk hemoglobinopathies Condition(s): Sickle Cell Anemia; Hemoglobinopathy; Thalassemia Study Status: This study is currently recruiting patients. Sponsor(s): Baylor College of Medicine; The Methodist Hospital; Texas Children's Hospital Purpose - Excerpt: The major goal of this study is to determine the risks and benefits of bone marrow transplants in patients with severe thalassemia or sickle cell disease. Participation in this project will be for two years. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00040469

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Stem Cell Transplantation after Reduced-Dose Chemotherapy for Patients with Sickle Cell Disease or Thalassemia Condition(s): Hemoglobinopathies; Anemia, Sickle Cell; Hemoglobin SC Disease; Thalassemia; Thalassemia Major Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: The purpose of this study is to find out if using a lower dose of chemotherapy before stem cell transplantation can cure patients of sickle cell anemia or thalassemia while causing fewer severe side effects than conventional high dose chemotherapy with transplantation. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00034528

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The Effect of Oral Magnesium Pidolate on How Often Painful Crises Happens in Patients with Hemoglobin SC Disease Condition(s): Hemoglobin SC Disease Study Status: This study is currently recruiting patients. Sponsor(s): Baylor College of Medicine; Texas Children's Hospital; Children's Hospital Boston Purpose - Excerpt: The purpose of this study is to find out whether treatment with magnesium pidolate will increase the amount of water in the red blood cell and result in fewer painful crises in patients with hemoglobin SC disease while not causing diarrhea. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00040456

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Transfer of GPI-Linked Proteins to Transfused Patients with Paroxysmal Nocturnal Hemoglobinuria Condition(s): Paroxysmal Hemoglobinuria Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will examine blood cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) after they receive a blood transfusion to determine if certain proteins (GPI-linked proteins) in the transfused blood transfer to the patient's blood cells. GPI-linked proteins, which are normally present on red cells and regulate red cell survival, are absent in patients with PNH. Their lack is believed to account for the premature destruction of red blood cells in these patients, resulting in a low hemoglobin and hematocrit. Patients may experience fatigue, flank pain and other symptoms, requiring treatment with blood transfusion. Patients with PNH 18 years of age or older with group A1 blood who require at least three units of red cells and who have not been transfused with group O blood within the last 3 months may be eligible for this study. Participants will come to the NIH Clinical Center for the following procedures: - Interview about the severity of their anemia-related symptoms - Blood test - Blood transfusion, if required. Patients will be transfused with compatible group O blood. The donor blood will be washed (rinsed with a salt solution) until it is 99% free of donor plasma. Group O blood is given instead of group A1 in order to be able to distinguish the patient's cells from the transfused cells. Blood samples of 3 teaspoons each will be drawn 1 day, 1 week, and 3 weeks after the transfusion. These samples may be collected by the patient's doctor locally and sent to NIH by mail. If it is found that GPI-linked proteins transfer to the patient's cells, the study will also examine how long the proteins remain attached and will assess whether the proteins are functional and prevent cell destruction. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00039923

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A Phase I/II Trial of Recombinant-Methionyl Human Stem Cell Factor (SCF) in Adult Patients with Sickling Disorders Condition(s): hemoglobin SC disease; sickle cell anemia Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: Sickle cell anemia is a genetic disorder that results from a single nucleotide substitution in codon 6 of the beta-globin gene which, in the homozygous state, produces an abnormal hemoglobin that is prone to polymer formation when deoxygenated. The polymerized hemoglobin leads to impaired deformability and sickling of red blood cells which subsequently lodge in end-arterioles producing the classic and most prominent feature of the disorder, repeated vasoocclusive crises. Despite knowledge of the precise genetic defect for decades, only recently has there been therapeutic impact based upon this knowledge when a clear benefit from treatment with hydroxyurea, a cell cycle-specific agent administered to induce production of fetal hemoglobin (HbF) by stimulating gamma-globin synthesis, was reported in patients with sickle cell disease (SCD). The reduction in the frequency and severity of vasoocclusive crises seen has been attributed to the increase in HbF levels in responsive patients. While the majority of patients demonstrate a rise in HbF, not all

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such patients benefit from treatment. Given these results, alternative agents that also stimulate the production of HbF warrant investigation in the treatment of SCD. Recombinant-methionyl human stem cell factor (SCF) is a hematopoietic growth factor with activity on immature hematopoietic progenitor cells. SCF stimulates the production of HbF in vitro and in vivo, and this effect is attainable without the myelosuppression associated with hydroxyurea. In this phase I/II trial, we will administer SCF in a dose escalating fashion to patients with sickling disorders. Parameters to be measured are HbF levels, F cell levels, peripheral blood CD34 levels, frequency, duration, and severity of vasoocclusive crises, and toxicity. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005783 •

Hydroxyurea to Treat Beta-Thalassemia (Cooley's Anemia) Condition(s): Beta Thalassemia; Hemoglobinopathy Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: This 12-month study will evaluate the safety and effectiveness of hydroxyurea in treating beta-thalassemia, a type of anemia caused by defective hemoglobin (the oxygen-carrying pigment in blood). Hemoglobin is composed of two protein chains-alpha globin chains and beta globin chains; patients with betathalassemia do not make beta globin. Patients often require frequent red blood cell transfusions. This leads to iron overload, which, in turn, requires iron chelation therapy (removal of iron from the blood). Some drugs, including hydroxyurea, can stimulate production of a third type of protein chain called gamma chains. In the womb, the fetus makes this type of protein instead of beta globin. It is not until after birth, when the fetus no longer produces gamma globin that the beta globin deficiency becomes apparent. Gamma chain synthesis improves hemoglobin and red blood cell production, correcting the anemia. This study will determine if and at what dose hydroxyurea treatment reduces patients' need for red blood cell transfusions and whether certain factors might predict which patients are likely benefit from this treatment. Patients 15 years and older with moderately severe beta-thalassemia may be eligible for this study. Participants will take hydroxyurea daily at a dose calculated according to the patient's body size. Blood will be drawn weekly to measure blood cell and platelet counts. The drug dosage may be increased after 12 weeks of treatment and again after 24 weeks if the white cell and platelet counts remain stable. Patients who respond dramatically to treatment may continue to receive hydroxyurea for up to 3 years. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001958

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Phase II Study To Evaluate The Safety and Efficacy of Hemoglobin Raffimer in Patients Undergoing First Time CABG Surgery Condition(s): Cardiovascular Disease

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Study Status: This study is suspended. Sponsor(s): Hemosol Purpose - Excerpt: To evaluate the efficacy of Hemolink(tm) in combination with Intraoperative Autologous Donation (IAD) versus control (IAD alone) in facilitating avoidance of allogeneic RBC transfusion during and following primary CABG surgery Phase(s): Phase II; Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00038454 •

Vascular Effects of Endothelium-Derived Versus Hemoglobin-Transported Nitric Oxide in Healthy Subjects Condition(s): Diabetes Mellitus; Healthy; Hypercholesterolemia; Hypertension Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Nitric oxide (NO) is a soluble gas, continuously synthesized by the endothelium, that contributes importantly to vasodilator tone of the coronary and systemic circulations by activating guanylyl cyclase in vascular smooth muscle, causing relaxation. Although regional synthesis of NO by the endothelium contributes to local vasodilator tone, Stamler and co-workers have proposed that regional vascular tone may also be regulated by NO transported from the lungs by hemoglobin as a consequence of enhanced binding of NO to reactive thiols of oxygenated hemoglobin. This study is designed to determine the contribution of hemoglobin-transported NO to forearm microvascular dilator tone in healthy subjects at rest and during regional hypoxia associated with forearm exercise stress, with measurements made before and after regional blockade of endothelial NO synthesis. Findings in this study may be relevant to understanding the physiological contribution and therapeutic potential of hemoglobin-transported NO in the regulation of vasodilator tone in diseases and conditions associated with regional endothelial dysfunction and reduced endothelial NO bioactivity (e.g., hypertension, diabetes mellitus, hypercholesterolemia, cigarette smoking, and estrogen deficiency). Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001963

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately

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5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “hemoglobin” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

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CHAPTER 6. PATENTS ON HEMOGLOBIN Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “hemoglobin” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on hemoglobin, we have not necessarily excluded nonmedical patents in this bibliography.

Patents on Hemoglobin By performing a patent search focusing on hemoglobin, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 9Adapted

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

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example of the type of information that you can expect to obtain from a patent search on hemoglobin: •

Alexandrite laser system for hair removal and method therefor Inventor(s): Cho; George (Hopkinton, MA), Furumoto; Horace W. (Wellesley, MA), Koschmann; Eric (Hudson, NH), McDaniel; David H. (Virginia Beach, VA), Rizzo; Antonio G. (Nashua, NH) Assignee(s): Cynosure, Inc. (Chelmsford, MA) Patent Number: 6,632,218 Date filed: October 21, 1999 Abstract: A long pulse alexandrite laser hair removal system is disclosed using light pulses of greater than 1 msec and fluences between 10 and 50 J/cm.sup.2. The use of an alexandrite laser allows good penetration while still achieving an acceptable combination of hemoglobin and melanin absorption. The use an index-matching application on the skin sections to be treated is also described. This substance will be absorbed into the epidermal layer to provide better coupling of the laser light into the skin. Also, and most advantageously, it will reduce reflections at the epidermal-dermal junction, which can lead to the damage of the skin. Also a topical thermal or photochromic indicator is suggested since skin irradiation in the near-infrared generally does not produce any characteristic skin color change as is found when using pulsed dye lasers, for example. Excerpt(s): Historically, there have been a number of options for the permanent removal of hair. Electrolysis has been the most commonly selected approach, in which an operator, usually a electrologist, attaches an electrode to each individual hair shaft, with the patient typically holding a second electrode. An electrical current is then passed through the hair shaft and the hair follicle through the papilla. This precisely directed current can induce permanent injury in the follicle and papilla, stopping the future production of the hair shaft. Problems exist with the electrolysis technique, however. The success with which hair is permanently removed varies greatly from patient to patient. Moreover, the process is slow since each hair follicle must be individually treated, and there is some discomfort associated with the electric current. The removal of hair using lasers is another approach that has found only limited success. Numerous techniques have been taught in the prior art. Each, however, suffers from drawbacks such as poor ultimate success in stopping hair growth even after multiple treatments, excessive injury to the tissue surrounding the hair follicles and papilla, and excessively large and expensive laser systems. Web site: http://www.delphion.com/details?pn=US06632218__

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Allosteric inhibitors of pyruvate kinase Inventor(s): Abraham; Donald J. (Midlothian, VA), Burnett; James C. (Ashland, VA), Danso-Danquah; Richmond (Richmond, VA), Hoffman; Stephen J. (Carlisle, MA), Joshi; Gajanan S. (Glen Allen, VA), Wang; Changging (Richmond, VA) Assignee(s): Allos Therapeutics, Inc. (Denver, CO), Virginia Commonwealth University (Richmond, VA) Patent Number: 6,534,501 Date filed: March 7, 2001 Abstract: Chemical structures have been identified which allosterically modify pyrvate kinase and inhibit enzymatic activity. These compounds can be used as pharmaceuticals in the treatment of a wide variety of diseases and disorders where influencing metabolic processes is beneficial, such as the glycolytic pathway, all pathways which use ATP as an energy source, and all pathways which involve 2,3-diphosphoglycerate related to the delivery of oxygen by modifying hemoglobin's oxygen affinity, treatments of tumor and cancer and Alzheimer's disease (AD). Excerpt(s): The invention is generally related to pharmaceuticals, which are useful for allosterically modifying pyruvate kinase. Mammalian pyruvate kinase (PK) is a key regulatory glycolytic enzyme that exhibits allosteric kinetic behavior. The basic mechanism of the allosteric regulation of PK at the molecular level is still not known. There are reports that PK undergoes conformational changes and that the changes involve domain events. PK is found in all cells and tissues. It catalyzes the conversion of phospho-enolpyruvate (PEP) and adenosine diphosphate (ADP) into pyruvate and adenosine triphosphate (ATP), as shown in reaction scheme 1. The reaction proceeds in two steps. First, the 2-phosphate is removed from PEP to yield ATP and the enolate ion form of pyruvate. The second step involves the protonation and tautomerization of the ion to yield the keto form of pyruvate. The enzyme requires three cation cofactors, two divalent (Mg.sup.2+ or Mn.sup.2+) and one monovalent (K.sup.+). Positive factors of PK include fructose 1,6 diphosphate, PEP, and low pH. Negative factors of PK include ATP, high pH, and glycogenic amino acids such as alanine and phenylalanine. The products of reaction scheme 1, pyruvate and ATP, are involved in a wide variety of metabolic pathways; therefore, PK can be considered a key enzyme in the glycolytic pathway as well as many other pathways in the cellular metabolism. Web site: http://www.delphion.com/details?pn=US06534501__

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Analysis method and cuvette therefor Inventor(s): Eriksson; Annika (Helsingborg, SE), Lilja; Jan (Helsingborg, SE), Nilsson; Sven-Erik (Nyhamnslage, SE), Svensson; Johnny (Angelholm, SE) Assignee(s): Migrata UK Ltd. (Cy-Limassol, CY) Patent Number: 6,638,769 Date filed: October 10, 2001 Abstract: A method for hemoglobin determination is described which includes the steps of introducing a sample of undiluted whole blood by capillary action into a disposable microcuvette having at least one cavity for receiving the sample. The cavity includes a dry essentially non-hygroscopic hemolysing agent, which is dissolved by the blood, hemolyses the red blood cells and releases the haemoglobin contained in the blood cells.

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A first absorption measurement at a wavelength range 490-520 nm is then performed directly on the sample in the microcuvette, and a second absorption measurement is performed to compensate for background interference. Excerpt(s): The present invention concerns an analysis method and a cuvette for performing this analysis. Specifically the invention concerns a method for determination of haemoglobin in undiluted whole blood and a disposable cuvette which can be used in this determination. A disposable cuvette for sampling a fluid, mixing the sample with a reagent and directly making optical analyses of the sample mixed with the reagent is previously known from U.S. Pat. No. 4,088,448. This known cuvette has several advantages as it i.a. simplifies the sampling procedure, reduces the number of utensils and considerably improves the accuracy of analysis by making the analysing procedure independent of the operating technique of the operator making the analysis. A cuvette construction based on the same principle and with improved flow characteristics is disclosed in the U.S. Pat. No. 5,674,457. A disposable cuvette developed according to these patents is currently widely used for haemoglobin measurement(Hb determination) of undiluted whole blood. To this end the cuvette cavity has been pretreated with a reagent, such that when a blood sample is drawn into the cuvette, the walls of the red blood cells are disintegrated and a chemical reaction is initiated. The result of the reaction allows Hb determination by absorption measurement directly through the transparent walls of the cuvette which, in the measuring zone, also called the optical window, has a predetermined and accurately defined distance between the inner surfaces of the opposing planar walls. The measurement method is based on a modified azidmethemoglobin method according to Vanzetti, G., Am.J. Lab.& Clin. Med. 67, 116 (1966). Web site: http://www.delphion.com/details?pn=US06638769__ •

Antidiabetic formulation and method Inventor(s): Piper; Beth Anne (Hopewell, NJ) Assignee(s): Bristol-Myers Squibb Co. (Princeton, NJ) Patent Number: 6,586,438 Date filed: November 3, 1999 Abstract: A low dose antidiabetic pharmaceutical formulation is provided, especially adapted for treating Type II diabetes in drug naive patients, which includes a combination of metformin (employed in a reduced amount (less than 800 mg metformin per day) compared to that employed in generally accepted medical practice) and at least one other antidiabetic agent such as a sulfonyl urea, for example, glyburide, which combination provides at least about substantially equivalent efficacy in treating diabetes in drug naive patients, as do antidiabetic formulations containing metformin employed in dosages prescribed in generally accepted medical practice for first line therapy in treating diabetes, but with substantially reduced side effects, such as hypoglycemia and/or gastrointestinal distress. A method for treating diabetes in drug naive human patients is also provided employing the above formulation to reduce insulin resistance and/or post-prandial glucose excursion and/or hemoglobin 1Ac, and/or increase postprandial insulin, thereby treating the diabetes. Excerpt(s): The present invention relates to a low dose pharmaceutical formulation for treating type 2 diabetes in drug naive patients, which includes metformin (preferably employed in reduced amounts compared to that employed in generally accepted

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medical practice) and another antidiabetic agent such as a sulfonyl urea, for example, glyburide, which formulation has at least substantially equivalent efficacy in treating type 2 diabetes as compared to prior art antidiabetic formulations containing metformin, but with substantially reduced side effects, and to a method for treating diabetes employing such formulations. The biguanide antihyperglycemic agent metformin disclosed in U.S. Pat. No. 3,174,901 is currently marketed in the U.S. in the form of its hydrochloride salt (Glucophage.RTM.), Bristol-Myers Squibb Company). The diagnosis and management of type 2 diabetes mellitus is rapidly undergoing progressive changes. It is now widely accepted that glycemic control makes a difference. The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications of an elevated blood glucose. The diagnosis of diabetes has undergone significant changes as evidenced by the new ADA diagnostic and classification guidelines. Oral therapeutic options for the treatment of type 2 diabetes mellitus, until recently, have been severely limited. Prior to 1995, sulfonyl ureas had been the mainstay of oral diabetes agents in the United States. Sulfonyl ureas target one mechanism of hyperglycemia by augmenting insulin secretion from the beta cell. Since 1995, three new classes of agents have been added to the antidiabetes armamentarium for the management of hyperglycemia. Metformin, a biguanide, targets additional mechanisms of hyperglycemia by inhibiting hepatic glucose production and enhancing peripheral glucose uptake and thereby reduce insulin resistance; thiazolidinediones such as troglitazone, rosiglitazone and pioglitazone decrease peripheral insulin resistance; and alpha-glucosidase inhibitors such as acarbose and miglitol help control postprandial glucose excursion by delaying absorption of dietary carbohydrate. These agents are all indicated as monotherapy and some are indicated for use in combination therapy, generally, after monotherapy has been found to be inadequate. Web site: http://www.delphion.com/details?pn=US06586438__ •

Apparatus for measuring hematocrit Inventor(s): Cadell; Theodore E. (Conestogo, CA), Samsoondar; James (Cambridge, CA) Assignee(s): CME Telemetrix Inc. (Ontario, CA) Patent Number: 6,522,398 Date filed: December 8, 2000 Abstract: A method and apparatus for use in respect of samples which are assessed for quality prior to testing in a clinical analyzer. The method and apparatus identify parameters such as gel level and height of fluid above the gel in blood samples, where appropriate, for the purposes of positioning the specimen for determination of interferents. Such interferents include hemoglobin (Hb), total bilirubin and lipids. These interferents are determined by measurement of absorption of different wavelengths of light in serum or plasma, or other speciments, which are then compared with values obtained through calibration using reference measurements for the respective interferents in serum or plasma or other type of specimen. Determination of temperature of the specimen, as well as specimen type, for example whether the specimen is urine or plasma or serum, may also be carried out. Excerpt(s): This invention relates to spectrophotometry and the spectrophotometric analysis of blood samples. In particular, this invention relates to a method and apparatus for providing a rapid pre-test determination of interferent concentration, specimen type and physical properties of a blood sample for a blood analyzer by

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measurement of absorbance or reflectance. Clinical laboratory tests are routinely performed on the serum or plasma of whole blood. In a routine assay, red blood cells are separated from plasma by centrifugation, or red blood cells and various plasma proteins are separated from serum by dotting prior to centrifugation. Haemoglobin (Hb), bilirubin (Bili) and light-scattering substances like lipid particles are typical substances which will interfere with, and affect spectrophotometric and other blood analytical measurements. Such substances are referred to as interferents. Web site: http://www.delphion.com/details?pn=US06522398__ •

Automated method for detecting, quantifying and monitoring exogenous hemoglobin in whole blood, plasma and serum Inventor(s): Malin; Michael J. (South Nyack, NY), Shapiro; Phyllis (Stamford, CT) Assignee(s): Bayer Corporation (Tarrytown, NY) Patent Number: 6,623,972 Date filed: May 18, 2001 Abstract: The invention provides a new method and system for detecting and monitoring extracellular or exogenously added hemoglobin, i.e., a cell-free hemoglobin substitute or derivative, in a blood, plasma, or serum sample of an individual, particularly a whole blood sample. The invention further describes the use of automated hematology analyzers to determine and quantify at the same time the concentration of total, cellular and exogenous hemoglobin in a blood, plasma, or serum sample, and is particularly advantageous for medical use during or after patient trauma or surgery, as well as for monitoring hemoglobin levels during patient recovery. Excerpt(s): The present invention relates generally to new methods and systems for detecting, quantifying and monitoring extracellular or exogenously added hemoglobin, including hemoglobin substitutes, in a blood sample, particularly a whole blood sample, as well as in plasma and serum samples. The present invention further relates to the use of automated hematology analyzers to determine and quantify the concentration of extracellular and exogenous hemoglobin, including cell-free hemoglobin substitutes, in a blood, plasma, or serum sample, and is particularly advantageous for medical use during patient trauma or surgery, as well as for monitoring hemoglobin levels during recovery. Whole blood substitutes have long been sought after as alternatives to whole blood for use in the medical field, particularly following trauma and/or surgery where transfusions are needed. Motivated by the need to supply large quantities of blood to the military on the battlefield, but limited by the resources to insure the safety of the blood supply in the face of contamination by human pathogens and viruses, notably hepatitis viruses and HIV, blood banks abandoned their whole blood supply programs in the early 1980s. However, the search for blood substitutes, e.g., synthetic blood substitutes, that are free of contaminants and that can be used in patient treatment has continued. Currently, there is a renewed interest to produce and/or isolate a blood substitute. However, because of the complexity of blood and the various components that comprise whole blood, as well as the stringent federal regulations governing the testing and use of such synthetic products, industry has focused its research efforts on the development of products which temporarily deliver oxygen, rather than on the development of a variety of different products having other functions that transfused blood provides. Web site: http://www.delphion.com/details?pn=US06623972__

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Automatic hematologic counting and analysing device Inventor(s): Melet; Francois (9, Chaussee Jules Cesar, OSNY, 95528 Cergy Pontoise Cedex, FR) Assignee(s): none reported Patent Number: 6,555,065 Date filed: May 18, 2000 Abstract: A compact apparatus for automatically analyzing a blood sample having a pumping assembly, a dilution assembly and a measuring assembly. The pumping assembly includes pumps for air, lysis and diluent. The dilution assembly includes a sampling needle, and containers for waste, white corpuscle dilution, and red corpuscle dilution. The measuring assembly includes a measuring chamber, and a device for counting platelets, red corpuscles, white corpuscles and hemoglobin in the blood sample. Both red and white corpuscles are counted in the same measuring chamber. A plurality of pipes establish fluid communication between the elements of the apparatus. A plurality of electro-valves are adapted to automatically open and close the pipes thereby regulating fluid flow between the pumping assembly, the dilution assembly and the measuring assembly. One of the electro-valves is adapted to shutoff a diluent source and substitute water therefor, whereby the apparatus is rinsed with the water to avoid crystalization. Excerpt(s): This application claims the benefit of French Patent Application No. 97 14520 filed Nov. 19, 1997 and International Application No. PCT/FR98/02440 filed Nov. 16, 1998. The present invention relates to an automatic hematologic counting and analyzing device. More precisely it relates to a device making it possible, in particular, to automatically measure platelets, red corpuscles, white corpuscles and hemoglobin in blood. French Patent No. 2,629,208 describes an automatic hematologic analyzer. This device, even though already simplified, remains relatively complex. This complexity means that such a device is necessarily bulky and furthermore its manufacturing cost is high. The purpose of the present invention is to overcome the known difficulties of the prior art by reducing the number of useful parts in the device thereby minimizing the volume of the device. Web site: http://www.delphion.com/details?pn=US06555065__

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Chemical modification of biomedical materials with genipin Inventor(s): Lee; Thomas Chau-Jen (late of Walnut Creek, CA), Lin; Ching-Kuan (Taichung, TW), Sung; Hsing-Wen (Hsinchu, TW) Assignee(s): Challenge Bioproducts Co., Ltd. (Taichung, TW) Patent Number: 6,608,040 Date filed: September 27, 2001 Abstract: Biocompatible cross-linked materials, suitable for use in implants, wound dressings, and blood substitutes, are described. The materials are prepared by crosslinking biological substances, such as collagen, chitosan, or hemoglobin, with genipin, a naturally occurring cross-linking agent. The cross-linking agent has much lower toxicity than conventionally used reagents, and the cross-linked products have good thermal and mechanical stability as well as biocompatibility.

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Excerpt(s): The present invention relates to chemical modification of biomedical materials, such as collagen, chitosan, and hemoglobin, with a naturally occurring crosslinking reagent, genipin, and to biocompatible materials, useful in biological implants, adhesives, wound dressings, and blood substitutes, which are crosslinked or polymerized with genipin. Buchi, G. et al., J. Am. Chem. Soc. 89:2776-7 (1967). Chanda, J. et al., Artif Organs 18(10):752-7 (1994). Web site: http://www.delphion.com/details?pn=US06608040__ •

Chemically modified hemoglobin for burn shock resuscitation Inventor(s): Burhop; Kenneth E. (Mundelein, IL), Hansbrough; John F. (Rancho Santa Fe, CA), Soltero; Raluan G. (La Jolla, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,566,326 Date filed: March 13, 1996 Abstract: Hemoglobin chemically modified to reduce oxygen affinity and prevent dissociation are administered parenterally during resuscitation to patients suffering from burn shock. Such treatment, reduces base deficit, increases cardiac output and mean arterial blood pressure, and improves survival. Excerpt(s): The present invention relates to the field of trauma intervention, and in particular, the treatment of severe burns with parenteral therapy involving administration of chemically modified hemoglobin. The occurrence of severe burn injury sets in motion a complex series of biochemical and physiological events that critically affect the course of recovery and even the survival of the patient. In the early hypodynamic stage of burn shock, there is a marked suppression of mean arterial blood pressure (MAP), cardiac output (CO), systemic vascular resistance (SVR), oxygen delivery (DO2), and an increase in base deficit. Associated with these changes is a profound increase in capillary permeability resulting in extravasation of large amounts of plasma fluids. Most of these fluids are retained in the extravascular tissue matrix as edema. Many of these effects are mediated by vasoactive hormones and other substances. Levels of IL-1, IL-6, vasopressin and nitric oxide are elevated, and contribute to the systemic effects. At the local inflammatory level, products of arachidonic acid metabolism such as leukotrienes and prostaglandins increase microvascular permeability. Thromboxane A2, and related metabolites, are produced locally in the burn wound and cause injury by increasing tissue ischemia. Other vasoactive mediators, such as histamine, bradykinin, and oxygen radicals generated post-burn contribute to edema either directly by affecting vascular permeability, or indirectly by causing an increase in microvascular hydrostatic pressure. Web site: http://www.delphion.com/details?pn=US06566326__

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Complex of lipoprotein with hemoglobin or hemoglobin analog Inventor(s): Nakano; Hajime (Kyoto, JP), Okamoto; Masashi (Kyoto, JP) Assignee(s): Arkray, Inc. (Kyoto, JP) Patent Number: 6,524,862 Date filed: June 8, 2001

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Abstract: A selective complex of a lipoprotein with hemoglobin or a hemoglobin analogue. A method of assaying hemoglobin or a hemoglobin analogue in a sample, comprising reacting the sample with a lipoprotein which is capable of selectively forming a complex with hemoglobin or a hemoglobin analogue. A kit for assaying hemoglobin or a hemoglobin analogue, comprising a lipoprotein which is capable of selectively forming a complex with hemoglobin or a hemoglobin analogue. Excerpt(s): The present invention relates to a selective complex of a lipoprotein with hemoglobin or a hemoglobin analogue; a method of assaying hemoglobin or a hemoglobin analogue in a sample, using the selective complex, and a kit for assaying hemoglobin or a hemoglobin analogue, using the selective complex in clinical examinations. In clinical examinations, it is required to selectively assay a target substance from a sample containing various coexisting substances. Accordingly, there have been employed a number of substances that specifically binds to target substances to form a pair just like a key and a keyhole, for example, antigen (including hapten)antibody, ligand-receptor, substrate-enzyme, inhibitor-enzyme, or the like. For example, the sandwich method is an immunoassay method using antibodies which is frequently employed. In this method, an antigen to be assayed is sandwiched between two kinds of antibodies. One of these antibodies is immobilized on a solid phase for capturing the antigen, while the other antibody is labeled. Then, the antigen to be assayed is allowed to react with the antibodies to thereby form a sandwich complex of immobilized antibody-antigen-labeled antibody. After removing the unreacted labeled antibody, the amount of the antigen is determined by measuring the label. Web site: http://www.delphion.com/details?pn=US06524862__ •

Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules Inventor(s): Hsia; Jen-Chang (Irvine, CA) Assignee(s): Synzyme Technologies, Inc. (Irvine, CA) Patent Number: 6,458,758 Date filed: March 26, 1997 Abstract: Compositions and processes to alleviate free radical toxicity are disclosed based on the use of nitroxides in association with physiologically compatible macromolecules. In particular, hemoglobin-based red cell substitutes are described featuring stable nitroxide free radicals for use in cell-free hemoglobin solutions, encapsulated hemoglobin solutions, stabilized hemoglobin solutions, polymerized hemoglobin solutions, conjugated hemoglobin solutions, nitroxide-labelled albumin, and nitroxide-labelled immunoglobulin. Formulations are described herein that interact with free radicals, acting as antioxidant enzyme-mimics, which preserve nitroxides in their active form in vivo. Applications are described including blood substitutes, radioprotective agents, imaging agents, agents to protect against ischemia and reperfusion injury, particularly in cerebral ischemia in stroke, and in vivo enzyme mimics among others. Excerpt(s): This invention relates to the therapeutic and diagnostic use of nitroxides, including the combined use of a membrane permeable nitroxide with a membrane impermeable nitroxide including nitroxide-labelled macromolecules, including polypeptides e.g., hemoglobin, albumin, immunoglobulins, and polysaccharides, e.g., dextran, hydroxylethyl starch, and artificial membranes, e.g., liquid bilayer,

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hemoglobin and albumin microbubbles. Nitroxide-containing formulations are disclosed which alleviate the toxic effects of oxygen-related species in a living organism and provide ability to diagnose and treat a wide variety of pathological physiological conditions. This invention also relates to nitroxides, synthetic nitroxide polymers and copolymers and nitroxide-labelled macromolecules used in combination with low molecular weight and membrane-permeable nitroxides to sustain the in vivo effect of nitroxides. This invention also discloses novel compounds and methods featuring nitroxides used in combination with physiologically compatible cell-free and encapsulated hemoglobin solutions for use as a red cell substitute. Furthermore, this invention describes the methods and novel compounds for the topical delivery of cell membrane impermeable nitroxides in its membrane permeable form leading to intracellular accumulation of therapeutic concentrations of the said nitroxide for treatment of skin photo aging and as an anti-skin wrinkle agent. Additionally, this invention describes the above nitroxides in combination with other physiologically active compounds, including other nitroxides, to protect from pathological damage and oxidative stress caused by free radicals and describes their use in diagnosis and in the treatment of disease. Although the physiological mechanisms of oxygen metabolism have been known for many years, the role played by oxidative stress in physiology and medicine is not completely understood. The impact of oxygen-derived free radicals on physiology and disease is a topic of increasing importance in medicine and biology. It is known that disease and injury can lead to levels of free radicals which far exceed the body's natural antioxidant capacity--the result is oxidative stress. Oxidative stress is the physiological manifestation of uncontrolled free radical toxicity, most notably that which results from toxic oxygen-related species. Toxic free radicals are implicated as a causative factor in many pathologic states, including ischemia-reperfusion injury resulting from heart attack or stroke, shock, alopecia, sepsis, apoptosis, certain drug toxicities, toxicities resulting from oxygen therapy in the treatment of pulmonary disease, clinical or accidental exposure to ionizing radiation, trauma, closed head injury, burns, psoriasis, in the aging process, and many others. Therefore, a need exists for compositions and methods which detoxify free radicals and related toxic species and which are sufficiently active and persistent in the body to avoid being rapidly consumed when increases in free radical concentrations are encountered. Web site: http://www.delphion.com/details?pn=US06458758__ •

Identification of objects of interest using multiple illumination schemes and finding overlap of features in corresponding multiple images Inventor(s): Ravkin; Ilya (Palo Alto, CA) Assignee(s): Applied Imaging Corporation (Santa Clara, CA) Patent Number: 6,633,662 Date filed: July 9, 2001 Abstract: Detection of fetal nucleated red blood cells (NRBCs) is achieved by employing a combination of brightfield and fluorescence images of nuclear and cytoplasmic markers. The brightfield and fluorescence images are all obtained with a single multibandpass dichroic mirror. The objects in the sample are stained with a fluorescent dye that selectively stains nuclei and a dye that selectively stains fetal hemoglobin in the cytoplasm of fetal RBCs. UV excitation provides fluorescent emissions from the stained cell nuclei and visible illumination provides brightfield transmission of light that is absorbed by the stained cytoplasm. The images are processed to determine regions

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where the fluorescent emissions by cell nuclei in response to the UV excitation and the absorption by fetal hemoglobin of the brightfield illumination overlap or are in close proximity. The brightfield and fluorescence images may be sequentially acquired or derived from a single image where the UV excitation and visible illumination occur simultaneously. Excerpt(s): The present invention relates generally to image processing, and more particularly to identifying objects of interest in a sample. It is known to perform image processing on images of biological samples where different dyes are caused to reside on different portions of the sample, each dye residing on a particular feature that characterizes an object of interest. The sample is then illuminated and imaged in a manner that the different features of interest can be distinguished from each other and from the background. This typically entails acquiring separate images using the appropriate light sources, filters, and optical setup so that each image's particular type of feature appears recognizably. It is also known that certain brightfield dyes, while nominally assumed to stain different portions of the sample, are not perfectly selective, and stain both features of interest and features not of interest. For example, a dye that is considered to stain nuclei will often also, to a lesser extent, stain cytoplasmic structures. Further, many of the dyes in common use are characterized by a broad absorption spectrum, and therefore objects stained with the dye may show up in images acquired with a different illumination scheme. Web site: http://www.delphion.com/details?pn=US06633662__ •

Laser system and method for treatment of biologic targets Inventor(s): Furumoto; Horace W. (Wellesley, MA) Assignee(s): Cynosure, Inc. (Chelmsford, MA) Patent Number: 6,610,052 Date filed: August 9, 2001 Abstract: A long pulse alexandrite laser for treating dermatological specimens is disclosed. The use of alexandrite allows operation in the near-infrared, specifically in a 50 nm range surrounding 755. Infrared in this range allows good penetration while still achieving an acceptable ratio of hemoglobin to melanin absorption. In operation, the laser generates pulses having a durations between 5 and 100 msec and fluences between 10 and 50 J/cm.sup.2. A light delivery system is provided that transmits the laser light output pulse to dermatological targets of a patient. The invention is also directed to a hair removal system. Here, it is desirable to use an index-matching application on the skin sections to be treated, and a visual indicator is thermo- or photo-responsive or otherwise responsive to the laser light pulse to generate a visible change. Also, the invention is directed to a combined sclerotherapy and light treatment method and kit for unwanted veins. Substantially increased success has been achieved by implementing a dwell time of between 12 hours and 6 months between the light-based therapy and the sclerotherapy. Finally, the invention relates to pulse periodic heating of biologic targets, including systems and methods for generating an effective light output pulse comprising a series of sub-pulses with a limited duty cycle and a periodicity that is less than the thermal relaxation time of the targeted structure. Excerpt(s): The principle of selective photothermolysis underlies many laser therapies and is used to treat such diverse dermatological problems as leg veins, portwine stain birthmarks, other ectatic vascular lesions, and pigmented lesions including tattoos. The

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dermal and epidermal layers containing the targeted structures are irradiated with light, usually from lasers or flashlamps. The wavelength or color of this light is chosen so that its energy will be preferentially or selectively absorbed in the structures. This leads to the localized heating with the intent of raising the temperature to a point at which constituent proteins will denature or pigment particles will disperse. The pulse duration of the irradiating light is also important for selectivity. If the pulse duration is too long, heat absorbed by the structures will diffuse out into the surrounding tissues and will not be selectively heated to the degree necessary. If the pulse durations are too short, however, the light absorbing chemical species such as blood hemoglobin or tattoo dye particle will be heated too quickly causing vaporization. Theory dictates that the proper pulse width should match the thermal diffusion time of the targeted structures. For smaller vessels contained in portwine stain birthmarks, for example, these thermal diffusion times can be on the order of hundreds of microseconds (.mu.sec) to several milliseconds (msec). Larger leg veins have thermal diffusion times in the 5 to 100 msec range. Pigmented lesion particles can have diffusion times as short as nanoseconds (nsec). Various types of lasers have been tested for selective photothermolysis in dermatological specimens. Q-switched alexandrite lasers have been successfully used to treat naturally occurring dermatological pigmentations and also tattoos. Long-pulsed ruby lasers have been proposed for the removal of hair. Nd:YAG lasers (operating at 1060 nm), carbon dioxide (operating at 10.6 micrometers), and argon (operating in the 488-514 nm range) have been suggested for the treatment of ectatic vessels. The most successful vascular treatments have been achieved using dye lasers, and specifically flashlamp-excited pulse dye lasers. These lasers operate in the 577-585 nm range where there are absorption band peaks for hemoglobin and also operate well in the pulsed mode that provides for good selectivity. With the proper selection of color and pulse duration, success rates of higher than 50% are common when treating smaller vessels. Unfortunately, dye lasers are limited in pulse durations to less than 1.5 milliseconds. Thus, they tend to be inappropriate for the treatment of larger structures that would require pulse durations of hundreds of milliseconds, at least according to the principle. Attempts are being made to solve this problem. Frequency doubling Nd:YAG has been proposed as a technique to generate long pulses at 532 nm. Web site: http://www.delphion.com/details?pn=US06610052__ •

Low oxygen affinity mutant hemoglobins Inventor(s): Fang; Tsuei-Yun (Yunlin, TW), Ho; Chien (Pittsburgh, PA), Shen; Tong-Jian (Pittsburgh, PA), Tsai; Ching-Hsuan (Pittsburgh, PA) Assignee(s): Carnegie Mellon University (Pittsburgh, PA) Patent Number: 6,486,123 Date filed: June 21, 2000 Abstract: Non-naturally occurring mutant hemoglobins rHb (.beta.N108Q) and rHb (.beta.L105W) are provided that have a lower oxygen affinity than that of native hemoglobin, but high cooperativity in oxygen binding. rHb (.beta.N108Q) also exhibits enhanced stability against autoxidation. The mutant hemoglobins are preferably produced by recombinant DNA techniques. Such mutant hemoglobins may be used as a component of a blood substitute and hemoglobin therapeutics. Excerpt(s): This invention relates generally to novel mutant hemoglobins and more particularly relates to recombinant mutant hemoglobins "rHb (.beta.N108Q)" (alternative designation "rHb (.beta.108Asn.fwdarw.Gln)") and "rHb (.beta.L105W)"

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(alternative designation "rHb (.beta.105Leu.fwdarw.Trp") that possess low oxygen affinity, and high cooperativity in oxygen binding. In particular, rHb (.beta.N108Q) exhibits increased resistance to autoxidation as compared to other known low oxygen affinity mutants. This invention further relates to the preparation of mutant hemoglobins using recombinant DNA technology that are useful as substitutes for red blood cells and for hemoglobin-based therapeutics. The prevalence of infectious agents such as HIV and hepatitis in red blood cells of human blood products coupled with blood shortages from lack of suitable donors has led to great interest in the development of red blood cell substitutes, particularly human hemoglobin ("Hb") and its derivatives. Hemoglobin-based oxygen carriers are potential sources of blood substitutes during emergency medical situation See for example Winslow, R. M., et al. Hemoglobin-Based Red Cell Substitutes, Johns Hopkins University Press, Baltimore (1992) (hereinafter "Winslow, et al. (1992)"), the disclosure of which is incorporated herein by reference. Hemoglobin is the oxygen-carrying component of blood, circulated through the blood stream inside erythrocytes (red blood cells). Human normal adult hemoglobin ("Hb A") is a tetrameric protein with a molecular weight of about 64,500 containing two identical a chains having 141 amino acid residues each and two identical.beta. chains having 146 amino acid residues each, with each also bearing prosthetic groups known as hemes. The erythrocytes help maintain hemoglobin in its reduced, functional form. The hemeiron atom is susceptible to oxidation, but may be reduced again by one of two systems within the erythrocyte, the cytochrome b.sub.5, and glutathione reduction systems. For a review on hemoglobin, see, Dickerson, R. E., et al. Hemoglobin: Structure, Function, Evolution, and Pathology pp. 22-24. Benjamin/Cummings, Menlo Park, Calif. (1983) (hereinafter "Dickerson, et al. (1983)"), the disclosure of which is incorporated herein by reference. Web site: http://www.delphion.com/details?pn=US06486123__ •

Lytic reagent composition for determination of nucleated blood cells Inventor(s): Li; Jing (Miami, FL), Li; Yi (Miami, FL) Assignee(s): Coulter International Corp. (Miami, FL) Patent Number: 6,573,102 Date filed: July 27, 2001 Abstract: A lytic reagent composition for measuring nucleated blood cells in a blood sample is described. The lytic reagent composition contains a quaternary ammonium surfactant, an ethoxylated phenol, and an ethoxylated alcohol. When mixed with a blood sample, the lytic reagent composition lyses red blood cells and enables a differentiation of nucleated red blood cells from other cell types by DC impedance measurement. The lytic reagent composition can further contain an organic ligand for determining total hemoglobin concentration of a blood sample photometrically. Further disclosed is a lytic reagent system including the lytic reagent composition and a diluent. In addition, a single reagent composition containing salts is also disclosed, which can be used without a separate diluent. The lytic reagent compositions can be used for concurrent measurement of nucleated red blood cells, WBC, and hemoglobin of a blood sample. Excerpt(s): The present invention relates to a lytic reagent composition for determination of nucleated blood cells in a blood sample. More specifically the lytic reagent composition enables differentiation of nucleated red blood cells from other cell types in a blood sample by a direct current impedance measurement. In addition, the

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lytic reagent composition can further be used for measuring total hemoglobin concentration of the blood sample. Normal peripheral blood contains mature red blood cells which are free of nucleus. Nucleated red blood cells (NRBCs), or erythroblasts, are immature red blood cells. They normally occur in the bone marrow but not in peripheral blood. However, in certain diseases such as anemia and leukemia, NRBCs also occur in peripheral blood. Therefore, it is of clinical importance to measure NRBCs. Traditionally, differentiation and enumeration of NRBC are performed manually. The process involves the smearing of a blood sample on a microscope slide and staining the slide, followed by manual visual analysis of the individual slide. The NRBC concentration is reported as numbers of NRBC per 100 white blood cells. Usually, 200 white blood cells and the numbers of NRBC present in the same region on a blood smear are counted and the numbers are divided by 2 to express the NRBC concentration as the numbers of NRBC/100 WBC. This approach is extremely time-consuming as well as being subjective to the interpretation of the individual analyzing the slide. In recent years, several fluorescence flow cytometry methods have been developed for differentiating NRBCs. These methods utilizes specific nuclear staining technique to distinguish NRBCs from other cell types because it is difficult to differentiate NRBCs based on their electronic or optical properties. Web site: http://www.delphion.com/details?pn=US06573102__ •

Method and apparatus for determining oxygen saturation of blood in body organs Inventor(s): Jobsis; Frans F. (1834 Bushy Cook Rd., Efland, NC 27243), Jobsis; Paul D. (647 Chestnut St., Dubuque, IA 52001) Assignee(s): none reported Patent Number: 6,594,513 Date filed: January 12, 2000 Abstract: A spectrophotometric method and apparatus for determining the degree of oxygen saturation of the hemoglobin in the blood within a body part utilizes differences in light absorption based on differences in extinction coefficients at different wavelengths. Oxygen saturation is determined by utilizing absorption at three or more wavelengths of radiation preferably in the near red and infrared region (NIR) of the spectrum, specifically tailored to two or more components to be detected by the radiation. The first (reference) wavelength is preferably chosen to be at an isosbestic point for the two components, commonly the oxygenated and deoxygenated forms of hemoglobin. The absorption at the isosbestic point is subtracted from the absorption at the other wavelengths. Using these differences in absorption, the amount of each of the components encountered by the light may be determined without determination of pathlength, which would be required to determine the concentration. In order to determine the oxygenation state, i.e. ratio of oxygenated to deoxygentaed blood components, knowledge of the relative amounts suffices. Interference from other lightabsorbing components, specifically those that respond to the oxygenation state of the body part (such as cytochrome c oxidase) is in the three wavelength method eliminated by reiterative correction. Excerpt(s): This invention relates to spectrophotometric methods and apparatus for quantitatively determining the degree of oxygen saturation of the hemoglobin in the blood within a body part or organ, and in particular pertains to determination of the percent oxygen saturation of intra-cerebral blood. It is generally known that metabolism and more particularly oxygen sufficiency and adequacy of utilization are parameters of

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fundamental importance in assessing the function of any body organ. This is made selfevident when one considers that the energy provision for tissue function is underwritten for better than 90 percent by oxidative reactions involving the reduction of O.sub.2 to H.sub.2 O. In the absence of sufficient oxygen, this process becomes impaired with a corresponding impairment in organ function. Also recognized is the fact that an excess of oxygen also impairs organ function. For ease of explanation, the description to follow is based primarily on considering the effect of an insufficiency rather than an excess of oxygen. In instances of extensive oxygen deprivation, over a period of time the organ loses viability and as a result the individual often has the same fate, especially if that organ is the brain. Although all organs are adversely affected by oxygen insufficiency, perhaps the problem is most acute in the case of the brain because of its complete dependence on oxidative metabolism for proper function and viability. For example, an absence of oxygen in the brain for more than a dozen seconds produces dysfunction and an absence for longer than a few minutes spells irreversible damage. A less acute impairment of oxygen availability leads to a gradual loss in brain function, especially with respect to the higher centers of the cerebral cortex. An excess of oxygen will also adversely affect the brain. For example, a neo-natal patient may well go blind by reason of excess oxygen. Web site: http://www.delphion.com/details?pn=US06594513__ •

Method and apparatus for improving the accuracy of noninvasive hematocrit measurements Inventor(s): Schmitt; Joseph M. (Andover, MA) Assignee(s): Nellcor Puritan Bennett Incorporated (Pleasanton, CA) Patent Number: 6,606,509 Date filed: March 16, 2001 Abstract: A device and a method to provide a more reliable and accurate measurement of hematocrit (Hct) by noninvasive means. The changes in the intensities of light of multiple wavelengths transmitted through or reflected light from the tissue location are recorded immediately before and after occluding the flow of venous blood from the tissue location with an occlusion device positioned near the tissue location. As the venous return stops and the incoming arterial blood expands the blood vessels, the light intensities measured within a particular band of near-infrared wavelengths decrease in proportion to the volume of hemoglobin in the tissue location; those intensities measured within a separate band of wavelengths in which water absorbs respond to the difference between the water fractions within the blood and the displaced tissue volume. A mathematical algorithm applied to the time-varying intensities yields a quantitative estimate of the absolute concentration of hemoglobin in the blood. To compensate for the effect of the unknown fraction of water in the extravascular tissue on the Hct measurement, the tissue water fraction is determined before the occlusion cycle begins by measuring the diffuse transmittance or reflectance spectra of the tissue at selected wavelengths. Excerpt(s): This invention relates to systems and methods for spectrophotometric measurement of biochemical compounds in the skin for non-invasive medical diagnosis and monitoring. Specifically, the present invention relates to the determination of the hematocrit or the absolute concentration of hemoglobin in the blood by multiplewavelength optical plethysmography. The total concentration of hemoglobin in blood (Hb.sub.T) or the hematocrit (Hct), defined as the fraction or percentage of red cells in

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whole blood, are primary variables used by physicians to assess the health of a patient. The hematocrit is the fraction of the total blood volume occupied by the red blood cells, and hemoglobin is the principal active constituent of red blood cells. Approximately 34% of the red cell volume is occupied by hemoglobin. A value of Hb.sub.T less than 10 g/dl or Hct <0.30 indicates an anemic state which can impair the normal functions of the body. Severe anemia can lead to death when the quantity of hemoglobin becomes insufficient to supply oxygen to the brain and other vital organs. Patients with kidney disease, pregnant women, and young children in developing countries are especially susceptible to chronic anemia. Acute anemia resulting from loss of blood, infection, or autoimmune disorders can be life-threatening and requires close monitoring. The conventional means employed to measure Hct in clinical medicine is to puncture the skin, draw blood from a vein or capillary into a small-diameter tube, and measure the solid (packed-cell) fraction that remains after centrifugation of the blood. Measurement of Hb.sub.T in accordance with standard practice also requires drawing a blood sample, which is then subjected to a chemical or mechanical process to lyse the red cells and release the liquid hemoglobin. After transferring the hemoglobin to a cuvette, its concentration is measured either by direct spectrophotometry or by colorimetry following the addition of a chemical reagent. Web site: http://www.delphion.com/details?pn=US06606509__ •

Method and apparatus for preparing an acellular red blood cell substitute Inventor(s): DeWoskin; Richard E. (St. Charles, IL), Doubleday; Marc D. (Cary, IL) Assignee(s): Northfield Laboratories, Inc. (Evanston, IL) Patent Number: 6,498,141 Date filed: May 10, 1999 Abstract: A process is disclosed for the preparation of an essentially tetramer-free, substantially stroma-free, polymerized, pyridoxylated hemoglobin. Also disclosed is an essentially tetramer-free, substantially stroma-free, polymerized, pyridoxylated hemoglobin product capable of being infused into human patients in an amount of up to about 5 liters. Excerpt(s): This invention relates to methods and apparatus for preparing red blood cell substitute products, i.e., hemoglobin products. It further relates to an acellular red blood cell substitute comprising an essentially tetramer-free, cross linked, polymerized, pyridoxylated hemoglobin solution which is free of stromal contaminants. For a number of years, blood banks have provided whole blood for replacement during surgery, because of trauma, or for other situations. However, whole blood obtained from human donors is not suitable for a variety of uses. In particular, the use of whole blood is problematic because of the requirement for donor-typing, stability and shelf-life problems and toxicity caused by viruses and other contaminants. These problems are especially pertinent to emergency situations, such as the use of blood by the military. Consequently, much effort has been devoted to the development of substitutes for whole blood obtained from human donors. This development has resulted in various modifications to blood from human or other mammalian sources. Stroma-free hemoglobin is known in the art to have oxygen transport and reversible oxygen (or ligand) binding capacities. Since toxicity problems have precluded use as a blood substitute, stroma-free hemoglobin has required further modifications to provide a nontoxic, useful pharmaceutical product. These modifications include (1) rendering hemoglobin free or substantially free of stroma and stromal contaminants; (2)

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pyridoxylation; (3) polymerization or cross-linking; (4) removal of tetramer, and (5) modification with carbon monoxide or other ligands. Web site: http://www.delphion.com/details?pn=US06498141__ •

Method for stimulating the production of fetal hemoglobin producing erythroid cells Inventor(s): Bohmer; Ralph M. (Brookline, MA) Assignee(s): New England Medical Center (Boston, MA) Patent Number: 6,617,158 Date filed: August 11, 2000 Abstract: The present invention provides a method for ameliorating.beta.-globin disorders in a mammal. In one aspect of the invention, the treatment involves ex vivo treatment of early erythroid progenitor cells that leads to an increase in the relative amounts of cells subsequently expressing and accumulating HbF. The cell treatment is to be followed by transplantation of the modified cells. In another aspect of the invention, the same modification of progenitor cells occurs in vivo. Both treatments are based on the novel discovery that the modification can be performed very early in the erythroid maturation process, without disturbance of the subsequent proliferation and maturation of the erythroid precursor. The present invention also provides a procedure for the monitoring of.beta.-globinopathies and the response of a patient to treatment. In this aspect of the invention, erythropoiesis of a patient is studied (in vivo or in vitro) by generating profiles of correlated contents of different types of hemoglobin present in nucleated red cells. Excerpt(s): The present invention relates generally to a method for treatment of.beta.hemoglobinopathies. More specifically, this invention relates to the treatment of.beta.hemoglobinopathies by administering a composition that promotes an increase in the relative amount of fetal erythropoiesis. Normal adult hemoglobin comprises four globin proteins, two of which are alpha (.alpha.) proteins and two of which are beta (.beta.) proteins. During fetal development in mammals (particularly in humans) the fetus produces a fetal hemoglobin which comprises two gamma (.gamma.)-globin proteins instead of the two.beta.-globin proteins. At some point during fetal development or infancy, depending on the particular species and individual, there is a globin switch wherein the erythrocytes in the fetus switch from making predominantly.gamma.globin to making predominantly.beta.-globin. The developmental switch from production of predominantly fetal hemoglobin (HbF,.alpha.sub.2.gamma.sub.2) to production of adult hemoglobin (HbA,.alpha.sub.2.beta.sub.2) occurs beginning at about 28 to 34 weeks of gestation and continues shortly after birth until HbA becomes predominant. This switch results primarily from decreased transcription of the gammaglobin genes and increased transcription of beta-globin genes. The blood of a normal adult contains only about 2% HbF. Peripheral blood contains clonogenic cells that produce erythroid colonies and bursts in semisolid culture, given the appropriate combination of growth factors. Individual cells in such colonies can accumulate fetal hemoglobin (HbF), adult hemoglobin (HbA) or a combination of both. The pattern of hemoglobin expression and accumulation is different in cultures from fetal and adult blood. In cultures from adult blood, nucleated red cells accumulate either HbA (F-A+) only or a combination of HbF and HbA (F+A+). Papayannopoulou, et al., Science 199: 1349-1350 (1978); Migliaccio, et al., Blood 76: 1150-1157 (1990). Individual colonies contain both F+ and F- cells, indicating that both types are progeny from the same circulating stem cells. Thus, during the early stages of development in culture, cells

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execute an option whether or not to express HbF. The proportion of adult F+ cells developing in culture does not appear to be preprogrammed in vivo, but appears to depend on culture conditions: A shift into the combined HbF and HbA expression pathway can, for example, be achieved in vitro by high serum concentrations, due to the activity of an unidentified compound that can be absorbed on activated charcoal. Bohmer, et al., Prenatal Diagnosis 19: 628-636 (1999); Migliaccio, et al., Blood 76: 1150 (1990); Rosenblum, et al., in: Experimental Approaches for the Study of Hemoglobin 397 (1985). Web site: http://www.delphion.com/details?pn=US06617158__ •

Method for treating, controlling, and preventing Diabetes Mellitus Inventor(s): Farouqi; Hafez Taji (Amman, JO), Murad; Osama Mansour (Amman, JO), Seir; Husni Abu (Amman, JO) Assignee(s): Diabex, Inc. (Wake Forest, NC) Patent Number: 6,555,126 Date filed: January 2, 2001 Abstract: This invention pertains to a method that can control, treat, and prevent Diabetes Mellitus. The method includes means of administering a potent product, including mainly the active ingredient Linalool, in any one of several forms, alone or with other additives and catalysts, such as vitamin E to enable the body to handle and control, then correct the complications of Diabetes Mellitus. A modest percentage of users suffering from this disease can be cured completely while the majority of others improve remarkably and experience lower blood glucose and reduce the glycated hemoglobin HbAlc readings to what are medically acceptable and healthy levels. Others, who are vulnerable to the disease due to hereditary factors, or other reasons, can help prevent it. The method works in several ways, including activation of the pancreas and re-establishing the ability of body cells to utilize and handle better and well, the glucose in the blood, and regulate the level of natural insulin in the body. The method employs Linalool in any one of its forms that can be found naturally or synthetically. Excerpt(s): This invention relates to a method that can be used to treat, control, cure, and prevent Diabetes Mellitus, of all types, through the administration of Linalool, alone, in any form, and possibly with other hypoglycemic additives in several forms, and by various means. The method does not cause any harmful or unpleasant side effects. Diabetes Mellitus is a feared and complex disorder. It has been a most distressing disease that can develop to a seriously life threatening condition. For ages, society was resigned to accepting various methods and medications that became a standard with no real hope for a cure, or drastic eradication of the disease. In fact, many of the drugs used cause serious side effects. A most important indicator of the ability of the body to deal with the complications of diabetes is the glycated hemoglobin HbAlc, that gives an integrated reading of the level of blood glucose. While all other known methods and medications help lower the glucose level at limited periods of the day or night time, the HbAlC remains higher than the normal 4.3 to 6.7 range regardless of the insulin dosage and other medicines. No full cure is expected or hoped for by the present regimens. The described method herein is new and unique, and actually reduces the HbAlc reading to the normal levels and for all patients. This method has actually cured some patients of both types I and II diabetes to such a degree that they stopped taking any medication while leading normal lives.

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Web site: http://www.delphion.com/details?pn=US06555126__ •

Method of assessing tissue viability using near-infrared spectroscopy Inventor(s): Mantsch; Henry H. (435 Ellice Avenue, Winnipeg Manitoba, CA R3B 1Y6), Sowa; Michael G. (435 Ellice Avenue, Winnipeg Manitoba, CA R3B 1Y6), Stranc; Miroslaw F. (295 Lindsay Street, Winnipeg Manitoba, CA R3N 1H2) Assignee(s): none reported Patent Number: 6,587,701 Date filed: February 17, 2000 Abstract: Prolonged and severe tissue hypoxia results in tissue necrosis in pedicled flaps. We demonstrate the potential of near-infrared spectroscopy for predicting viability of compromised tissue portions. This approach clearly identifies tissue regions with low oxygen supply, and also the severity of this challenge, in a rapid and noninvasive manner, with a high degree of reproducibility. Tissues remaining below a certain hemoglobin oxygen saturation threshold (oxygen saturation index<1) for prolonged periods (>6 h) became increasingly dehydrated, eventually becoming visibly necrotic. Tissues above this threshold (oxygen saturation index>1), despite being significantly hypoxic relative to the pre-elevation saturation values, remained viable over the 72 h post-elevation monitoring period. The magnitude of the drop in tissue oxygen saturation, as observed immediately following surgery, correlated with the final clinical outcome of the flap tissue. These results indicate the potential of near infrared spectroscopy and imaging to monitor tissue oxygenation status and assess tissue viability following reconstructive surgery. Early, nonsubjective detection of poor tissue oxygenation following surgery increases the likelihood that intervention aimed at saving the tissue will be successful. Excerpt(s): The present invention relates generally to a method of determining tissue viability. More specifically, the present invention relates to a non-invasive method of determining tissue viability using visible and near-infrared spectroscopy. In surgery, the ability to determine whether or not a tissue will survive is of paramount importance. This is particularly true in plastic surgery where efforts to develop a reliable method to predict skin flap viability are ongoing. It is therefore not surprising that efforts to develop a reliable method to predict tissue viability go back to the very beginnings of plastic surgery. Clinical assessment, based on observations of color, temperature and capillary perfusion have always been, and remain, the basis of good management. However, the clinical signs which arise as a consequence of poor blood perfusion along the flap become evident only after several hours of compromised perfusion. Prolonged and severe deprivation of oxygen and other nutrients to the tissues results in irreversible tissue damage leading to necrosis and loss of tissue. Early, nonsubjective detection of poor tissue oxygenation following surgery increases the likelihood that intervention aimed at saving the tissue will be successful. As a consequence, a variety of methods have evolved over the years to augment clinical judgement. Broadly speaking, these methods fall into two categories: those that are based on an assessment of blood flow within tissues and those that examine the cellular metabolism within tissues. Early studies depended on the use of pharmacological agents to assess blood flow (Hynes, 1948, Br J Plast Surg 1:159-171; Conway et al, 1951, Surg Gynecol Obstet 93:185-189). It was soon realized that the use of pharmacologic agents gave inconsistent results which were difficult to interpret. Web site: http://www.delphion.com/details?pn=US06587701__

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Method of separating hemoglobin A2 Inventor(s): Kawabe; Toshiki (Shiga, JP), Oishi; Kazuyuki (Tokuyama, JP), Setoguchi; Yuji (Shinnanyo, JP), Shimada; Kazuhiko (Tokuyama, JP) Assignee(s): Sekisui Chemical Co., Ltd. (Osaka, JP) Patent Number: 6,488,857 Date filed: April 18, 2001 Abstract: A method for separating hemoglobin A.sub.2 from a hemoglobin mixture according to a cation exchange liquid chromatography characterized that at least two types of eluents are used including an eluent (hereinafter referred to as "eluent A") for elution of faster hemoglobins than hemoglobin A.sub.0 and an eluent (hereinafter referred to as "eluent B") for elution of hemoglobin A.sub.0 and slower hemoglobins than hemoglobin A.sub.0, and that the eluent A has a pH of 4.0-6.0 and the eluent B is maintained at a pH of at least 0.5 higher than that of the eluent A. Excerpt(s): The present invention relates to a method for separating hemoglobin A.sub.2 by cation exchange liquid chromatography. Hemoglobin A.sub.2 is composed of.alpha. and.delta. chains, and is used, like hemoglobin F, as a diagnostic indicator of Mediterranean anemia (thalassemia). For testing of Mediterranean anemia, cation exchange liquid chromatography is generally employed to separate from a hemoglobin mixture and quantitate hemoglobin A.sub.2 (hereinafter referred to as HbA.sub.2). Separation of a hemoglobin mixture, i.e., a hemolyzed sample, with the use of cation exchange liqud chromatography generally results in the appearance of peaks of hemoglobin A.sub.1a (hereinafter referred to as HbA.sub.1a ) and hemoglobin A.sub.1b (hereinafter referred to as HbA.sub.1b), hemoglobin F (hereinafter referred to as HbF), labile hemoglobin A.sub.1c, (hereinafter referred to as labile HbA.sub.1c), stable hemoglobin A.sub.1c (hereinafter referred to as stable HbA.sub.1c), hemoglobin A.sub.0 (hereinafter referred to as HbA.sub.0) and the like. On this occasion, an extended time has been required to achieve complete separation of HbA.sub.0 and HbA.sub.2 from each other since they show the similar retention behaviors with respect to a cation exchange column and their peaks occur in close proximity to each other. Web site: http://www.delphion.com/details?pn=US06488857__

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Multi-channel non-invasive tissue oximeter Inventor(s): Barrett; Bruce J. (Birmingham, MI), Gonopolsky; Oleg (West Bloomfield, MI), Scheuing; Richard S. (Rochester Hills, MI) Assignee(s): Somanetics Corporation (Troy, MI) Patent Number: 6,615,065 Date filed: July 12, 2001 Abstract: A method and apparatus for spectrophotometric in vivo monitoring of blood metabolites such as hemoglobin oxygen concentration at a plurality of different areas or regions on the same organ or test site on an ongoing basis, by applying a plurality of spectrophotometric sensors to a test subject at each of a corresponding plurality of testing sites and coupling each such sensor to a control and processing station, operating each of said sensors to spectrophotometrically irradiate a particular region within the test subject; detecting and receiving the light energy resulting from said spectrophotometric irradiation for each such region and conveying corresponding

Patents 183

signals to said control and processing station, analyzing said conveyed signals to determine preselected blood metabolite data, and visually displaying the data so determined for each of a plurality of said areas or regions in a comparative manner. Excerpt(s): This invention relates generally to in vivo spectrophotometric examination and monitoring of selected blood metabolites or constituents in human and/or other living subjects, e.g., medical patients, and more particularly to spectrophotometric oximetry, by transmitting selected wavelengths (spectra) of light into a given area of the test subject, receiving the resulting light as it leaves the subject at predetermined locations, and analyzing the received light to determine the desired constituent data based on the spectral absorption which has occurred, from which metabolic information such as blood oxygen saturation may be computed for the particular volume of tissue through which the light spectra have passed. A considerable amount of scientific data and writings, as well as prior patents, now exist which is/are based on research and clinical studies done in the above-noted area of investigation, validating the underlying technology and describing or commenting on various attributes and proposed or actual applications of such technology. One such application and field of use is the widespread clinical usage of pulse oximeters as of the present point in time, which typically utilize sensors applied to body extremities such as fingers, toes, earlobes, etc., where arterial vasculature is in close proximity, from which arterial hemoglobin oxygenation may be determined non-invasively. A further and important extension of such technology is disclosed and discussed in U.S. Pat. No. 5,902,235, which is related to and commonly owned with the present application and directed to a non-invasive spectrophotometric cerebral oximeter, by which blood oxygen saturation in the brain may be non-invasively determined through the use of an optical sensor having light emitters and detectors that is applied to the forehead of the patient. Earlier patents commonly owned with the '235 patent and the present one pertaining to various attributes of and applications for the underlying technology include U.S. Pat. Nos. 5,139,025; 5,217,013; 5,465,714; 5,482,034; and 5,584,296. The cerebral oximeter of the aforementioned '235 patent has proved to be an effective and highly desirable clinical instrument, since it provides uniquely important medical information with respect to brain condition (hemoglobin oxygen saturation within the brain, which is directly indicative of the single most basic and important life parameter, i.e. brain vitality). This information was not previously available, despite its great importance, since there really is no detectable arterial pulse within brain tissue itself with respect to which pulse oximetry could be utilized even if it could be effectively utilized in such an interior location (which is very doubtful), and this determination therefore requires a substantially different kind of apparatus and determination analysis. In addition, there are a number of uniquely complicating factors, including the fact that there is both arterial and venous vasculature present in the skin and underlying tissue through which the examining light spectra must pass during both entry to and exit from the brain, and this would distort and/or obscure the brain examination data if excluded in some way. Furthermore, the overall blood supply within the skull and the brain itself consists of a composite of arterial, venous, and capillary blood, as well as some pooled blood, and each of these are differently oxygenated. In addition, the absorption and scatter effects on the examination light spectra are much greater in the brain and its environment than in ordinary tissue, and this tends to result in extremely low-level electrical signal outputs from the detectors for analysis, producing difficult signal-to-noise problems. Web site: http://www.delphion.com/details?pn=US06615065__

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Multi-purpose reagent system and method for enumeration of red blood cells, white blood cells and thrombocytes and differential determination of white blood cells Inventor(s): Carter, II; James Harrison (Plantation, FL), Crews; Harold Richardson (Coral Springs, FL), Sena; Ted (Naples, FL) Assignee(s): Clinical Diagnostic Solutions (Plantation, FL) Patent Number: 6,632,676 Date filed: September 24, 1999 Abstract: A novel reagent system for use with automated and semi-automated hematology analyzers including an essentially isotonic blood diluting reagent, a blood cell lysing and hemoglobin conversion reagent, and a second lysing reagent for differentiating white blood cells into classes by size and functional characteristics. The diluent reagent enhances properties for counting and sizing blood specimens, while stabilizing cellular volume and cellular integrity for many hours. The blood cell lysing reagent removes red blood cells and enables subsequent enumeration of white blood cells and simultaneous determination of hemoglobin without use of the toxic cyanide anion. The third lysing reagent and a companion quenching differentiates blood cells into classes by size and functional characteristics, based on d.c. impedance volume, conductivity/opacity and light scatter measurements. The companion quenching reagent adjusts pH and conductivity of the final measurement solution to match the analyzer system requirements. Novel methods for use of the reagents with automated and semi-automated hematology analyzers are also provided. Excerpt(s): The invention relates to a multi-purpose reagent system and method for enumeration of red blood cells, white blood cells and thrombocytes and differential determination of white blood cells. The art recognizes that the ability to resolve the various populations of blood cells into their constituent classes, particularly those of the leukocytes, provides an invaluable diagnostic aid in the study, diagnosis and treatment of various diseases. As is further appreciated, the greater the number of sub-populations that are identifiable and enumeratable, the more accurate and reliable the identification of any single sub-population is likely to be. Previous scientific publications and patents have described reagents and methods for enumerating these cell types by a variety of mechanisms. U.S. Pat. No. 4,485,175 (to Ledis, et al.) describes a reagent system comprising a multipurpose blood diluent and a lysing reagent, and a method for utilizing same to produce a hemoglobin measurement and differentiation of white blood cells into at least one and up to three sub-populations of leukocytes. U.S. Pat. No. 5,731,206 (to Ledis, et al.) describes a lytic reagent composition, a kit of a lytic reagent system and a method for isolating, identifying and analysis of at least one and up to five sub-populations of leukocytes from a whole blood sample. Other representative patent references pertinent to this field include U.S. Pat. Nos. 3,874,852; 4,286,963; 4,346,018; 4,528,274 and 4,751,179. All are hereby incorporated by reference in their entirety. Web site: http://www.delphion.com/details?pn=US06632676__

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No-modified hemoglobins and uses therefor Inventor(s): Gow; Andrew J. (Durham, NC), Stamler; Jonathan S. (Chapel Hill, NC) Assignee(s): Duke University (Durham, NC) Patent Number: 6,627,738 Date filed: August 6, 1999

Patents 185

Abstract: Nitrosylhemoglobin can be produced by introducing gaseous NO into an aqueous solution of hemoglobin. It has been demonstrated that nitrosylhemoglobin in aqueous solution can be converted to SNO-hemoglobin upon introduction of oxygen to the solution, as is postulated to occur in the lungs. Nitrosylhemoglobin can be used in methods to produce the physiological effects of NO, for example, to reduce vasoconstriction and to inhibit platelet aggregation. Excerpt(s): Interactions of hemoglobin (Hb) with small diffusible ligands, such as O.sub.2, CO.sub.2 and NO, are known to occur at its metal centers and amino termini. The O.sub.2 /CO.sub.2 delivery functions, which arise in the lung and systemic microvasculature, are allosterically controlled. Such responsiveness to the environment has not been known to apply in the case of NO. Specifically, it has been thought previously that NO does not modify the functional properties of Hb to any physiologically significant degree. Kinetic modeling predicts that the vast majority of free NO in the vasculature should be scavenged by Hb (Lancaster 1994). Accordingly, the steady-state level of NO may fall below the K.sub.m for target enzymes such as guanylate cyclase (Lancaster 1994), if not in the unperturbed organism, then with oxidant stress such as that found in atherosclerosis. These considerations raise the fundamental question of how NO exerts its biological activity. One answer to this question is found in the propensity of nitric oxide to form S-nitrosothiols (RSNOS) (Gaston, B. et al., Proc. Natl. Acad. Sci. USA 90:10957-10961 (1993)), which retain NOlike vasorelaxant activity (Stamler, J. S., et al., Proc. Natl. Acad. Sci. USA 89:444-448 (1992)), but which can pass freely in and out of cells, unlike Hb. In particular, the NO group of RSNOs possesses nitrosonium (NO.sup.+) character that distinguishes it from NO itself. It is increasingly appreciated that RSNOs have the capacity to elicit certain functions that NO is incapable of (DeGroote, M. A. et al., Proc. Natl. Acad. Sci. USA 92:6399-6403 (1995); Stamler, J. S., Cell 78:931-936 (1994)). Moreover, consideration has been given to the possibility that --SNO groups in proteins serve a signaling function, perhaps analogous to phosphorylation (Stamler, J. S. et al., Proc. Natl. Acad. Sci. USA 89:444-448 (1992); Stamler, J. S. Cell, 78:931-926 (1994)). Although S-nitrosylation of proteins can regulate protein function (Stamler, J. S. et al., Proc. Natl. Acad. Sci. USA 89:444-448 (1992); Stamler, J. S., Cell, 78:931-936 (1994)), intracellular S-nitrosoproteins-the sine qua non of a regulatory posttranslational modification--has heretofore not been demonstrated. Hemoglobin is a tetramer composed of two alpha and two beta subunits. In human Hb, each subunit contains one heme, while the beta (.beta.) subunits also contain highly reactive SH groups (cys.beta.93) (Olson, J. S., Methods in Enzymology 76:631-651 (1981); Antonini, E. & Brunori, M. In Hemoglobin and Myoglobin in Their Reactions with Ligands, American Elsevier Publishing Co., Inc., New York, pp. 29-31 (1971)). These cysteine residues are highly conserved among species although their function has remained elusive. Web site: http://www.delphion.com/details?pn=US06627738__ •

Non-invasive measurement of blood components using retinal imaging Inventor(s): Rice; Mark J. (Johnson City, TN), Rioux; James M. (Lexington, KY), Routt; Wilson (Lexington, KY), Sweat, Jr.; Robert H. (Lexington, KY), Williams; William T. (Jonesborough, TN) Assignee(s): Fovioptics, Inc. (Lexington, KY) Patent Number: 6,477,394 Date filed: September 12, 2001

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Abstract: Illuminating light of selected wavelengths in the visible or infrared range is projected through the pupil of the eye onto the fundus, and the light reflected back and out through the pupil is detected and analyzed, preferably using the area of the optic disk for analyzing the retinal vessels overlying the optic disk. Specific wavelengths of illuminating light may be chosen for each blood component to be analyzed depending on the spectral characteristics of the substance being analyzed. The reflected image from the retina may be used to measure non-photoreactive blood components such as hemoglobin, and photoreactive components such as bilirubin. For the measurement of photoreactive components, images may be taken before and after, or during, illumination of the eye with light at wavelengths which will affect the photoreactive analyte, enabling measurements of the concentration of the analyte. Excerpt(s): This invention pertains to the field of non-invasive in vivo measurement of blood components such as glucose, hemoglobin, and bilirubin. The measurement of the concentration of blood components such as hemoglobin and glucose has required the drawing of a blood sample for in vitro analysis. The need to draw blood for analysis is undesirable for several reasons, including discomfort to the patient, the time required of medical personnel to draw and handle the samples, and the potential risk of spread of disease through punctures of the skin. Repeated drawing of blood samples is especially undesirable in infants. Many diabetics must test their blood up to six times a day to monitor their blood glucose levels. It would thus be desirable to be able to obtain fast and reliable estimates of the concentration of blood components in blood, such as hemoglobin and glucose, through a simple and non-invasive technique. Prior efforts have involved an examination of blood in the skin or extremities, such as fingers and ear lobes, or in observable surface blood vessels, but these efforts have had limited practical success due to the presence of tissue components that interfere with accurate reading of only the concentration of blood components. There are approximately four million newborns in the United States alone each year. About 50% of newborns are clinically jaundiced from elevated bilirubin levels. If the serum bilirubin reaches very high levels during the post-natal period, kernicterus, neural damage resulting from sustained high levels of serum bilirubin, may occur. Frequent monitoring of serum bilirubin is critical to the care of these infants. Of the newborns that have recognizable jaundice during the first 5 days of life, 1.7 million receive at least one blood test for bilirubin. Of those tested, about 700,000 undergo phototherapy treatment; these infants receive an estimated two to three additional blood tests. Presently, blood is drawn through the heel of the neonate, resulting in occasional infections and other complications. Other drawbacks to this process are its high cost and the delay in lab results reaching the physician. Recently introduced non-invasive devices for measuring bilirubin do not provide the accuracy level required to diagnose or treat elevated serum bilirubin levels, rendering them virtually useless in practice. Web site: http://www.delphion.com/details?pn=US06477394__ •

Non-invasive method for optimizing the respiration of atelectatic lungs Inventor(s): Bohm; Stephan (Kegelhofstrasse 22, D-20251 Hamburg-Eppendorf, DE), Leonhardt; Steffen (Arnimstrasse 10b, D-23566 Lubeck, DE) Assignee(s): none reported Patent Number: 6,612,995 Date filed: July 26, 2001

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Abstract: The invention relates to a method and an apparatus to identify alveolar opening and collapse of a lung. To automatically generate the settings of ventilator parameters in a simple and gentle way, the hemoglobin oxygen saturation and/or the endtidal CO.sub.2 concentration and/or the CO.sub.2 output are-measured and processed to detect alveolar opening and closing. From the knowledge of the corresponding airway pressures, a central processing unit may generate the settings of ventilation parameters such that gas exchange is maximal while the mechanical stress of the lung tissue is minimal. Excerpt(s): The present invention relates to a method and an apparatus to determine the alveolar opening and/or closing of a lung. Such a method and such an apparatus are especially useful to optimally set the control variables of an artificial ventilator as both the alveolar opening and the alveolar closing are important parameters of an atelectatic (=partially collapsed) lung. In German intensive care units (ICUs), approximately 8.00010.000 are artificially ventilated each day. The ventilator control variables, such as airway pressure (P.sub.aw) and respiratory rate (RR), are usually chosen based on known standard procedures, but often left constant afterwards and not adapted to the changing needs of a specific patient. Web site: http://www.delphion.com/details?pn=US06612995__ •

Preserving a hemoglobin blood substitute with a transparent overwrap Inventor(s): Gawryl; Maria S. (Charlestown, MA), Houtchens; Robert A. (Milford, MA), Light; William R. (Natick, MA) Assignee(s): Biopure Corporation (Cambridge, MA) Patent Number: 6,610,832 Date filed: July 7, 1999 Abstract: The invention relates to a method for preserving the stability of a hemoglobin blood substitute comprising maintaining the hemoglobin blood substitute in an atmosphere substantially free of oxygen. The invention also involves a method for producing a stable polymerized hemoglobin blood-substitute from blood. The method of this invention includes mixing blood with an anticoagulant to form a blood solution, washing the red blood cells in the blood solution and then separating the washed red blood cells from the white blood cells. This method also includes disrupting the red blood cells to release hemoglobin and form a hemoglobin solution, which is then treated by high performance liquid chromatography to form a hemoglobin eluate. The hemoglobin eluate is then deoxygenated, contacted with a first sulfhydryl compound to form an oxidation-stabilized deoxygenated hemoglobin solution, and mixed with a cross-linking agent to form a polymerization reaction mixture, which is then polymerized. The polymerized hemoglobin solution is then diafiltered with a physiologic solution and with a sulfhydryl compound, whereby the polymerized hemoglobin solution is made physiologically acceptable, and whereby the sulfhydryl compound scavenges oxygen, to form a stable polymerized hemoglobin bloodsubstitute, which is then packaged and stored in an atmosphere substantially free of oxygen. Excerpt(s): There exists a need for a blood-substitute to treat or prevent hypoxia resulting from blood loss (e.g, from acute hemorrhage or during surgical operations), resulting from anemia (e.g., pernicious anemia or sickle cell anemia), or resulting from shock (e.g, volume deficiency shock, anaphylactic shock, septic shock or allergic shock).

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The use of blood and blood fractions as in these capacities as a blood-substitute is fraught with disadvantages. For example, the use of whole blood often is accompanied by the risk of transmission of hepatitis-producing viruses and AIDS-producing viruses which can complicate patient recovery or result in patient fatalities. Additionally, the use of whole blood requires blood-typing and cross-matching to avoid immunohematological problems and interdonor incompatibility. Human hemoglobin, as a blood-substitute, possesses osmotic activity and the ability to transport and transfer oxygen, but it has the disadvantage of rapid elimination from circulation by the renal route and through vascular walls, resulting in a very short, and therefore, a typically unsatisfactory half-life. Further, human hemoglobin is also frequently contaminated with toxic levels of endotoxins, bacteria and/or viruses. Non-human hemoglobin suffers from the same deficiencies as human hemoglobin. In addition, hemoglobin from non-human sources is also typically contaminated with proteins, such as antibodies, which could cause an immune system response in the recipient. Web site: http://www.delphion.com/details?pn=US06610832__ •

Probe for localized tissue spectroscopy Inventor(s): Khan; Tania (Worcester, MA), Soller; Babs R. (Northboro, MA) Assignee(s): University of Massachusetts (Worcester, MA) Patent Number: 6,564,088 Date filed: January 22, 2001 Abstract: An optical probe structure for illuminating and collecting returned light from a region of tissue. The optical probe is configured with illumination and collection windows to controllably collect light from the region of tissue in vivo. The probe is designed to have a defined spacing between the fiber or fibers connected to the light source, and the fiber or fibers connected to the optical detector, so that light reaching the detector has passed through a localized region of tissue of a small and well-defined size or dimension. The probe can assay or detect tissue cell distribution, a tissue constituent such as hydrogen ions (pH), lactate, or an endogenous tissue component such as hemoglobin, myoglobin, or lipids in plaque. Measurements may indicate conditions such as metabolic state, stress, shock or ischemia in different tissues. Excerpt(s): The invention relates to a probe for spectroscopic measurement of tissue. Optical spectroscopy is a valuable tool for determining the chemical composition and concentration of specific analytes present in biological material. In vivo applications of optical spectroscopy to tissue include determining tissue pH, distinguishing cancerous from noncancerous tissue, and analyzing atherosclerotic plaque. Often, such a spectroscopic assay proceeds by measurement of a secondary parameter, e.g., an indicator compound for the condition of interest. The signal analysis may also proceed by relatively complex processing, such as correlation of spectral samples with an empirically-compiled database of tissue spectra. Much of the prior work in this area is accomplished by broad illumination of the sample and collection of reflected, transmitted or emitted light from a large area of the sample. By way of example, detection of tissue pH by spectroscopic means has been found to be feasible, and to serve as a reliable indicator of tissue damage. Basically, under conditions of greatly reduced blood flow, hydrogen ions accumulate as anaerobic, metabolism commences, resulting in a tissue pH decline, indicating that the tissue is compromised. Irreversible ischemic damage may occur if tissue pH declines to 6.3 pH units or below. Continuous monitoring of tissue pH with suitably constructed electrodes has been known to provide

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valuable information to the surgeon to assess tissue viability during procedures such as heart surgery, and to monitor post-operative metabolism and blood flow. Spectroscopic monitoring as described for example in U.S. Pat. No. 5,813,403 offers a valuable alternative to such electrode-based monitoring. That patent, which is hereby incorporated herein by reference, describes a method and device for optical measurement of tissue pH. The method employs multivariate calibration techniques to relate reflected light to a reference pH measurement. For open surgery or endosurgical applications, near infrared spectroscopic measurement of tissue pH with such an instrument is useful in identifying regional areas of ischemia. This information can be used to evaluate myocardial protection and to monitor graft patency during or following heart surgery, and may be used to evaluate reperfusion injury during liver transplant procedures. Web site: http://www.delphion.com/details?pn=US06564088__ •

Single light sensor optical probe for monitoring blood parameters and cardiovascular measurements Inventor(s): Krivitski; Nikolai M. (Ithaca, NY), Starostin; Dimitry (Ithaca, NY) Assignee(s): Transonic Systems, Inc. (Ithaca, NY) Patent Number: 6,493,567 Date filed: March 20, 2000 Abstract: A method and device for the continuous real-time monitoring of relative blood volume change, based on registration of blood hemoglobin concentration, during long periods of time, such as dialysis session. A method and device for cardiac output measurement, based on optical dilution technique, during dialysis, surgeries, intensive care procedure. The effects of blood electrolyte composition change which result in a change of light beam geometry are eliminated by the relative orientation between a light source and a single light or photodetector. An illumination axis and a detection axis are oriented in an offset, non collinear configuration at a sufficient angle to substantially eliminate the scattering properties of the blood. A primary implementation of the device is extracorporeal paths, such as hemodialysis tubing systems, artery-vein extracorporeal artificial shunts, other extracorporeal systems. It also may be applied to vessels, tissues or to body parts being capable of transillumination. Excerpt(s): The present invention relates to the photometric analysis of blood properties to monitor changes in blood volume, blood proteins concentration, cardiac output and other hemodynamic parameters. More particularly, the invention includes a method and apparatus for employing a single light emitter and a single photodetector, the single photodetector is oriented with respect to the emitter to minimize a scattering effect of the light from the electrolyte composition of the blood, blood flow rate, blood hematocrit level and other factors. The optical density of blood corresponds to a number of factors and the measurement of the optical density of the blood has been used to determine certain blood parameters. For example, during a hemodialysis session when fluid is being removed from the blood stream by a dialyzing machine, the concentration of hemoglobin, naturally occurring in the red blood cells, may decrease or, generally increase, with respect to the equilibrium processes of the fluid removal and mobilization from the body tissues. The change in the concentration of hemoglobin results in a corresponding change in the optical density of the blood and may be registered. Web site: http://www.delphion.com/details?pn=US06493567__

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Superoxygenating blood substitutes based on hemoglobin and dihydropyidine compositions Inventor(s): Rooney; Michael W. (202 Aaron Ct., Vernon Hills, IL 60061) Assignee(s): none reported Patent Number: 6,599,878 Date filed: November 30, 2000 Abstract: The present invention provides superoxygenating compositions that comprise hemoglobin and guanosine 3':5'-cyclic monophosphate (cyclic GMP) generating compounds, and methods for treatment of diseases or medical conditions which utilize the superoxygenating compositions as biocolloids, i.e. hemodiluents, blood substitutes, plasma expanders, or resuscitative fluids. The cardiac output-increasing compositions comprise a simple mixture of hemoglobin and the cyclic GMP generating compounds or hemoglobin physically or chemically coupled to the cyclic GMP generating compounds. The invention also provides time-controlled superoxygenating compositions of hemoglobin and cyclic GMP generating compounds that would be used for treatment of specific diseases or medical conditions requiring time-dependent use of biocolloids, i.e. hemodiluents, blood substitutes, plasma expanders, or resuscitative fluids. Excerpt(s): The present invention relates generally to compositions that enhance the in vivo oxygenating properties of hemoglobin products. More particularly, the present invention relates to time-controlled superoxygenating compositions that comprise hemoglobin colloid and guanosine 3':5'-cyclic monophosphate (cyclic GMP) generating compounds, and to methods for treatment of diseases or medical conditions which utilize the time-controlled superoxygenating compositions as biocolloids, i.e. hemodiluents, blood substitutes, plasma expanders, or resuscitative fluids. There are many medical conditions, for example hemorrhagic hypotension and anaphylactic shock, in which significant blood loss and/or hypotension (abnormally low blood pressure) occur leading to reduced tissue oxygenation. For patients with such medical conditions, it is desirable and often critical for their survival to stabilize their blood pressure and to increase the amount of oxygen provided to body tissues by their circulatory systems. Considerable effort has therefore been expended in developing colloidal substances which may be used as resuscitation fluids and/or blood plasma expanders for stabilizing blood pressure by hemodilution (i.e., increasing blood plasma volume) and which are capable of carrying and delivering oxygen to bodily tissues. The costs, risks (including contamination with disease-causing viruses) and histocompatibility requirements associated with the transfusion of whole blood or blood fractions have stimulated researchers to develop alternate oxygen-carrying substances. Web site: http://www.delphion.com/details?pn=US06599878__

Patents 191

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Synthesis of functional human hemoglobin and other proteins in erythroid tissues of transgenic non-human mammals Inventor(s): Behringer; Richard R. (Philadelphia, PA), Brinster; Ralph L. (Gladwyne, PA), Palmiter; Richard D. (Seattle, WA), Ryan; Thomas M. (Birmingham, AL), Townes; Tim M. (Birmingham, AL) Assignee(s): The UAB Research Foundation (Birmingham, AL) Patent Number: 6,613,957 Date filed: September 1, 1999 Abstract: The present invention relates to the synthesis of functional human hemoglobin and other proteins in erythroid tissues of transgenic non-human animals and erythroid cell lines. It is based on the discovery that two of the five hypersensitivity sites of the.beta.-globin locus are sufficient to result in high level expression of human.alpha.- or.beta.-globin transgenes. Excerpt(s): The present invention relates to the synthesis of functional human hemoglobin and other proteins in erythroid tissues of transgenic non-human animals or erythroid cell lines. In addition, the present invention provides for novel expression vectors which may be used to produce.alpha.-globin as well as other proteins of interest in quantity in the red blood cells of transgenic animals or erythroid cell lines; these proteins may subsequently be purified and utilized for a multitude of purposes. The human hemoglobin produced in transgenic animals according to the invention can be used as an effective, nonimmunogenic red blood cell substitute for transfusion in humans which is free of hepatitis virus and human retrovirus contamination. Native hemoglobin exists as a tetrameric protein consisting of two.alpha. chains and two.beta. chains. Each.alpha. and.beta. chain binds a heme residue in noncovalent linkage. The.alpha. and.beta. chains are also held together by noncovalent bonds resulting from hydrogen bonding and Van der Waals forces. Hemoglobin constitutes about 90% of the total protein in red blood cells, 100 ml of whole blood is capable of absorbing approximately 21 ml of gaseous oxygen. Different molecular species of hemoglobin are produced during the embryonic, fetal, and adult life of an animal. The genes encoding the globin molecules expressed during the various developmental stages are arranged in clusters. In humans and most other mammals the.alpha. and.beta.-like gene clusters are arranged in order of their expression during development, with the embryonic genes followed by the fetal and adult globin genes (Watson et al., 1987, in "Molecular Biology of the Gene", Fourth Edition, The Benjamin/Cummings Publishing Co., Inc., Menlo Park, Calif., p. 650). This developmental order is not obligatory, however; for example, in the chicken, the adult.beta.-globin genes are flanked by embryonic genes. Web site: http://www.delphion.com/details?pn=US06613957__

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Therapeutic use of hemoglobin for preserving tissue viability and reducing restenosis Inventor(s): Burhop; Kenneth E. (Mundelein, IL), McKenzie; Jack E. (McLean, VA) Assignee(s): Baxter International, Inc. (Deerfield, IL) Patent Number: 6,458,762 Date filed: December 2, 1994 Abstract: Administration of low doses of hemoglobin minimizes damage to the myocardium after blockage and significantly reduces reperfusion injury. Hemoglobin

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exerts a pharmacological effect by increasing perfusion and blocking the molecular events leading to permanent injury following an ischemic episode. Additional benefits include a reduction in the number of post-ischemic arrhythmias, reduction in the incidence of restenosis, and improved contractile function in the area of risk. Excerpt(s): The blockage of an arterial vessel produces ischemia in the tissue normally nourished by the occluded vessel. If the blockage is removed permitting reperfusion of the affected area after greater than sixty minutes of ischemia, further injury, called reperfusion injury, is paradoxically observed. This reperfusion injury is associated with a number of biochemical and physiological events such as release of intracellular enzymes, transient rise in blood pressure, reduction in contractility, influx of calcium, disruption of cell membranes, and eventual tissue necrosis (see Ferrari, et al., Am. J. Clin. Nutr. 53:2158 (1991)). It is thought that much of the tissue damage arising during ischemia and reperfusion results from the chemical action of excess amounts of accumulated oxygen free radicals (Lefer, et al., Basic Res. Cardiol., 86 Suppl. 2:109 (1991); Kirsh, et al., J. Neurotrauma, 9 Suppl. l:S157 (1992); and Bolli, Cardiov. Drugs & Ther., 5:249 (1991)). Experiments in a number of animal models have investigated the use of antioxidants or enzymes to control reperfusion injury. For example, Weyrich, et al., Circulation, 86:279 (1992) showed that administration of L-arginine reduced necrotic injury in a cat model of myocardial infarction. McMurray et al., J. Clin. Pharmac., 31:373 (1991) investigated sulfhydryl containing angiotensin converting enzyme inhibitors. Naslund, et al., Circ. Res., 66:1294 (1990) concluded from their work on a swine coronary model, that infarct size could be limited by administration of superoxide dismutase, but only during a very narrow window of time post-infarction. Schaer, et al., JACC, 15:1385 (1990) report a reduction in reperfusion injury by administering an acellular oxygenated perfluorochemical emulsion called Fluosol. An important model system is percutaneous transluminal coronary angioplasty in the pig. McKenzie, et al., Cardiovascular Research, "Effects of diaspirin cross-linked hemoglobin during coronary angioplasty in the swine", 28(8):1188-1193 (1994) utilized this technique to study the effects of temporary regional myocardial ischemia. They inserted a catheter into the proximal left anterior descending coronary artery and inflated the catheter balloon to occlude the artery for a period of 4 minutes. A significant reduction in cardiac function compared to controls was observed as measured by mean arterial blood pressure (MAP), peak systolic left ventricular pressure (IVP), rate of left ventricular pressure development (dP/dt), pressure rate product (PRP), and cardiac output (CO). In addition, electrocardiograms showed elevation of the S-T segment of the ECG. These experiments are significant because McKenzie, et al. compared controls to animals receiving infusions of hemoglobin, and found that cardiac function increased significantly and the S-T segment of the ECG returned toward baseline. Web site: http://www.delphion.com/details?pn=US06458762__ •

Time-resolved spectroscopic apparatus and method using streak camera Inventor(s): Chance; Britton (Marathon, FL) Assignee(s): Non-Invasive Technology, Inc. (Philadelphia, PA) Patent Number: 6,564,076 Date filed: November 21, 2000 Abstract: Methods and apparatus using the principles of time-resolved spectroscopy are disclosed. The present invention employs incident light pulses of sufficiently short duration to permit the rate of the rise and decay of such pulses to be measured.

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Consequently, the rate of decay, u, permits a determination of the concentration of an absorptive pigment, such as hemoglobin. The present invention also allows the precise path length the photons travel to be determined. Using this path length information and by measuring changes in optical density using known continuous light (CW) spectrophotometry systems, the methods and apparatus disclosed allow changes in the concentration of an absorptive pigment to be correctly be measured. From these data, the oxygenation state of a tissue region, such as the brain, can be accurately determined in real time. Excerpt(s): The present invention relates to methods an apparatus for determining the concentration of tissue pigments, such as hemoglobin, using time-resolved pulses of light. The present invention relies upon the decay characteristics associated with absorptive pigments to derive their concentrations. The utility of optical methods for studying metabolism and oxidative processes in cells and tissues was significantly enhanced in the early 1950's when time-sharing dual-wavelength systems were developed for the quantitation of small changes in the absorption of light in the visible and near-infrared (NIR) regions in highly scattering media, such as cell suspensions or muscle tissues. See Chance, B. Rev. Sci. Instrum. 22,619-627 (1951); Chance B. Biochemistry of Copper, ed. Peisach, J. (Academic, New York), pp. 293-303 (1966), which are incorporated by reference as if fully reproduced herein. Fluorescence signals from mitochondrial NADH complemented the absorption method for studies of the surface of heart, brain, and skeletal tissue. See Chance, B., et al., Nature (London) 195, 1073-1075 (1962) and Chance B. Science 120, 767-775 (1954). NIR spectroscopy has been used to detect the redox state of the copper component of cytochrome oxidase in mitochondria and yeast cells. See Chance, B. Biochemistry of Cooper, ed. Peisach, J. (Academic, New York), pp. 293-303 (1966); Chance, B. J. Biol. Chem 234, 3036-3040 (1959). Jobsis-Vander Vliet and coworkers pioneered the study of NIR absorption in tissue by transillumination. See Jobsis-Vander Vliet, F. F. Adv. Exp. Med. Biol. 191, 833-842 (1985); Jobsis-Vander Vliet, F. F., et al., J. Appl. Physiol. 113, 858,872 (1977); see also Rosenthal, M., et al., Brain Res. 108, 143-154 (1976). Algorithms have been developed to compensate for the interference from hemoglobin and myoglobin with cytochrome copper, as the latter may constitute as little as 5% of the total signal at 830 nm. See vanderZee. P. & Delpy, D. T. (1988) Oxygen Transport to Tissue X, eds. Mochizuki, M., et al., (Plenum, New York), pp. 191-197); see also Tamura, M. H., et al., Chemoreceptors and Reflexes in Breathing, ed. Lahiri, S. (Oxford, New York), in press. An application of the principles of spectrophotometry is the use of continuous light (CW) illumination to determine the attenuation characteristic of light in systems containing localized deoxyhemoglobin (Hb) and to observe hypoxia in the brain. However, although CW systems can be used to quantify changes in optical density, they cannot quantify the concentration of an absorptive pigment. Web site: http://www.delphion.com/details?pn=US06564076__ •

Total hemoglobin concentration measurement Inventor(s): Myers; Dean E. (Stewart, MN) Assignee(s): Hutchinson Technology Incorporated (Hutchinson, MN) Patent Number: 6,473,632 Date filed: June 16, 2000 Abstract: A method for operating a spectrophotometric instrument of the type for measuring the oxygenation state of hemoglobin in tissue. The method includes the use

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of stored hemoglobin concentration relationship data characterizing the relationship between second derivative absorbance values at a hemoglobin-absorbing wavelength and hemoglobin concentration in a tissue as a function of hemoglobin oxygenation state. Data representative of a second derivative absorbance value of tissue being analyzed is received. The hemoglobin oxygenation state of the tissue is determined as a function of the second derivative absorbance value. The hemoglobin concentration in the tissue is then determined as a function of the hemoglobin concentration relationship data, the second derivative absorbance value and the hemoglobin oxygenation state. The accuracy of the hemoglobin oxygenation state can be determined as a function of the hemoglobin concentration value. Excerpt(s): The present invention relates generally to methods and instruments for measuring the concentration of a chromophore such as hemoglobin in tissue. Spectrophotometric instruments and methods for measuring the amount of a tissue chromophore having a certain functional state (e.g., the percentage of oxidized hemoglobin or StO2, and the percentage of oxidized cytochrome aa3) are generally known and disclosed, for example, in the Anderson et al. U.S. Pat. No. 5,879,294, which is hereby incorporated by reference in its entirety. The Anderson et al. patent discloses in particular a measurement algorithm which makes use of scaled second derivative spectrum values. The Kuestner U.S. Pat. No. 5,377,674 discloses a spectrophotometric instrument and method for measuring the total concentration of a chromophore such as hemoglobin in tissue. The measurement algorithm uses a single term ratio of second derivative absorbance measured at a wavelength at which hemoglobin absorption occurs (analyte wavelength), and a second derivative absorbance measured in a wavelength region where no hemoglobin absorption occurs (reference wavelength) (e.g, 2.sup.nd derivative of absorbance at 1740 nm / 2.sup.nd derivative of absorbance at 1346 nm). Web site: http://www.delphion.com/details?pn=US06473632__ •

Ultra pure hemoglobin solutions and blood-substitutes Inventor(s): Feola; Mario (Lubbock, TX), Rausch; Carl W. (Providence, RI) Assignee(s): BioPure Corporation (Cambridge, MA) Patent Number: 6,506,725 Date filed: May 10, 1999 Abstract: A blood substitute and plasma expander comprising a cross-linked, substantially endotoxin-free hemoglobin solution and process for preparing same. The process comprises fractionating whole blood, separating out a stromal-free, sterile hemoglobulin solution, chromatographically separating endotoxins from said hemoglobin solution and crosslinking the resulting endotoxin-free hemoglobin solution. Excerpt(s): This invention relates to a process for producing a novel semi-synthetic blood substitute and the novel semi-synthetic blood substitute resulting therefrom. The novel semi-synthetic blood substitute is a hemoglobin preparation characterized by its purity, its exceptionally low levels of endotoxin, the absence of non-hemoglobin proteins, and its molecular cross-linking profile. The semi-synthetic blood substitute has no toxic activity when used in a substitute fashion and possesses the property of reversibly binding gaseous ligands such as oxygen and is useful for transporting and supplying oxygen to vital tissues and organs. Additionally, the blood substitute serves

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as a blood plasma expander for management of disease and for maintaining circulatory integrity. A further aspect of the invention is the preursor or intermediate, the substantially pure, phospholipid-free, endotoxin-free hemoglobin solution in uncrosslinked form. Complex multicellular organisms are equipped with specialized tissues which are concerned with the processes of nutrition and excretion. It is the primary function of blood to provide a link between various organs and cells of the body. Blood, red cells, plasma and other components maintain a constant cellular environment by circulating through every tissue and continuously delivering nutrients to the tissues and removing waste products and various tissues which are concerned with the tissue secretions from them. PHYSIOLOGY, Third Edition, Edited by Edward E. Selkurt, Page 223 (1971). Blood is a viscous fluid composed of cells and plasma. More than 99% of the cells are red blood cells. The major function of red blood cells is to transport hemoglobin, which in turn carries oxygen from the lungs to the tissues and CO.sub.2 from the tissues to the lungs. Normal red blood cells contain approximately 34 grams of hemoglobin per 100 ml of cells. Each gram of hemoglobin is capable of combining with approximately 1.33 ml of oxygen. See Guyton, A. C., BASIC HUMAN PHYSIOLOGY: NORMAL FUNCTION IN MECHANISMS OF DISEASE, Pages 84-85 (1971). Because of the critical and ongoing need for a therapeutic agent useful as a blood substitute for carrying and supplying oxygen and as a blood plasma expander, intense research efforts have been directed to the development of an adequate blood substitute. The need for a blood substitute exists for replacing blood lost by acute hemorrhage, blood losses occuring during surgical operations, resuscitation procedures after accidental blood loss, and the like. Further, as a plasma expander, a blood substitute serves as a therapeutic to treat volume deficiency shock, as an alleviant in anaphylactic and allergic shock, and for replacing plasma lost after burns and as a result of severe diarrhea. Web site: http://www.delphion.com/details?pn=US06506725__

Patent Applications on Hemoglobin As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to hemoglobin: •

Acellular red blood cell substitute Inventor(s): DeWoskin, Richard E.; (Mount Prospect, IL), Gould, Steven A.; (Highland Park, IL), Moss, Gerald S.; (Highland Park, IL), Rosen, Arthur L.; (Wilmette, IL), Sehgal, Hansa; (Flossmoor, IL), Sehgal, Lakshman R.; (Flossmoor, IL) Correspondence: Steven J. Sarussi; Mcdonnell Boehnen Hulbert & Berghoff; 32nd Floor; 300 S. Wacker Drive; Chicago; IL; 60606; US Patent Application Number: 20030130487 Date filed: January 21, 2003 Abstract: An acellular red blood cell substitute which comprises an essentially tetramerfree, substantially stroma-free, cross-linked, polymerized, pyridoxylated hemoglobin and a nontoxic, pharmaceutically acceptable carrier, its use and a process for preparing said acellular red blood cell substitute.

10

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

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Excerpt(s): This invention relates to an acellular red blood cell substitute comprising an essentially tetramer-free, cross-linked, polymerized, pyridoxylated hemoglobin solution which is free of stromal contaminants. It further relates to a method of preparing the acellular red blood cell substitute. For several years, stroma-free hemoglobin has been known in the art to have oxygen transport and reversible oxygen (or ligand) binding capacities. Since toxicity problems have precluded use as a blood substitute, stroma-free hemoglobin has required further modifications to provide a nontoxic, useful pharmaceutical product. In U.S. Pat. Nos. 4,001,200; 4,001,401 and 4,053,590, a polymerized, cross-linked, stroma-free hemoglobin is disclosed as a blood substitute for carrying oxygen to tissues and organs and as a blood plasma expander. Pyridoxylating the stroma-free hemoglobin has been shown to favorably alter reversible oxygen binding capacities and increase the stability and shelf-life of the biological product. J. Surgical Research 30:14-20 (1981). Pyridoxylated hemogobin polymerized with glutaraldehyde has been described and characterized in L. R. Sehgal, et al. In Vitro and In Vivo Characteristics of Polymerized, Pyridoxylated Hemoglobin Solution, Fed. Proc. 39:2383 (1980); L. R. Sehgal, et al., Preparation and In Vitro Characteristics of Polymerized, Pyridoxylated Hemoglobin, Transfusion 23(2):158 (March-April 1983). Further, the ability of the polymerized, pyridoxylated hemoglobin to act as an oxygen carrier has been disclosed in L. R. Sehgal, et al., Polymerized, Pyridoxylated Hemoglobin: A Red Cell Substitute with Normal Oxygen Capacity, Surgery 95(4):433-38 (April 1984); L. R. Sehgal, et al., An Appraisal of Polymerized, Pyridoxylated Hemoglobin as an Acellular Oxygen Carrier, Advances in Blood Substitute Research 1928 (Alan R. Liss, Inc. 1983). For years investigators have reported that hemoglobin solutions prepared by various techniques, while capable of carrying sufficient quantities of oxygen to support life, have undesirable side effects. The most troubling side effect is a decrease in kidney performance. These changes were thought to be due to the presence of unwanted contaminants such as bacterial endotoxin or fragments of red cell membranes (stroma). While contaminants such as these can indeed produce renal alterations, hemoglobin solutions essentially free of the above contaminants still produce substantial renal dysfunction. Although this dysfunction is temporary and reversible, it can be very alarming in a clinical situation such as hemorrhagic shock, as the kidney is already at risk in this low blood flow state. The cause for the renal dysfunction has been ascribed to physiologically unacceptable amounts of unpolymerized hemoglobin tetramer. Other undesirable side effects of the infusion of tetrameric hemoglobin are renal toxicity, vasoconstriction, hemoglobinurea, depression of heart rate, elevation of mean arterial blood pressure and extra-vasation of infusate especially into the peritoneal cavity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Analysis method and system therefor Inventor(s): Pettersson, Joakim; (Angelholm, SE), Svensson, Johnny; (Angelholm, SE) Correspondence: Burns, Doane, Swecker & Mathis, L.L.P.; P.O. Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20030123047 Date filed: December 20, 2002 Abstract: The invention concerns a method for quantitative hemoglobin determination in undiluted, unhemolyzed whole blood comprising the steps of:providing a disposable, capillary, which has an optical path length of less than 1 mm;filling said cuvette with a

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sample of unaltered whole blood;performing a first absorption measurement at a wavelength in the range 490-520 nm directly on the sample in the cuvette, andfurther conducting a second absorption measurement, andprocessing results of the first and second absorption measurements to determine the concentration of hemoglobin in the sample, wherein the step of processing comprises compensating for scattering in the sample, said compensating being dependent on the result of the second absorption measurement.A system for implementing the method is also disclosed. Excerpt(s): The present invention concerns an analysis method and a system for performing this analysis. Specifically the invention concerns a method for determination of hemoglobin in unaltered whole blood and a system which can be used in this determination. A disposable cuvette for sampling a fluid, mixing the sample with a reagent and directly making optical analyses of the sample mixed with the reagent is previously known from U.S. Pat. No. 4,088,448. This known cuvette has several advantages as it i.a. simplifies the sampling procedure, reduces the number of utensils and considerably improves the accuracy of analysis by making the analysing procedure independent of the operating technique of the operator making the analysis. A cuvette construction based on the same principle and with improved flow characteristics is disclosed in the U.S. Pat. No. 5,674,457. A disposable cuvette developed according to these patents is currently widely used for hemoglobin measurement (Hb determination) of undiluted whole blood. To this end the cuvette cavity has been pre-treated with a reagent, such that when a blood sample is drawn into the cuvette, the walls of the red blood cells are disintegrated and a chemical reaction is initiated. The result of the reaction allows Hb determination by absorption measurement directly through the transparent walls of the cuvette which, in the measuring zone, also called the optical window, has a predetermined and accurately defined distance between the inner surfaces of the opposing planar walls. The measurement method is based on a modified azidmethemoglobin method according to Vanzetti, G., Am.J. Lab.& Clin. Med. 67, 116 (1966). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compositions and methods utilizing hydroxamates to scavenge oxidant toxins Inventor(s): Nelson, Deanna Jean; (Cary, NC) Correspondence: Deanna J. Nelson, PH.D.; 104 Tasman Court; Cary; NC; 27513; US Patent Application Number: 20030171260 Date filed: March 11, 2002 Abstract: Macromolecule compositions using hydroxamate or oxime groups covalently coupled with biological cells and macromolecules, and in particular, with albumin and acellular hemoglobin, are provided. In particular embodiments, hydroxamate or oxime groups are covalently coupled with acellular hemoglobin and compounded to provide several formulations for a red cell substitute that will possess oxidant toxin-scavenging properties. The invention also provides a method of preventing and treating pathologies related to the actions of oxidant toxins or oxidative stress in a mammal. The method comprises administering to a mammal a therapeutically effective amount of a macromolecule composition comprising a macromolecule coupled with at least one hydroxamate or oxime group. Excerpt(s): None. No Federally sponsored research and development were used in making this invention. This invention relates to the use of hydroxamate and oxime

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groups that are covalently coupled with cells or macromolecules, including hemoglobin, albumin, polysaccharides, lipopolysaccharides, polynucleotides, liposomes, and natural and synthetic polymers, and have the ability to alleviate the toxic effects of oxidant toxins presumed to cause harmful oxidant stress in a living organism. In particular, this invention discloses compounds and methods featuring hydroxamate and oxime groups covalently coupled with physiologically compatible acellular and encapsulated hemoglobin solutions for use as a red cell substitute; and hydroxamate and oxime groups covalently coupled with other physiologically compatible macromolecules for alleviation and prevention of biological damage and oxidative stress caused by free radicals. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Cyanide-free reagent, and method for detecting hemoglobin Inventor(s): Cousino, Melissa; (Creve Coeur, MO), Merabet, Eddine; (St. Louis, MO), Shapiro, Karina; (Ballwin, MO) Correspondence: Stephen M. Haracz, Esq; Bryan Cave Llp; 245 Park Avenue; New York; NY; 10167-0034; US Patent Application Number: 20030044995 Date filed: October 15, 2002 Abstract: A cyanide-free reagent for detecting hemoglobin is provided. The cyanidefree reagent includes a surfactant, a cyanide-free ligand selected from a nitrate, a nitrate salt, a nitrite, a nitrite salt, and combinations thereof, and a hydrogen ion concentration sufficient to maintain the pH of the reagent below about 9. A method and a kit for detecting hemoglobin in a blood sample using the cyanide-free reagent are also provided. Excerpt(s): The present invention relates to a cyanide-free reagent for detecting hemoglobin. More particularly, the invention relates to a cyanide-free reagent containing a surfactant and a cyanide-free ligand, which are maintained at a pH below about 9. Methods and kits using the cyanide-free reagent for detecting hemoglobin in blood are also provided. The measurement of hemoglobin concentration in a whole blood sample is useful for clinical diagnosis of diseases such as leukemia, anemia, polycythemia, and other hematological disorders. As is well known, hemoglobin is located in erythrocytes (i.e., red blood cells) and functions to transport oxygen from the lungs to various tissues and organs in the body. The determination of hemoglobin concentration in a patient's blood sample is one of the most common, and important hematological assays ordered in the clinical setting. Current methods utilize spectrophotometry to quantitate the amount of hemoglobin in a blood sample. These methods typically require that the hemoglobin be released from the erythrocyte, and that the hemoglobin be converted into a single chromogenic species. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Dextran-hemoglobin conjugates as blood substitutes Inventor(s): Tsai, Sheung Pun; (Hong Kong, CN), Wong, Jeffrey Tze-Fei; (Hong Kong, CN) Correspondence: Howard M. Ellis; Simpson, Simpson & Snyder, Pllc; 5555 Main Street; Williamsville; NY; 14221-5404; US Patent Application Number: 20030073820 Date filed: April 24, 2002 Abstract: An hemoglobin (Hb)-Dextran (Dx) conjugate having a molecular weight between 50 kD and 500 kD provides a blood substitute that results in acceptable erythrocyte sedimentation rate (ESR) and excretion rate (EXC) values. DxHb conjugates of the invention can be used for a variety of purposes as an alternative to blood. Excerpt(s): This application is a Continuation of PCT application number PCT/CA01/01329, filed on Sep. 19, 2001. This invention relates to blood substitutes, and methods of their preparation. More particularly, the invention relates to improved polysaccharide-hemoglobin conjugates for use as a blood substitute for mammals and to methods of their preparing such conjugates. In recent years the quest for a safe blood substitute has accelerated rapidly. The demand often exceeds the supplies of blood available from human donors. In addition, in many parts of the world, the whole blood supply can be hazardous. Therefore, there is a need to develop blood substitutes. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Disposable electrode for whole blood hemoglobin (HGB) and hematocrit (HCT) measurement, and preparation and application Inventor(s): Lin, Yueh-Hui; (Hsinchu, TW), Shen, Thomas Y.S.; (Hsinchu, TW) Correspondence: Rothwell, Figg, Ernst & Manbeck, P.C.; 1425 K Street, N.W.; Suite 800; Washington; DC; 20005; US Patent Application Number: 20030082076 Date filed: December 10, 2002 Abstract: The subject invention relates to a disposable hemoglobin and hematocrit detecting electrode strip, the preparation and the use thereof. The concentration of hemoglobin and hematocrit in a liquid sample can be determined by electrochemically analyzing the liquid sample under a low operation voltage of below 400 mV. When the electrode strip is applied to detect the concentration of hemoglobin and hematocrit in human body, the whole blood is directly used as the sample. The hemoglobin and hematocrit detecting electrode strip is modified by a water-soluble redox electron mediator. The electrode strip simplifies the analysis of hemoglobin and hematocrit, is conveniently portable and can be easily manufactured in mass-production. Excerpt(s): The subject application is a continuation-in-part application of U.S. Ser. No. 09/771,634 filed on Jan. 30, 2001. The subject invention relates to an electrode strip which can easily determine the concentration of hemoglobin and hematocrit in a liquid sample, and to the preparation and the applications thereof. More specifically, the invention relates to a disposable hemoglobin and hematocrit electrode strip based on the theory of electrochemistry modified by a water-soluble redox electron mediator, which is disposable, and suitable for household use, screening for blood banks. In addition, said electrode strip can precisely detect the concentration of hemoglobin and

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hematocrit without any interference caused by other components in a liquid. Hemoglobin is also called hematochrome, which is 90% of erythrocyte and is composed of four globins and four ferrohemes. The main function of hemoglobin is to transport oxygen and carbon dioxide. The decrease of the concentration of hemoglobin shows anemia; and the increase shows polycythemia. Many methods can be used to determine the concentration of hemoglobin, including: (1) chemical method; (2) gas determination method; (3) specific density method; and (4) calorimetric method. The drawback of the former three methods are respectively: (1) being troublesome and time-consuming, (2) requiring specific equipment and (3) providing poor preciseness. Therefore, those methods are not useful in routine tests. Normally, routine test is performed by colorimetric method. In general, the calorimetric method includes acid hematin method and cyanmet-hemoglobin method. The acid hematin method: Sahli's method is normally used, which utilizes Sahli's tube to suck up 0.2 ml of HCl (0.1N) to mix with 0.1 ml of blood for hemolysis and reaction for 15 minutes. Water is dropwise added to the solution until the color of the solution and the color standards are consistent while the color of the solution is colorimetered with the color standards of the Sahli-Hellige hemoglobinometer. Because the color is subjectively judged by the operator in this method, the CV % is larger (about 5% to 10%). The cyanmet-hemoglobin method: the Drabkin's solution is used to dissolve the erythrocyte, and the component of the Drabkin's solution, K.sub.3Fe(CN).sub.6, can oxidize the ferrous moiety of hemoglobin into ferric moiety to form ferriheme (met-Hb; MHb). Ferriheme may combine with potassium cyanide (KCN) to form stable ferriheme cyanide, then ferriheme cyanide is colorimetered at 540 nm with a photoelectric colorimeter. This method is rapid and precise, and is publicly recognized as a standard method. Except that sulfhemoglobin does not show reaction, all types of hemoglobin can be detected. In this method, there is a hypertoxic pollution problem caused by potassium cyanide. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Enzyme-mimicking polymers Inventor(s): Sode, Koji; (Tokyo, JP) Correspondence: Birch Stewart Kolasch & Birch; PO Box 747; Falls Church; VA; 220400747; US Patent Application Number: 20030186330 Date filed: March 12, 2003 Abstract: The present invention provides synthetic polymers having novel catalytic functions which mimic enzymatic reactions. The invention also provides a method for measuring glycated proteins such as glycated hemoglobin (HbA1c) and glycated albumin and for measuring their decomposition products fructosylamines, such as fructosylvaline, as well as assay reagents and sensors for use in the method. Excerpt(s): The present invention relates to synthetic polymers having novel catalytic functions which mimic enzymatic reactions and to novel methods for measuring glycated proteins using the synthetic polymers. More specifically, it relates to polymers obtained by polymerizing a monomer having a catalytic function and a monomer having a molecular-recognition function in the presence of a molecule to be assayed as a template. In addition, it relates to methods for measuring glycated hemoglobin (HbA1c), glycated albumin, and fructosylvaline and other fructosylamines which are the decomposition products of these proteins, as well as assay reagents and sensors for use in these methods. The glycated proteins are used in the fields of, for example, clinical

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laboratory tests as markers for diagnosis of diabetes mellitus. Amino groups in the backbone and side chains of a protein can be non-enzymatically bound to a reducing end-group of a reducing sugar, such as glucose, to form an amadori compound, i.e. a glycated protein. In the blood, hemoglobin is glycated to form glycated hemoglobin (glycohemoglobin; HbA1c). The ratio of HbA1c to hemoglobin in patients with diabetes mellitus is higher than that in healthy persons, and the blood level of HbA1c reflects a blood glucose level over a period of past several weeks. Thus, the blood level of HbA1c is very important in diagnosis of diabetes mellitus and as an indicator of blood glucose level control in patients suffering from diabetes mellitus. Fructosamine oxidases that act upon amadori compounds have been isolated from various species. It has been suggested that glycated albumin, HbA1c, and other glycated proteins and fructosamines can be assayed by the use of fructosamine oxidase (Japanese Patent Public Disclosure No. 61-268178, No. 61-280297, No. 03-155780, No. 05-192193, No. 07-289253, and No. 08154672; Agric. Biol. Chem., 53(1), 103-110, 1989; Agric. Biol. Chem., 55(2), 333-338, 1991; J. Biol. Chem., 269(44), 27297-27302, 1994; Appl. Environ. Microbiol., 61(12), 4487-4489, 1995; Biosci. Biotech. Biochem., 59(3), 487-491, 1995; J. Biol. Chem., 270(1), 218-224, 1995; J. Biol. Chem., 271(51), 32803-32809, 1996; J. Biol. Chem., 272(6), 3437-3443, 1997); Electrochemistry, 68(11), 869-871, 2000; and Marine Biotechnology, 3, 126-132, Sep. 5, 2001). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Erythropoietin dosing regimen for treating anemia Inventor(s): Farrell, Francis; (Doylestown, PA) Correspondence: Audley A. Ciamporcero JR.; Johnson & Johnson; One Johnson & Johnson Plaza; New Brunswick; NJ; 08933-7003; US Patent Application Number: 20030134795 Date filed: November 26, 2002 Abstract: The present invention provides a new subcutaneous injection dosing regimen for erythropoietin to treat anemia. The new erythropoietin treatment regimen of the present invention results in improved hemoglobin levels with less frequent dosing. Excerpt(s): The present invention provides a method to treat anemia whereby an alternate dosing regimen is used to raise and maintain hemoglobin levels with dosing intervals greater than one week after the hemoglobin level was elevated with weekly administration. Erythropoietin (EPO) is a glycoprotein hormone secreted by the kidneys in response to tissue hypoxia, which stimulates red blood cell production in the bone marrow (1). The gene for EPO has been cloned and expressed in Chinese hamster ovary cells (2,3). This recombinant human erythropoietin (epoetin alfa, rhEPO) has an amino acid sequence identical to that of human urinary erythropoietin, and the two are indistinguishable on the basis of functional and immunological assays, although differences exist regarding protein glycosylation, affecting in vivo efficacy (4,5). In clinical trials to date, rhEPO has been evaluated in normal subjects as well as in patients with various anemic conditions (6,7). EPO induces a brisk hematologic response in normal human volunteers, provided that adequate supplies of iron are available to support increased hemoglobin synthesis (8). The majority of trials have investigated the safety and effectiveness of rhEPO in the treatment of chronic renal failure maintained on dialysis and in those not yet on maintenance dialysis. Other indications approved in the US include anemia secondary to chemotherapy treatment in cancer and anemia associated with zidovudine treatment of human immunodeficiency virus infection.

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Worldwide, EPO has been used to treat anemia associated with rheumatoid arthritis, prematurity, myelofibrosis, sickle cell anemia, bone marrow transplantation, thermal injury,.beta.-thalassemia, as a facilitator of presurgical autologous blood donation, and use as a presurgical adjuvant (6,7). Although rhEPO is generally well tolerated, occasional skin rashes and urticaria have been observed suggesting allergic hypersensitivity to some components of the Epoetin alfa formulation, likely human serum albumin. Further, despite blood screening, there exists a risk of infection with a transmissible agent when a pharmaceutical agent is formulated using human blood products. Therefore pharmaceutical formulations of rhEPO that are stable and are free of human blood products, such as albumin are needed. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Fuel additives for fuel cell Inventor(s): Hanson, Eric G.; (Burlingame, CA), Pan, Alfred I-Tsung; (Sunnyvale, CA) Correspondence: Hewlett-packard Company; Intellectual Property Administration; P.O. Box 272400; Fort Collins; CO; 80527-2400; US Patent Application Number: 20030064258 Date filed: September 28, 2001 Abstract: A method of enhancing performance of liquid-type fuel cells by adding additives to the liquid fuel. For example, hemoglobin, surfactants, oxygen scavengers, and chelating agents, may be added to the fuel to resolve problems such as CO poisoning of catalyst, wettability of electrodes, and electrode poisoning, and therefore enhance the performance of the fuel cell. The additives may be added individually based on needs, or mixed in a desired ratio for a given type of fuel cell. The additives may be used on a regular basis to improve fuel efficiency and prolong the life span of the fuel cells. The additives may also be pre-packed for field use when high quality fuel is not available. Excerpt(s): The technical field generally relates to fuel cells and in particular to fuel additives that enhance performance of liquid-type fuel cells. A fuel cell is an electrochemical apparatus wherein chemical energy generated from a combination of a fuel with an oxidant is converted to electric energy in the presence of a catalyst. The fuel is fed to an anode, which has a negative polarity, and the oxidant is fed to a cathode, which, conversely, has a positive polarity. The two electrodes are connected within the fuel cell by an electrolyte to transmit protons from the anode to the cathode. The electrolyte can be an acidic or an alkaline solution, or a solid polymer ion-exchange membrane characterized by a high ionic conductivity. The solid polymer electrolyte is often referred to as a proton exchange membrane (PEM). The goal in methanol fuel processing is complete methanol oxidation for maximum energy generation shown in the equation. Catalysts that promote the rates of electrochemical reactions, such as oxygen reduction and hydrogen oxidation in a fuel cell are often referred to as electrocatalysts. Electrocatalysts are important because the energy efficiency of any fuel cell is determined, in part, by the overpotentials necessary at the fuel cell's anode and cathode. In the absence of an electrocatalyst, a typical electrode reaction occurs, if at all, only at very high overpotentials. Thus, the oxidation and reduction reactions require catalysts in order to proceed at useful rates. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Hemoglobin assay calibration and control Inventor(s): Jacobs, Merrit; (Foxboro, NY), Love, James E. JR.; (Penfield, NY), Warren, Karen; (Rush, NY) Correspondence: Audley A. Ciamporcero JR.; Johnson & Johnson; One Johnson & Johnson Plaza; New Brunswick; NJ; 08933-7003; US Patent Application Number: 20030068822 Date filed: September 28, 2001 Abstract: Methods of calibrating and validating the calibration of hemoglobin assays include the use of calibrators and/or controls that incorporate cross linked blood substitute. The calibrators and controls can be formulated into kits. Excerpt(s): The invention relates to the calibration and control of assays for hemoglobin including assays for the determination of hemolized body fluids. Many conventional clinical assays rely on well-established procedures by which standard curves relate analyte concentration or activity to some spectrophotometric measurement such as absorbance, transmission, or reflectance. This can be done by taking advantage of reactions with reagents that produce a detectable result such as color change but it is also possible to use this method in reagentless systems using, for example, near infrared radiation. Typically, spectrophotometric measurements are taken of solutions containing known analyte concentrations that span the dynamic range for that analyte. A curve is then fit to the data that can then be used to relate concentration of unknown samples to their spectrophotometric properties. The curve is typically validated from time to time by comparing concentrations arrived at by use of the standard curve against solutions having known concentrations. Such solutions of known concentration are referred to as controls. If the computed concentration values of the controls do not correspond sufficiently to the known values then the instrument used is recalibrated. Controls and calibrators must have substantially similar spectrophotometric characteristics over the same concentration range one would expect to find in actual samples. This is often achieved by using aliquots of the same analyte for which the assay is conducted. Unfortunately, these analytes are sometimes not stable making controls and calibrators made from them unreliable. Hemoglobin is one such analyte. It gradually converts to methemoglobin over time which has a different spectra than does hemoglobin. One could use a dye that mimics the spectra of hemaglobin but thus far such dyes have only been found to simulate hemoglobin in portions of the spectra. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Hemoglobin mutants with increased soluble expression and/or reduced nitric oxide scavenging Inventor(s): Doherty, Daniel H.; (Boulder, CO), Glascock, Christopher B.; (Louisville, CO), Lemon, Douglas D.; (Louisville, CO), Mathews, Antony J.; (Houston, TX), Olson, John S.; (Houston, TX), Weickert, Michael J.; (Belmont, CA) Correspondence: Senniger Powers Leavitt And Roedel; One Metropolitan Square; 16th Floor; ST Louis; MO; 63102; US Patent Application Number: 20030017537 Date filed: March 27, 2002

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Abstract: The invention relates to novel recombinant hemoglobins having reduced nitric oxide scavenging and/or increased high soluble expression. The invention further relates to methods of increasing the soluble expression of recombinant hemoglobin by adding exogenous hemin in molar excess of the heme binding sites of recombinant hemoglobin. Excerpt(s): The invention relates to novel hemoglobin mutants having one or more desired functions, including reduced nitric oxide scavenging and increased soluble expression. The invention further relates to methods of increasing soluble expression of recombinant hemoglobin by the addition of excess heme. Hemoglobin (Hb) is the oxygen-carrying component of blood that circulates through the bloodstream inside small enucleate cells known as erythrocytes or red blood cells. It is a protein comprised of four associated polypeptide chains that bear prosthetic groups known as hemes. The structure of hemoglobin is well known and described in Bunn & Forget, eds., Hemoglobin: Molecular, Genetic and Clinical Aspects (W. B. Saunders Co., Philadelphia, Pa.: 1986) and Fermi & Perutz "Hemoglobin and Myoglobin," in Phillips and Richards, Atlas of Molecular Structures in Biology (Clarendon Press: 1981). Expression of various recombinant hemoglobins containing naturally-occurring and non-naturally occurring globin mutants has been achieved. Such expression methods include individual globin expression as described, for example, in U.S. Pat. No. 5,028,588, and di-alpha globin expression created by joining two alpha globins with a glycine linker through genetic fusion coupled with expression of a single beta globin gene to produce a pseudotetrameric hemoglobin molecule as described in WO 90/13645 and Looker et al., Nature 356:258-260 (1992). Other modified recombinant hemoglobins are disclosed in PCT Publication WO 96/40920. Similar to other heterologous proteins expressed in E. coli, recombinant hemoglobins have N-terminal methionines, which in some recombinant hemoglobins replace the native N-terminal valines. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Hemoglobin-haptoglobin complexes Inventor(s): Adamson, J. Gordon; (Georgetown, CA), Moore, M.S. Celine; (Georgetown, CA), Wodzinska, Jolanta M.; (Brampton, CA) Correspondence: Nixon & Vanderhye P.C.; 8th Floor; 1100 North Glebe Road; Arlington; VA; 22201-4714; US Patent Application Number: 20030013642 Date filed: August 30, 2002 Abstract: Construct-complexes of a hemoglobin, a hepatocyte modifying substance bound to the hemoglobin, and a haptoglobin bound to the hemoglobin, are provided, for administration to mammalian patients. The construct-complex may be formed ex vivo, or a hemoglobin-hepatocyte modifying substance combination may be administered to the patient so that haptoglobin in the mammalian body bonds thereto to form the construct-complex in vivo. Disorders of the liver may be diagnosed and treated using construct-complexes described herein. Excerpt(s): This invention relates to protein complexes and use thereof in medical applications. More specifically, it relates to complexes of hemoglobin compounds with therapeutic substances such as drugs, genes etc. which have a therapeutic action on specific parts and/or organs of the body, and means for targeting such complexes to specific body parts and body organs. Also within the scope of the invention are

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complexes of hemoglobin with diagnostic substances, such as imaging agents. The use of hemoglobin and modified hemoglobin as a drug delivery means has been proposed previously. Hemoglobin, as a natural component of red blood cells, present and circulating throughout the body in relatively large quantities, has well-established bioacceptability and the potential to deliver drugs throughout the body. Thus, Kluaer et al., U.S. Pat. No. 5,399,671 describe a hemoglobin compound which has been crosslinked to effect intramolecular stabilization of the tetrameric structure thereof, but which contains a residual functional group on the cross-linker residue to which drugs for delivery can be covalently attached. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Hemoglobin-polysaccharide conjugates Inventor(s): Adamson, Gordon J.; (Georgetown, CA) Correspondence: Nixon & Vanderhye, PC; 1100 N Glebe Road; 8th Floor; Arlington; VA; 22201-4714; US Patent Application Number: 20030125238 Date filed: November 26, 2002 Abstract: Hemoglobin conjugates useful as a hemoglobin-based oxygen carriers are prepared by reacting hemoglobin with oxidatively ring-opened polysaccharides such as hydroxyethyl starch or dextran, and storing the resultant conjugate under conditions which allow it to transform to a lower molecular weight product, after conjugation. The conjugate is then reductively stabilized to form secondary amino bonds between the hemoglobin and the polysaccharide, and formulated as an HBOC. Excerpt(s): This invention relates to biocompatible oxygen carriers for administration to patients as a supplement for or a partial replacement for whole blood. More specifically, the invention relates to hemoglobin-based oxygen carriers (HBOCs) for administration to mammals as a blood substitute or supplement, and processes for their preparation. Hemoglobin, as the natural oxygen transporter component of blood, is an obvious candidate to form the basis of a blood substitute, e.g. as an aqueous solution. Extensive scientific work has been done and reported, on attempts to provide a satisfactory hemoglobin solution to act as a blood substitute. The chemical properties of hemoglobin outside the red blood cells are, however, markedly different from its properties inside the red blood cells, e.g. as regards its oxygen affinity. The need for some form of chemical modification of hemoglobin to render it suitable for use as a blood substitute has long been recognized and has been quite expensively investigated. It is well known that hemoglobin comprises a tetramer of four sub-units, namely two.alpha. sub-units each having a globin peptide chain and two.beta. sub-units each having a globin peptide chain. The tetramer has a molecular weight of approximately 64 kilodaltons, and each sub-unit has approximately the same molecular weight. The tetarameric hemoglobin in dilute aqueous solution readily dissociates into.alpha.-.beta. dimers, and even further under some conditions to.alpha.-sub-unit monomers and.beta.sub-unit monomers. The dimers and monomers have too low a molecular weight for retention in the circulatory system of the body, and are filtered by the kidneys for excretion with the urine. This results in an unacceptably short half life of such a product in the body. The benefit of chemical bonding between the sub-units to ensure the maintenance of the tetrameric form ("intramolecular cross-linking") has previously been recognized. Also, the linking together of two or more tetrameric units to form hemoglobin oligomers and polymers of molecular weight greater than 64 kilodaltons

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("inter-molecular cross-linking") has also been recognized as desirable in many instances. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Increasing function of organs having reduced red blood cell flow Inventor(s): Jacobs, Edward E. JR.; (Lexington, MA), Rausch, Carl W.; (Medford, MA) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20030158091 Date filed: January 24, 2003 Abstract: The present invention relates to a method of therapeutically, or prophylactically, treating a vertebrate to increase tissue oxygenation, or maintain issue oxygenation, in tissue of a vertebrate wherein the tissue has a reduced red blood cell flow, and wherein the vertebrate has a normovolemic blood volume and at least a normal systemic vascular resistance. The method comprises introducing into the circulatory system of the vertebrate at least one dose of hemoglobin. Excerpt(s): This application is a continuation of U.S. Ser. No. 09/749,504, filed Dec. 26, 2000, which is a continuation of U.S. Ser. No. 09/471,779 filed Dec. 23, 1999 which is a continuation of U.S. Ser. No. 09/215,714, filed Dec. 18, 1998, which is a continuation of U.S. Ser. No. 08/409,337, filed Mar. 23, 1995, the entire teachings of which are incorporated herein by reference. Classically, the transfer of oxygen to tissue locations in humans and other vertebrate animals has been defined as being functionally dependent upon red blood cell (RBC) flux associated with the tissue, specifically the flow rate and hematocrit of RBCs, and upon the difference in oxygen content between arterial and venous RBCs. Further, the amount of oxygen transfer from the flow of other components of the circulatory system, such as plasma, typically has been a negligible fraction of the total oxygen delivered by the RBCs. Normally, RBCs contain about 98% of the arterial oxygen content. Thus, a condition leading to a localized, regionalized and/or systemic reduction in the circulation of RBCs, often resulting from a blood vessel constriction or occlusion, or from a reduced number of normal RBCs in the cardiovascular system, can result in local, regional or systemic tissue hypoxia, tissue death and possibly even in the death of the human or other vertebrate. Current methods for treating many causes of tissue hypoxia, particularly hypoxia resulting from a reduction in RBC flow, are typically ineffectual and/or require long, time-consuming procedures before restoring adequate oxygen delivery to the hypoxic tissue. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Lytic reagent composition for determination of nucleated red blood cells Inventor(s): Li, Jing; (Miami, FL), Li, Yi; (Miami, FL) Correspondence: Mitchell E. Alter; Coulter International CORP.; P.O. Box 169015, Mail Code 32-a02; Miami; FL; 33116-9015; US Patent Application Number: 20030040115 Date filed: July 27, 2001

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Abstract: A lytic reagent composition for measuring nucleated blood cells in a blood sample is described. The lytic reagent composition comprises a quaternary ammonium surfactant, an ethoxlyated phenol, and an ethoxylated alcohol. When mixed with a blood sample, the lytic reagent composition lyses red blood cells and enables a differentiation of nucleated red blood cells from other cell types by DC impedance measurement. The lytic reagent composition can further comprise an organic ligand for determining total hemoglobin concentration of a blood sample photometrically. Further disclosed is a lytic reagent system including the lytic reagent composition and a diluent. In addition, a single reagent composition containing salts is also disclosed, which can be used without a separate diluent. The lytic reagent compositions can be used for concurrent measurement of nucleated red blood cells, WBC, and hemoglobin of a blood sample. Excerpt(s): The present invention relates to a lytic reagent composition for determination of nucleated blood cells in a blood sample. More specifically the lytic reagent composition enables differentiation of nucleated red blood cells from other cell types in a blood sample by a direct current impedance measurement. In addition, the lytic reagent composition can further be used for measuring total hemoglobin concentration of the blood sample. Normal peripheral blood contains mature red blood cells which are free of nucleus. Nucleated red blood cells (NRBCs), or erythroblasts, are immature red blood cells. They normally occur in the bone marrow but not in peripheral blood. However, in certain diseases such as anemia and leukemia, NRBCs also occur in peripheral blood. Therefore, it is of clinical importance to measure NRBCs. Traditionally, differentiation and enumeration of NRBC are performed manually. The process involves the smearing of a blood sample on a microscope slide and staining the slide, followed by manual visual analysis of the individual slide. The NRBC concentration is reported as numbers of NRBC per 100 white blood cells. Usually, 200 white blood cells and the numbers of NRBC present in the same region on a blood smear are counted and the numbers are divided by 2 to express the NRBC concentration as the numbers of NRBC/100 WBC. This approach is extremely time-consuming as well as being subjective to the interpretation of the individual analyzing the slide. In recent years, several fluorescence flow cytometry methods have been developed for differentiating NRBCs. These methods utilizes specific nuclear staining technique to distinguish NRBCs from other cell types because it is difficult to differentiate NRBCs based on their electronic or optical properties. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Medium and low density gene chips Inventor(s): Bangce, Ye; (Shanghai, CN) Correspondence: Patrea L. Pabst; Holland & Knight Llp; Suite 2000, One Atlantic Center; 1201 West Peachtree Street, N.E.; Atlanta; GA; 30309-3400; US Patent Application Number: 20030186230 Date filed: July 23, 2001 Abstract: This invention makes public a kind of DNA chip for diagnosing the mutation of the hereditary anemia related genes with the character of fixed specific NA probes for testing the mutation of hereditary anemia related gent on the glass slide, silica plate, membrane and macromolecular materials. In comparison with current techniques, in this invention a 70.times.4 DNA probe is fixed on the surface of a carrier the size of a microscope slide, and this probe can detect hereditary anemia such as.alpha.-, or.beta.-

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thalassemia, and hemoglobin abnormality caused by related gent mutation. The invention has the statistic characteristics of parallel analysis and multiple analysis. Under the specific elution conditions, the completely matched and single-base-nonmatched hybridization can be distinguished. Consequently, this DNA chip is appropriate for early diagnosis and prenatal screening of hereditary anemia. Excerpt(s): This invention is a kind of DNA chip for diagnosing the mutation of the hereditary anemia related genes. China is a big country where a large part of the population is afflicted with the hereditary disease. The hereditary disease is a kind of disease caused by the modification of the genetic materials in human germ cells or fertilized ova and transferred from parental generation to progeny, and usually include 3 big groups: monogenic hereditary disease, chromosome hereditary disease and polygenic hereditary disease. Considering the whole world, at least 2% of newborns are afflicted with evident congenital abnormality. Though the incidence of most hereditary diseases (except polygenic hereditary disease) is low, there are a great variety of hereditary diseases. There are more than 4000 monogenic hereditary diseases, more than 100 chromosome hereditary diseases, and no less than 100 polygenic diseases. Moreover, on the average more than 100 new monogenic hereditary diseases have been being found per years in the world, which reflects the severity of the problems hereditary diseases have brought to medicine, society and families. For most of the hereditary diseases, there is no effective treatment at present, and hence the prevention seems particularly important. If fetuses can be diagnosed to determine whether they are afflicted with hereditary diseases, artificial abortion can be conducted on ill fetuses to prevent their coming into the world. Prenatal genetic screening supplemented with artificial abortion has been approved to be an effective method for preventing hereditary diseases that seriously harm health. Presently there are about 50,000,000 disabled persons in our country, a considerable number of which are caused by hereditary diseases. Because the rate of consanguineous marriage is high in remote regions and some rural areas, the incidence of hereditary diseases still tends to increase. Therefore, widely implementing prenatal genetic screening to eliminate the birth of congenitally defected infants and lower disease incidence plays an important role in ensuring eugenically superior birth and rearing, and improving population quality. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method and apparatus for determining blood parameters and vital signs of a patient Inventor(s): Hanna, Charles F.; (Libertyville, IL), Hohs, Ronald R.; (Kenosha, WI), Kantor, Stanislaw; (Buffalo Grove, IL), Khalil, Omar S.; (Libertyville, IL), Koziarz, James J.; (Highland Park, IL), Leiden, Jeffrey M.; (Glencoe, IL), Shain, Eric Brian; (Glencoe, IL), Wu, Xiaomao; (Gurnee, IL), Yeh, Shu-jen; (Grayslake, IL) Correspondence: Steven F. Weinstock; Abbott Laboratories; 100 Abbott Park Road; DEPT. 377/ap6a; Abbott Park; IL; 60064-6008; US Patent Application Number: 20030212316 Date filed: May 10, 2002 Abstract: A method of monitoring a patient that comprises a non-invasive measurement of the hematocrit value or the concentration of hemoglobin coupled with the measurement of one or more vital signs. These vital signs include, but are not limited to, cardiac pulse rate, blood pressure, and arterial blood oxygenation. The invention also provides an apparatus for monitoring changes in the hematocrit value of a patient, in combination with one or more of the patient's vital signs.

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Excerpt(s): This invention relates to an apparatus and a method for monitoring the condition of a patient, more particularly, for monitoring the condition of a patient by monitoring the change in a blood parameter, such as the concentration of hemoglobin or the hematocrit value, combined with changes in the patient's vital signs, such as cardiac pulse rate, oxygen saturation, and blood pressure. Measuring the vital signs of a patient is a standard practice in the care of a patient. Vital signs include cardiac pulse rate, temperature, breathing frequency, and blood pressure. Vital signs are usually measured at the physician's office, before the patient is admitted to a hospital, and routinely during hospital care. Additionally, these vital signs are continuously, or at least frequently, monitored during and after a surgical operation. In addition to cardiac pulse rate, temperature, and blood pressure, another parameter, arterial blood oxygen saturation, is monitored during and after a surgical procedure. A decrease in cardiac pulse rate, blood pressure, or blood oxygen saturation is indicative of a deterioration of the condition of the patient. The cardiac pulse rate is an important vital sign for determining the health status of a patient and for monitoring the patient's status during intensive care and postoperative recovery. A decrease in cardiac pulse rate indicates a decrease in the frequency at which the heart contracts and expands, and thus indicates a decrease in cardiac sufficiency. An irregular cardiac pulse rate is an indication of heart murmur and asynchronous cardiac performance. Monitors that incorporate blood oxygen saturation measurements and cardiac pulse rate are commercially available. A single sensor is used to determine both parameters. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method and apparatus for direct spectrophotometric measurements in unaltered whole blood Inventor(s): Shepherd, A. P.; (San Antonio, TX), Steinke, John M.; (San Antonio, TX) Correspondence: David D. Bahler, ESQ.; Fulbright & Jaworski L.L.P.; Suite 2400; 600 Congress Avenue; Austin; TX; 78701; US Patent Application Number: 20030202170 Date filed: December 6, 2002 Abstract: A method and apparatus which allow accurate spectrophotometric determinations of the concentrations of various hemoglobin species in whole blood without hemolysis or dilution. To overcome the complex optical properties of whole blood, the invention employs 1) an optical apparatus designed to maximize the true optical absorbance of whole blood and to minimize the effects of light scattering on the spectrophotometric measurements of the concentrations of various constituent components, and 2) methods to correct the hemoglobin concentration measurements for light scattering and for the effects of the finite bandwidth of the substantially monochromatic light. In the optical apparatus (including an optical cuvette) all optical parameters, such as sample thickness, detector size and shape, sample-to-detector distance, wavelengths, monochromicity, and maximum angle of light capture by detector, are optimal values so as to minimize the contribution of light scattering to the total optical attenuation of unaltered whole blood and so as to maximize the contribution of true optical absorbance. Four of the seven wavelengths of light are chosen by a criterion that minimizes the spectrophotometric error in the measurements of the concentrations of oxy-, carboxy-, and methemoglobin. Additional wavelengths enable the invention to assess light scattering quantitatively and to measure the concentrations of bilirubin and sulfhemoglobin. After making measurements of a blood

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sample's optical density at each of the wavelengths, the invention makes corrections for the effects of light scattering by red blood cells, for light scattering produced by other causes, and (if necessary) for the effects of the finite bandwidth of the substantially monochromatic light. By eliminating the need for hemolysis or dilution, the present invention overcomes disadvantages of prior art that requires pumps, plumbing, ultrasonic hemolyzers, and associated control circuitry, yet it makes accurate spectrophotometric measurements of the bilirubin concentration, the total hemoglobin concentration, and the relative concentrations of oxy-, deoxy-, carboxy-, met-, and sulfhemoglobin. Because the sample is neither hemolyzed nor diluted, it can be subjected to further chemical or hematological analysis. Excerpt(s): A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever. This invention relates to a method and apparatus to assess the optical transmittance of a sample of unaltered whole blood at multiple wavelengths to attain an accurate measurement of its total hemoglobin concentration, the concentration of bilirubin, and the concentrations of oxy-, deoxy-, carboxy-, met-, and sulfhemoglobin. To the best of the Applicants' knowledge, no prior art whether patented or not has ever successfully exploited the optical transmittance of unaltered whole blood to achieve an accurate measurement of the total hemoglobin concentration (THb) in a blood sample that could possibly contain as many as five different species of hemoglobin. Several different properties of whole blood have precluded such measurements. These characteristics include 1) the complex chemical mixture of as many as five individual hemoglobin species that are present in varying concentrations in a typical blood sample, and 2) the complex optical properties of whole blood that result from a combination of true optical absorbance by multiple light-absorbing compounds (including the hemoglobins, bilirubin, and other pigments), and the pronounced light-scattering ability of the red blood cells that are present in high concentrations. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method and apparatus for noninvasively monitoring hemoglobin concentration and oxygen saturation Inventor(s): Jeon, Kye-Jin; (Suwon-city, KR), Yoon, Gil-Won; (Seoul, KR) Correspondence: Lee & Sterba, P.C.; Suite 2000; 1101 Wilson Boulevard; Arlington; VA; 22209; US Patent Application Number: 20030009090 Date filed: April 19, 2002 Abstract: A method and apparatus for noninvasively monitoring hemoglobin concentration and oxygen saturation, wherein the method includes selecting at least two wavelengths from a region of wavelengths in which an extinction coefficient for water is smaller that for hemoglobin, the at least two wavelengths including at least two isobestic wavelengths; sequentially radiating incident light beams having the selected wavelengths onto a predetermined site of a body which includes a blood vessel; receiving, at another site of the body, light beams sequentially transmitted through the predetermined site and converting the received light beams into electrical signals; calculating the light attenuation variation caused by pulses of blood for the respective

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wavelengths from the electrical signals; obtaining at least one ratio of the light attenuation variation between the selected wavelengths; and calculating the hemoglobin concentration C.sub.Hb in blood using the calculated at least one ratio of the light attenuation variation between the wavelengths. Excerpt(s): The present invention relates to monitoring a concentration of hemoglobin in a human body. More particularly, the present invention related to a method and apparatus for noninvasively monitoring hemoglobin concentration and oxygen saturation in blood. Human blood consists of liquid plasma and three different corpuscles (i.e., red corpuscles, white corpuscles, and platelets). A primary function of the blood is to carry oxygen through the human body. Oxygen is essential to keep human body cells in a normal condition. If oxygen content is reduced, the metabolism of tissue cells is restricted. Furthermore, if oxygen is not supplied to the human body for a long time, body activity may stop. This critical oxygen supply function of the body relies essentially on the presence of hemoglobin in the red corpuscles. Accordingly, the total hemoglobin content in red corpuscles is considered to be a critical value in the clinical medicine field. Conventionally, the total hemoglobin content has been chemically analyzed by withdrawing blood from the human body. That is, hemoglobin concentration has been measured by a hemoglobincyanide method in clinical laboratories. However, a need exists for real-time monitoring of a patient's hemoglobin concentration in operating rooms or emergency rooms. In addition, females, pregnant females, growing children, and teenagers may require occasional measurements of their hemoglobin concentration values at home. Therefore, there is a need for measuring the hemoglobin concentration noninvasively without having to withdraw blood from the body. Conventional methods of measuring hemoglobin concentration and oxygen saturation do not consider the scattering effects that occur because hemoglobin is present in red blood cells, which act to scatter incident light. Therefore, hemoglobin concentration and oxygen saturation cannot be measured accurately by conventional methods. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method and apparatus for preparing an acellular read blood cell substitute Inventor(s): DeWoskin, Richard E.; (St. Charles, IL), Doubleday, Marc D.; (Cary, IL) Correspondence: Steven J. Sarussi; Mcdonnell Boehnen Hulbert & Berghoff; 32nd Floor; 300 S. Wacker Drive; Chicago; IL; 60606; US Patent Application Number: 20030191050 Date filed: October 17, 2002 Abstract: A process is disclosed for the preparation of an essentially tetramer-free, substantially stroma-free, polymerized, pyridoxylated hemoglobin. Also disclosed is an essentially tetramer-free, substantially stroma-free, polymerized, pyridoxylated hemoglobin product capable of being infused into human patients in an amount of up to about 5 liters. Excerpt(s): This invention relates to methods and apparatus for preparing red blood cell substitute products, i.e., hemoglobin products. It further relates to an acellular red blood cell substitute comprising an essentially tetramer-free, cross linked, polymerized, pyridoxylated hemoglobin solution which is free of stromal contaminants. For a number of years, blood banks have provided whole blood for replacement during surgery, because of trauma, or for other situations. However, whole blood obtained

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from human donors is not suitable for a variety of uses. In particular, the use of whole blood is problematic because of the requirement for donor-typing, stability and shelf-life problems and toxicity caused by viruses and other contaminants. These problems are especially pertinent to emergency situations, such as the use of blood by the military. Consequently, much effort has been devoted to the development of substitutes for whole blood obtained from human donors. This development has resulted in various modifications to blood from human or other mammalian sources. Stroma-free hemoglobin is known in the art to have oxygen transport and reversible oxygen (or ligand) binding capacities. Since toxicity problems have precluded use as a blood substitute, stroma-free hemoglobin has required further modifications to provide a nontoxic, useful pharmaceutical product. These modifications include (1) rendering hemoglobin free or substantially free of stroma and stromal contaminants; (2) pyridoxylation; (3) polymerization or cross-linking; (4) removal of tetramer; and (5) modification with carbon monoxide or other ligands. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for determining physiological effects of hemoglobin Inventor(s): Gow, Andrew J.; (Princeton, NJ), Singel, David J.; (Bozeman, MT), Stamler, Jonathan S.; (Chapel Hill, NC) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20030022267 Date filed: January 31, 2002 Abstract: NO preferentially binds to the minor population of the hemoglobin's vacant hemes in a cooperative manner, nitrosylates hemoglobin thiols, or reacts with liberated superoxide in solution. The distribution of minor forms of hemoglobin can be tested and the results can be used to predict whether a composition of hemoglobin will scavenge, load, eliminate, or donate NO. Hemoglobin thus serves to regulate the chemistry of NO. SNO-hemoglobin transfers NO equivalents to the red blood cell anion transport protein AE1, which serves to export NO from red blood cells. Regulation of AE1 function is the basis for methods of therapy to affect levels of NO or its biological equivalent. Excerpt(s): This application is a continuation of International Application No. PCT/US00/21 101, which designated the United Sates and was filed on Aug. 2, 2000, published in English, which claims the benefit of U.S. Provisional Application No. 60/146,680 filed Aug. 2, 1999. The entire teachings of each of these applications are incorporated herein by reference. Nitric oxide has been associated with many physiological effects, among them, smooth muscle contraction, vasodilation, inflammation responses, and inhibition of platelet adhesion and aggregation. Finding the natural reservoirs of NO and finding ways to regulate the levels of biologically available NO and its alternative forms would provide the means to control these physiological effects. 4.) release (deoxyHb acting as a donor of NO, more specifically, a vasodilator). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method for improving oxygen transport by stored red blood cells Inventor(s): Jacobs, Edward E. JR.; (Lexington, MA), Light, William R.; (Natick, MA), Page, Thomas C.; (Watertown, MA) Correspondence: N. Scott Pierce, ESQ.; Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20030049232 Date filed: September 10, 2001 Abstract: A method of treatment of a patient includes administering to the patient stored red blood cells and a hemoglobin solution. The stored red blood cells and the hemoglobin solution can be administered to the patient simultaneously. Alternatively, the hemoglobin solution can be administered to the patient prior to administrating the stored red blood cells or the stored red blood cells can be administered to the patient prior to administering the hemoglobin solution. A composition of the invention includes stored red blood cells and a hemoglobin solution. Excerpt(s): Stored blood undergoes a number of deleterious biochemical changes over time, known collectively as "storage lesion." These changes can include microaggregation of cells, hemolysis, vesicle formation, decreased membrane flexibility, decreased stability, and increased hemoglobin-oxygen affinity. The changes reduce the overall benefit of administering stored blood or red blood cell containing blood products to the patient and may even cause deleterious effects when transfused into a patient. For example, increased microaggregate formation and loss of membrane flexibility of the red blood cells may cause blockage of microcirculatory vessels resulting in local ischemia and pulmonary dysfunction. Additionally, the loss of 2,3diphosphoglycerate (2,3-DPG) in red blood cells results in substantially increased hemoglobin-O.sub.2 affinity. Blood stored for greater than one week shows a significant decrease in 2,3-DPG levels. After two weeks, only about 40% of 2,3-DPG remains and by three weeks only about 10% remains. (S. P. Masouredis, Preservation and Clinical Use of Erythrocytes and Whole Blood, Chapter 164, In: Hemology, 3.sup.rd edition, Williams, Beutler, Erslev and Lichtman, (eds.) McGraw-Hill, N.Y., pp. 1529-1549 (1983)). The loss of 2,3-DPG produces a concomitant drop in P.sub.50. For example, after four weeks of storage in the preservative, citrate phosphate dextrose (CPD), the P.sub.50 of packed red cells drops to approximately 15 mm Hg (Wells et al., Transfusion 21:709-714 (1981)). Since release of oxygen from red blood cells usually is proportional to P.sub.50, the capacity of stored red blood cells to deliver oxygen also decreases over time. Storage lesions can cause deleterious changes in oxygen transport by decreasing both convective and diffusive oxygen delivery. Microaggregates and inflexible cells may be caught in microvessels, blocking flow to downstream tissue. Additionally, red blood cells containing hemoglobin with relatively high oxygen affinity have reduced ability to release oxygen to tissue. Stored red blood cells having high affinity for oxygen can "rejuvenate" over time after transfusion into the body. Levels of 2,3-DPG return to 30% to 50% of normal by four hours and to normal levels with approximately twenty-four hours, though this rate can be variable. (Valeri and Hirsch, J. Lab. Clin. Med. 73:722-733 (1969); Beutler and Wood, J. Lab. Clin. Med. 74:300-304 (1969)). The rate of 2,3-DPG recovery may be dependent upon the metabolic state of the patient. (O'Brien and Watkins, J. Thor. & Cardiovas. Surg. 40:611 (1960)). Ironically, stored red blood cells are transfused to meet an acute need, but suffer from acute lesion. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method for measuring hemoglobin concentration ( hgb) in the blood in a circuit of a dialysis machine, measuring device and circuit for the application of the method Inventor(s): Delnevo, Annalisa; (Correggio, IT), Fava, Massimo; (Mirandola, IT), Paolini, Francesco; (Modena, IT) Correspondence: Finnegan, Henderson, Farabow, Garrett & Dunner; Llp; 1300 I Street, NW; Washington; DC; 20005; US Patent Application Number: 20030138961 Date filed: October 21, 2002 Abstract: A method for measuring the hemoglobin concentration (HGB) in the blood in a circuit (2) of a dialysis machine (1), the method comprising the measurement of the values of absorption (A) of electromagnetic waves by the blood conveyed along a specified section (5a) of the said circuit (2), the measurement of the values of a physical quantity iron the group comprising the blood pressure (1)), the blood temperature (T) and the rate of flow (Q.sub.b) of the blood along the aforesaid section (5a), and the calculation of the hemoglobin concentration (HGB) as a function of the values of absorption (A) and of the aforesaid physical quantity Excerpt(s): The present invention relates to a method for measuring hemoglobin concentration in the blood in a circuit of a dialysis machine. There is a known way of determining the concentration of hemoglobin in the red corpuscles during the dialysis treatment, by means of highly accurate measurements of an intrusive kind, which require the laboratory examination of blood samples. Other dialysis machines enable non-intrusive measurements of the hemoglobin concentration to be made within the machine. The non-intrusive measurements made within the machine are markedly less accurate than laboratory measurements, but have the advantage of being provided in real time in such a way that the operating parameters of the dialysis machine can be corrected instantaneously. The patent IT 1,240,489 discloses a method of measuring the hemoglobin concentration within the machine and in a non-intrusive way, by measuring the absorption of electromagnetic waves of the blood flowing in the arterial branch of the first circuit. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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METHOD FOR HEMOGLOBIN

QUANTITATIVE

DETERMINATION

OF

GLYCATED

Inventor(s): Law, Wai Tak; (Moorestown, NJ), Nikolyukin, Yuri; (Moorestown, NJ) Correspondence: Browdy And Neimark, P.L.L.C.; 624 Ninth Street, NW; Suite 300; Washington; DC; 20001-5303; US Patent Application Number: 20030073243 Date filed: August 31, 2001 Abstract: A method and a system for separating glycated hemoglobin from nonglycated hemoglobin, and a method for one-read quantitative determination of the glycated hemoglobin and %HbA.sub.1c that does not require an additional measurement of total hemoglobin. Excerpt(s): The present invention relates to a novel method for measuring the concentration of glycated hemoglobin (gHb) and the percent hemoglobin A.sub.1c (HbA.sub.1c) in blood without using antibodies, and more particularly, to a one-read

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method which does not require an additional measurement of total hemoglobin for assessing percentage hemoglobin A.sub.1c. The importance of diagnosis and monitoring of diabetes is emphasized by the American Diabetes Association reporting that 15.7 million Americans have diabetes, or 5.9% of the population. However, routinely used direct measurement of blood glucose level in patients has a limited value since it gives information only about the glucose concentration at the time of sampling and is influenced dramatically by diet. Nevertheless, an accurate index of a person's mean blood glucose level over 2 to 3 months can be provided by measurement of a specific type of glycated hemoglobin called the hemoglobin A.sub.1c concentration in blood [The Diabetes Control and Complications Trial Research Group, N. Engl. J. Med., 329, 977-986 (1993)]. Glycated hemoglobin, of which about 60% is represented by HbA.sub.1c, is formed via nonenzymatic attachment of glucose to the hemoglobin molecule at a rate that is directly proportional to the ambient glucose concentration [Bunn H. F., Haney D. N., Gabbay K. H., Gallop P. N., Biochem. Biophys. Res. Commun., 67, 103-9 (1975)].In the uncontrolled diabetic, the proportion of HbA.sub.1c may be increased three to four fold. For example, a healthy person may have an HbA.sub.1c concentration of 4.1-6.5% of the total hemoglobin, whereas in the diabetic the concentration may be up to 20%. Therefore, HbA.sub.1c measurement can provide diabetic patients an overview of their success in meeting long-term goals for controlling their blood glucose levels. a) charge differences as in ion-exchange chromatography [U.S. Pat. No. 4,407,961, U.S. Pat. No. 4,649,122, U.S. Pat. No. 4,270,921, U.S. Pat. No. 4,389,491, U.S. Pat. No. 4,436,820] and in electrophoresis [U.S. Pat. No. 4,351,711]. Ionexchange chromatography involves separation of hemoglobin fractions in microcolumns of ion exchange resin. Glycated hemoglobin elutes first while the nonglycated hemoglobin remains attached to the resin and can be removed by changing the eluting buffer. For proper separation, the composition, pH and ionic strength of the eluting buffer must be maintained within narrow limits. Additionally, the temperature control is critical. Subsequent spectrophotometrical measurement provides the amount of the fraction constituting the glycated hemoglobin. Electrophoresis exploits relative mobility of the hemoglobin fractions in a specially prepared agar medium in an electric field. Common drawbacks for these methods are poor reproducibility, sensitivity to variations in temperature, pH, ionic strength, and sample storage conditions. Also they require expensive equipment and usually prove too slow and cumbersome for practical use. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for separating unmodified hemoglobin from cross-linked hemoglobin Inventor(s): Gawryl, Maria S.; (Charlestown, MA), Houtchens, Robert A.; (Milford, MA), Laccetti, Anthony J.; (North Andover, MA), Light, William R.; (Natick, MA) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20030203350 Date filed: April 18, 2003 Abstract: A method for separating unmodified hemoglobin from cross-linked hemoglobin in a hemoglobin solution. The method involves contacting the hemoglobin solution with a least one dissociating agent to form a dissociation solution wherein unmodified tetrameric hemoglobin is dissociated to form hemoglobin dimers.

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The hemoglobin dimers are then separated from the dissociation solution, while retaining the cross-linked hemoglobin in the dissociation solution. Excerpt(s): This application is a Continuation of U.S. Ser. No. 09/460,153, filed on Dec. 13, 1999, which is a Continuation of U.S. Ser. No. 09/305,412, filed on May 5, 1999, which is a Continuation of U.S. Ser. No. 08/477,916, filed on Jun. 7, 1995. The entire teachings of the above applications are incorporated herein by reference. There exists a need for a blood-substitute to treat or prevent hypoxia resulting from blood loss (e.g, from acute hemorrhage or during surgical operations), resulting from anemia (e.g., pernicious anemia or sickle cell anemia), or resulting from shock (e.g, volume deficiency shock, anaphylactic shock, septic shock or allergic shock). The use of blood and blood fractions as in these capacities as a blood-substitute is fraught with disadvantages. For example, the use of whole blood often is accompanied by the risk of transmission of hepatitis-producing viruses and AIDS-producing viruses which can complicate patient recovery or result in patient fatalities. Additionally, the use of whole blood requires blood-typing and cross-matching to avoid immunohematological problems and interdonor incompatibility. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method of measuring the stress or relaxation level of a mammal Inventor(s): Dean, Kathryn; (Ringoes, NJ), Kollias, Nikiforos; (Skillman, NJ), McCulloch, Laura; (Hampshire, GB), Tierney, Neena; (Yardley, PA), Wiegand, Benjamin; (Newtown, PA) Correspondence: Audley A. Ciamporcero JR.; Johnson & Johnson; One Johnson & Johnson Plaza; New Brunswick; NJ; 08933-7003; US Patent Application Number: 20030220550 Date filed: January 29, 2003 Abstract: A method of measuring the stress or relaxation level of a mammal and a method of measuring the activity of the sympathetic nervous system of a mammal by measuring quantititative levels of deoxyhemoglobin and oxyhemoglobin are disclosed. Preferably, the levels of deoxyhemoglobin and hemoglobin are measured by a noninvasive technique, such as spectroscopy. A method of changing the activity of the sympathetic nervous system of a mammal is also disclosed, wherein the method includes a step of administering an effective amount of sensory regimen to the mammal. The method is useful for humans who are operating vehicles or machinery, who are suffering from cardiovascular disease or related complications, who are pregnant, or who are preparing for sleep. In addition, a method of improving the complexion of the skin of a mammal is disclosed. Excerpt(s): This application claims priority to Great Britain Patent Application No. 0202032.9 filed Jan. 29, 2002. This invention is related to methods of measuring and changing the level of stress or relaxation level in mammals. More particularly, the invention is related to methods of measuring and changing the activity of the sympathetic nervous system of a mammal. Advances in technology in the last century have brought benefits to society but have resulted in a greater prevalence of stress in the daily lives of people at all levels of society. Our stress response mechanisms have not adapted at the same pace as advancing technology. The effect of stress on health and well being is well documented. See, for example, Robert M. Sapolsky, Why Zebra's Don't Get Ulcers-An Updated Guide to Stress, Stress Related Diseases and Coping, ISBN

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0-7167-3210-6, Chapter 1, (5.sup.th Edition 2000), and George P. Chrousos and Philip W. Gold, "The Concepts of Stress and Stress System Disorders-Overview of Physical and Behavioral Homeostasis," JAMA, Mar. 4, 1992, Vol. 267, No. 9. It is known that stress, particularly chronic stress, may cause or aggravate many conditions, including immunosuppression and susceptibility to infectious diseases, gastric conditions, sleep problems, depression, premature birth in expectant mothers, low birth weight, degeneration of brain neurons leading to memory and learning problems, elevated blood pressure, heart complications and stroke due to elevated blood lipid levels and other health complications. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method of quantifying hemoglobin and method of measuring glycation ratio of hemoglobin Inventor(s): Yagi, Yuji; (Kyoto, JP), Yonehara, Satoshi; (Kyoto, JP) Correspondence: Merchant & Gould PC; P.O. Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20030186449 Date filed: March 20, 2003 Abstract: A method of determining Hb is provided, by which an amount of Hb can be determined easily and accurately without fear of damage to the environment. Hemoglobin in a sample is denatured with a tetrazolium compound to give denatured hemoglobin, and an amount of an optical change in the sample is measured at an absorption wavelength specific to the denatured hemoglobin. Using the amount of the optical change thus measured, an amount of the hemoglobin in the sample can be determined. The amount of the optical change preferably is measured at a wavelength in a range from 520 to 670 nm. According to this method, an amount of Hb can be determined with high accuracy as shown in FIG. 1. Excerpt(s): The present invention relates to a method of determining an amount of hemoglobin (Hb) in a sample. Hb in the blood plays an important role in transporting oxygen from the lungs to organs and thus relates to diseases such as leukemia, anemia, and the like, for example. Therefore, determining an amount of Hb has been considered very important in the field of a clinical analysis. On the other hand, glycated Hb serves as an important index for the diagnosis, treatment, etc. of diabetes because it reflects previous blood glucose levels in vivo. Therefore, determining a ratio of glycated Hb also has been considered important. For determining the ratio of glycated Hb, it is necessary to determine the amount of Hb. Examples of a method of determining Hb include measuring an absorbance of Hb. However, the Hb that is not yet denatured (hereinafter, referred to as "undenatured Hb") exhibits an absorption maximum at different wavelengths depending on its state, e.g., the state where it is bound to oxygen, the state where it is not bound to oxygen, etc. Therefore, it is difficult to determine an amount of Hb accurately by merely measuring the absorbance of the Hb. On this account, conventionally, a method has been employed in which the absorbance of Hb is measured after the Hb has been denatured so as to be stabilized. Examples of such a method include a cyanmethemoglobin method (HiCN method), azide metohemoglobin method, sodium lauryl sulfate method (SLS method), alkaline hematin method, and the like. Among these, the HiCN method, which is an international standard method, is employed particularly widely. In this HiCN method, a reagent containing potassium ferricyanide and potassium cyanide is added to blood so that Hb is converted into stable

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cyanmethemoglobin, and the absorbance is measured at a predetermined wavelength (540 nm) to determine the amount of the Hb. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method of selectively determining glycated hemoglobin Inventor(s): Yonehara, Satoshi; (Kyoto, JP) Correspondence: Merchant & Gould PC; P.O. Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20030162242 Date filed: April 14, 2003 Abstract: A method of determining glycated hemoglobin is provided, by which a ratio of the glycated hemoglobin in a sample can be determined accurately and easily. The ratio of glycated hemoglobin can be determined by degrading a glycated hemoglobin in a whole blood sample selectively with a protease to give a glycated hemoglobin degradation product`; causing a redox reaction between a glycation site of the glycated hemoglobin degradation product and a fructosyl amino acid oxidoreductase; and determining this redox reaction. Further, as shown in FIG. 1, in a whole blood sample, there is a correlation between the ratio of the glycated hemoglobin determined by this method and an HbA1c concentration. Thus, without determining the glycated.alpha.amino group as a characteristic structure of HbA1c, an amount of HbA1c can be determined accurately and easily from the determined ratio of the glycated hemoglobin. Excerpt(s): The present invention relates to a method of determining an amount of glycated hemoglobin present in whole blood. Glycated hemoglobin in blood has served as an important index for the diagnosis, treatment, etc. of diabetes because it reflects previous blood glucose levels in vivo. The determination of such glycated hemoglobin has been carried out, for example, by high performance liquid chromatography (HPLC), a minicolumn method, immunoassays, and the like. According to these methods, the amount or ratio of hemoglobin that has been glycated can be determined. Recently, an enzymic method that enables the determination of glycated proteins by means of a fructosyl amino acid oxidoreductase (FAOD) has been developed, and attempts have been made to determine an amount of hemoglobin that has been glycated (i.e., glycated hemoglobin) by this enzymic method. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methods and compositions for oxygen transport comprising a high oxygen affinity modified hemoglobin Inventor(s): Vandegrift, Kim D.; (San Diego, CA), Winslow, Robert M.; (La Jolla, CA) Correspondence: Laurie A. Axford; Morrison & Foerster Llp; Suite 500; 3811 Valley Centre Drive; San Diego; CA; 92130; US Patent Application Number: 20030153491 Date filed: April 1, 2002 Abstract: The present invention relates to blood products, and more particularly to compositions comprising a modified oxygenated hemoglobin having a high affinity for

Patents 219

oxygen and methods for making such compositions. Such compositions according to the present invention have better stability to autooxidation and superior oxygen carrying characteristics. Excerpt(s): This application claims priority under 35 U.S.C.sctn.119(e) to U.S. Serial No. 60/327,741, filed Jan. 11, 2002. The present invention relates to blood products, and more particularly to compositions comprising a modified hemoglobin having a high affinity for oxygen and methods for making such compositions. The blood is the means for delivering nutrients to the tissues and removing waste products from the tissues for excretion. The blood is composed of plasma in which red blood cells (RBCs or erythrocytes), white blood cells (WBCs), and platelets are suspended. Red blood cells comprise approximately 99% of the cells in blood, and their principal function is the transport of oxygen to the tissues and the removal of carbon dioxide therefrom. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods for purification of an activated PEG solution and for the synthesis of a modified hemoglobin solution Inventor(s): Stacey, Cyrus John; (Raleigh, NC), Talarico, Todd Lewis; (Cary, NC) Correspondence: Alston & Bird Llp; Bank OF America Plaza; 101 South Tryon Street, Suite 4000; Charlotte; NC; 28280-4000; US Patent Application Number: 20030045602 Date filed: August 21, 2001 Abstract: The present invention employs a dissolved activated polyethylene glycol (aPEG) or related molecule that has been passed through a filtration means for the substantial reduction of bioburden or endotoxin levels in the aPEG solution. The resulting filtered aPEG solution can be used for the preparation of a PEGylated hemoglobin solution containing substantially reduced levels of bioburden or endotoxin. Excerpt(s): The invention relates to methods for the purification of an activated polyethylene glycol solution and for the synthesis of a modified hemoglobin solution. Blood is the circulating liquid that transports oxygen and nutritive materials to the tissues of the body and removes carbon dioxide and other metabolic products and wastes for excretion. Blood consists of a fluid, plasma, in which a variety of components including red blood cells are suspended. Stedman's Medical Dictionary, 26.sup.th edition, page 214 (1995). A particularly prevalent component of red blood cells is the protein hemoglobin, which is specifically responsible for the transport of oxygen from the lungs to other tissues in the body. Because of the great demand for blood in the United States and throughout the world, intense research efforts have been directed towards the development of hemoglobin-based blood substitutes. Such substitutes have been produced with a variety of modifications of purified hemoglobin in order to prevent toxicity or otherwise enhance the properties of the molecule, with one particularly important class of modification accomplished using molecules of the polyethylene glycol (PEG) family that have been activated (aPEGs) so as to be capable of chemically modifying proteins. Such PEGylation is important because it favorably alters the activity, solubility, circulating half-life in vivo, toxicity and immunogenicity of hemoglobins. See, generally, Delgado et al. (1992) Crit. Rev. Ther. Drug Carrier Sys. 9:249-304; Greenwald et al. (2000) Crit. Rev. Ther. Drug Carrier Sys. 17: 101-161. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Nitric oxide-scavenging system for culturing oocytes, embryos, or other cells Inventor(s): Hansel, William; (Baton Rouge, LA), Lim, Jeong-Mook; (Suwon, KR) Correspondence: Patent Department; Taylor, Porter, Brooks & Phillips, L.L.P; P.O. Box 2471; Baton Rouge; LA; 70821-2471; US Patent Application Number: 20030068816 Date filed: June 14, 2002 Abstract: Nitric oxide adversely affects survival and development of cells such as oocytes and embryos in vitro, particularly in a co-culture system. The addition of a nitric oxide inhibitor such as hemoglobin to such systems eliminates this toxic effect, and promotes mammalian oocytes, embryos, or other cells in vitro. Excerpt(s): This invention pertains to compositions and methods for mammalian cell culture in vitro, for example the culture of mammalian oocytes or embryos. Various cell culture media have been used to support the growth of mammalian cells in vitro. Many of these media are quite satisfactory in supporting the growth of certain cell types. Other cell types, however, have proven more difficult to support in vitro. There is a continuing need for improved media to support the growth of such cell types. There is a particular need for improved media to support mammalian oocytes and embryos. A high percentage of embryos that are fertilized or transferred in vitro cease development prematurely. The consequences are felt at both the economic and the human levels. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Nitrosylation of protein SH groups and amino acid residues as a therapeutic modality Inventor(s): Loscalzo, Joseph; (Dedham, MA), Simon, Daniel; (Waban, MA), Singel, David; (Arlington, MA), Stamler, Jonathan; (Boston, MA) Correspondence: Edward D Grieff; Hale & Dorr Llp; 1455 Pennsylvania Ave, NW; Washington; DC; 20004; US Patent Application Number: 20030007967 Date filed: August 13, 2002 Abstract: Nitrosylation of proteins and amino acid groups enables selective regulation of protein function, and also endows the proteins and amino acids with additional smooth muscle relaxant and platelet inhibitory capabilities. Thus, the invention relates to novel compounds achieved by nitrosylation of protein thiols. Such compounds include: Snitroso-t-PA, S-nitroso-cathepsin; S-nitroso-lipoprotein; and S-nitroso-immunoglobulin. The invention also relates to therapeutic use of S-nitroso-protein compounds for regulating protein function, cellular metabolism and effecting vasodilation, platelet inhibition, relaxation of non-vascular smooth muscle, and increasing blood oxygen transport by hemoglobin and myoglobin. The compounds are also used to deliver nitric oxide in its most bioactive form in order to achieve the effects described above, or for in vitro nitrosylation of molecules present in the body. The invention also relates to the nitrosylation of oxygen, carbon and nitrogen moieties present on proteins and amino acids, and the use thereof to achieve the above physiological effects. Excerpt(s): This application is a continuation of U.S. application Ser. No. 08/437,884 filed May 9, 1995, which is a continuation of U.S. application Ser. No. 08/287,830 filed

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Aug. 9, 1994, issued as U.S. Pat. No. 5,593,876, which is a continuation of U.S. application Ser. No. 08/198,854 filed Feb. 17, 1994, abandoned, which is a continuation of U.S. application Ser. No. 07/943,835 filed Sep. 14, 1992, abandoned, which is a continuation-in-part of U.S. application Ser. No. 07/791,668, filed Nov. 14, 1991, abandoned. This application is related to U.S. Pat. Nos. 5,863,890 and 6,291,424 and U.S. application Ser. No. 09/835,038 filed Apr. 16, 2001. This invention relates to nitrosylation of proteins and amino acids as a therapeutic modality. In particular, the invention relates to S-nitroso-protein compounds and their use as a means to selectively regulate specific protein functions, to selectively regulate cellular function, to endow the protein with new smooth muscle relaxant and platelet inhibitory properties and to provide targeted delivery of nitric oxide to specific bodily sites. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Optical method and apparatus for red blood cell differentiation on a cell-by-cell basis, and simultaneous analysis of white blood cell differentiation Inventor(s): Bearden, James C. JR.; (Milpitas, CA), Kim, Young Ran; (Sunnyvale, CA), Landayan, Marilou Z.; (Newark, CA), Oever, Ronny van?apos;t; (Enschede, NL) Correspondence: Steven F. Weinstock; Abbott Laboratories; DEPT. 377/ap6d-2; 100 Abbott Park Road; Abbott Park; IL; 60064-6050; US Patent Application Number: 20030025896 Date filed: June 5, 2001 Abstract: Methods and apparatus are disclosed for determining the volume, hemoglobin concentration, maturity and cell shape of mammalian red blood cells in a sample and simultaneously monitoring system standardization. Excerpt(s): Methods and apparatus are disclosed for determining the volume, hemoglobin concentration, maturity and cell shape of mammalian red blood cells in a sample and simultaneously monitoring system standardization. Methods for distinguishing red blood cells from other cellular particles, prior to the red blood cell analysis are also disclosed. The method can be applied with accuracy over a wide range of visible spectrum. A whole blood sample is treated with a reagent solution containing a nonionic surfactant in an isotonic buffered solution at neutral pH, the red blood cells are passed through a beam of light in single file at a selected wavelength, obtaining an initial cytogram by means of the resultant magnitude of one light loss signal and one forward angle light scatter signal at a selected angular interval and a third side angle light scatter or two forward angle light scatter signals at selected angular intervals and a third side-angle light scatter signal, projecting the cytogram, point by point, onto a precalibrated 3-dimensional surface containing grid lines of volume and hemoglobin concentration, determining accurate values of cell volume and hemoglobin concentration by means of the location of each projected intercept onto the three dimensional grid surface. The present invention relates to a method and apparatus for simultaneous monitoring of system standardization and automated analysis of mammalian red blood cell (RBC) and white blood cell (WBC) differentiation in a body fluid. The present invention particularly relates to a multi-angle light scatter and fluorescence apparatus such as multi-parameter hematology analyzer or flow cytometer that can perform both RBC and WBC differential analysis using the same optical detection system. The present invention more particularly relates to (i) a method for RBC analysis for volume, hemoglobin content, cell shape, and maturity in whole blood; (ii) an accurate method for determination of immature RBC (reticulocyte) volume and

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hemoglobin content; (iii) a RBC method that can continuously monitor the system standardization while a blood sample is being analyzed for RBC differentiation; and (iv) a method that can measure both mature RBC and reticulocyte volume and hemoglobin content, using one reagent and (v) an apparatus that can perform both WBC and RBC differential analysis using the same optical detection system. The conventional hematology method, microscopic examination of patient blood smears for RBC morphology for cell size, cell shape, color (for hemoglobin content) and inclusions provides a wealth of information leading towards the diagnosis and monitoring patient's clinical conditions. Quite misleading impressions can be drawn, however, from substandard blood films, besides the fact that this manual method is very subjective and time consuming. During the past three decades, a number of automated hematology analyzers have become available to handle heavy laboratory work loads and to reduce labor. Most of these instruments measure mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC) of red blood cells either by electrical impedance measurement or by light scatter optical measurement in combination with a colorimetric hemoglobin measurement. Because of incompleteness or ambiguity of morphological information in cell analysis from these systems, 5 to 10 percent of samples in hematology laboratories routinely undergo smear review for cell morphology using the microscopic method. More advanced hematology analyzers in terms of RBC morphology analysis are the Technicon H*1 and the Bayer ADVIA. Both systems are designed to measure red cell volume and hemoglobin concentration simultaneously on cell-by-cell basis, according to the teachings of D. H. Tycko, described in U.S. Pat. No. 4,735,504. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Preparation containing an oxygen carrier for regeneration of the skin in the case of oxygen deficiency Inventor(s): Barnikol, Wolfgang; (Mainz, DE) Correspondence: Kurt Briscoe; Norris, Mclaughlin & Marcus, P.A.; 220 East 42nd Street, 30th Floor; New York; NY; 10017; US Patent Application Number: 20030180365 Date filed: May 22, 2003 Abstract: The invention relates to an oxygen carrier-containing preparation, which can be applied externally, hemoglobin and optionally myoglobin being incorporated in a preparation in a gel-like consistency. The preparation is suitable for being rubbed into the skin in order to intensify the diffusive supply of oxygen to the skin from the outside in order to regenerate the skin and eliminate the oxygen deficiency. The agent is also suitable for preventing such conditions and is particularly suitable in the case of degenerative, radiation-induced, thermally induced and age-related skin changes, even after the skin has suffered burns, optionally in co-therapy with intravasal oxygen therapy.The invention furthermore relates to a method for preparing such a preparation and to its use. Excerpt(s): The invention relates to an oxygen carrier preparation, which can be administered externally, hemoglobin and optionally myoglobin being incorporated molecularly dispersed in a preparation of gel-like consistency. The preparation is suitable for being rubbed into the skin, in order to intensify the diffusive supply of oxygen to the skin from the outside in order to intensify the regeneration of the skin and eliminate the oxygen deficiency. The agent is also suitable for preventing such

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conditions and is particularly suitable in the case of degenerative, radiation-induced, thermal and age-related skin changes, even after the skin has suffered burns, optionally in co-therapy with intravasal oxygen therapy. The invention furthermore relates to a method for producing such a preparation and to the use of such a preparation. A series of degenerative changes in the skin are caused by chronic oxygen deficiency. One such deficiency is caused when the blood no longer flows adequately through the skin. This happens either due to a constriction of the small arteries--the blood-supplying vessels-or due to an obstruction of veins--the veins are the discharging vessels of the organism; especially the legs are affected. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Purification of red blood cells by separation and diafiltration Inventor(s): Baqai, Javed; (Lexington, MA), Gawryl, Maria S.; (East Boston, MA), Houtchens, Robert A.; (Milford, MA), Light, William R.; (Natick, MA) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20030165573 Date filed: February 28, 2002 Abstract: Red blood cells are purified by separating whole blood, such as by centrifugation, to form a red blood cell fraction and a liquid fraction. The whole blood can be defibrinated or treated to prevent coagulation prior to separation. Preferably, the whole blood is bovine blood. The red blood cell fraction is then diafiltered to purify the red blood cells. The purified red blood cells can then be lysed to form a lysate of purified red blood cells. The purified red blood cells and the lysate of purified red blood cells are suitable for use in producing hemoglobin blood substitute. Excerpt(s): The development of hemoglobin-based oxygen carriers has focused on oxygen delivery for use in medical therapies such as transfusions and the production of blood products. Hemoglobin-based oxygen carriers can be used to prevent or treat hypoxia resulting from blood loss (e.g, from acute hemorrhage or during surgical operations), from anemia (e.g., pernicious anemia or sickle cell anemia), or from shock (e.g, volume deficiency shock, anaphylactic shock, septic shock or allergic shock). Existing hemoglobin-based oxygen carriers include perfluorochemicals, synthesized hemoglobin analogues, liposome-encapsulated hemoglobin, chemically-modified hemoglobin, and hemoglobin-based oxygen carriers in which the hemoglobin molecules are cross-linked. Preparation of hemoglobin-based oxygen carriers includes several purification steps. In order to remove plasma proteins from whole blood, a process of microfiltration is used to wash the cells of whole blood. The cell washing operation removes plasma proteins from bovine whole blood using diafiltration over a 0.2.mu.m microfiltration membrane with isotonic saline/citrate solution. Diafiltration is a continuous filtration operation in which saline/citrate solution is added to the filter retentate to maintain a volume in the recirculation tank. The blood solution is recirculated across the filter and the filtrate, containing the plasma proteins, is sent to waste. Washing the blood solution using filtration results in highly variable processing times which adversely effect product throughput. Additionally, extended cell washing process times could lead to growth of unacceptable levels of bioburden and to cell lysis, thereby further reducing process yield. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Reagentless analysis of biological samples Inventor(s): Jeng, Tzyy-Wen; (Vernon Hills, IL), McDowell, Larry L.; (Beach Park, IL), Oosta, Gary M.; (Gurnee, IL), Pezzaniti, Joseph Larry; (Round Lake, IL), Shain, Eric B.; (Glencoe, IL) Correspondence: Steven F. Weinstock; Abbott Laboratories; 100 Abbott Park Road; DEPT. 377/ap6a; Abbott Park; IL; 60064-6008; US Patent Application Number: 20030048432 Date filed: July 9, 2002 Abstract: Apparatus and method for determining at least one parameter, e.g., concentration, of at least one analyte, e.g., urea, of a biological sample, e.g., urine. A biological sample particularly suitable for the apparatus and method of this invention is urine. In general, spectroscopic measurements can be used to quantify the concentrations of one or more analytes in a biological sample. In order to obtain concentration values of certain analytes, such as hemoglobin and bilirubin, visible light absorption spectroscopy can be used. In order to obtain concentration values of other analytes, such as urea, creatinine, glucose, ketones, and protein, infrared light absorption spectroscopy can be used. The apparatus and method of this invention utilize one or more mathematical techniques to improve the accuracy of measurement of parameters of analytes in a biological sample. The invention also provides an apparatus and method for measuring the refractive index of a sample of biological fluid while making spectroscopic measurements substantially simultaneously. Excerpt(s): This invention relates to the field of analysis of biological samples, both solids and liquids, e.g., urinalysis, and, in particular, to apparatus and method for conducting analysis of biological samples without the need for reagents. This invention also relates to detection of adulteration of samples of biological fluid to protect the integrity of analysis results. Determining the concentration of an analyte or a parameter of physical condition in a biological sample has been an important area in the field of diagnostics. Analytes that have diagnostic value includes nutrients, metabolites, enzymes, immunity entities, hormones, and pathogens. The physical characteristics of a biological sample, such as temperature, optical properties, density, and hardness, are also of interest because of their capability of providing indications for diagnostic purposes. Most determination methods use signal-enhancing agents. Urinalysis involves measuring critical components in a sample of urine to determine the condition of the body with respect to diseases and other substances, e.g., drugs. Urine contains a wide variety of substances. In current urinalysis systems, such as those provided by Bayer and Boehringer Mannheim, the analytes measured include glucose, bilirubin, ketones (80% 3-hydroxybutyrate, 17% acetoacetic acid, 3% acetone), blood (or hemoglobin), protein, urobilinogen, nitrites, and leukocytes. Specific gravity (or refractive index) and pH are also measured. In some cases, measurement of creatinine is suggested, but is not provided by Bayer's or Boehringer Mannheim's urinalysis systems. All of these analytes represent breakdown products of metabolism from various organ systems. The pattern of excretion is indicative of various disease states. The history and utility of urinalysis is discussed in Voswinckel, Peter, "A marvel of colors and ingredients. The story of urine test strips", Kidney International, Vol. 46, Suppl. 47 (1994), pp. S-3-S-7, and Free, Alfred H. & Free, Helen M., "Urinalysis: Its Proper Role in the Physician's Office", Office Practice of Laboratory Medicine, Clinics in Laboratory Medicine--Vol. 6, No. 2, June 1986, both of which are incorporated herein by reference.

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Red blood cells loaded with S-nitrosothiol and uses therefor Inventor(s): Bonaventura, Joseph; (Beaufort, NC), McMahon, Timothy J.; (Durham, NC), Pawloski, John R.; (Raleigh, NC), Stamler, Jonathan S.; (Chapel Hill, NC) Correspondence: David E. Brook, ESQ.; Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20030008300 Date filed: October 23, 2001 Abstract: Red blood cells can be loaded with low molecular weight nitrosylating agents, such as S-nitrosothiols, to act as a delivery system for NO.sup.+ groups to tissues. Loaded red blood cells can be used in methods of therapy for conditions which are characterized by abnormal O.sub.2 metabolism of tissues, oxygen-related toxicity, abnormal vascular tone, abnormal red blood cell adhesion, or abnormal O.sub.2 delivery by red blood cells. Such treatment of red blood cells can be extended to in vivo therapies, with the object to achieve an increase in the ratio of red blood cell Snitrosothiol to hemoglobin. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 09/724,305 filed on Nov. 28, 2000, which is a continuation of U.S. patent application Ser. No. 08/873,679 filed on Jun. 12, 1997 (now U.S. Pat. No. 6,203,789), which is a continuation-in-part of PCT/US96/14664 filed on Sep. 13, 1996, which is a continuation of U.S. patent application Ser. No. 08/616,255 filed on Mar. 15, 1996 (now U.S. Pat. No. 6,153,186), which claims the benefit of U.S. Provisional Application No. 60/003,801 filed on Sep. 15, 1995. The teachings of all of the above applications are each incorporated herein by reference in their entirety. Interactions of hemoglobin (Hb) with small diffusible ligands, such as O.sub.2, CO.sub.2 and NO, are known to occur at its metal centers and amino termini. The O.sub.2/CO.sub.2 delivery functions, which arise in the lung and systemic microvasculature, are allosterically controlled. Such responsiveness to the environment has not been known to apply in the case of NO. Specifically, it has been thought previously that NO does not modify the functional properties of Hb to any physiologically significant degree. Kinetic modeling predicts that the vast majority of free NO in the vasculature should be scavenged by Hb (Lancaster 1994). Accordingly, the steady-state level of NO may fall below the K.sub.m for target enzymes such as guanylate cyclase (Lancaster 1994), if not in the unperturbed organism, then with oxidant stress such as that found in atherosclerosis. These considerations raise the fundamental question of how NO exerts its biological activity. One answer to this question is found in the propensity of nitric oxide to form S-nitrosothiols (RSNOs) (Gaston, B. et al., Proc. Natl. Acad. Sci. USA 90:10957-10961 (1993)), which retain NOlike vasorelaxant activity (Stamler, J. S., et al., Proc. Natl. Acad. Sci. USA 89.444-448 (1992)), but which can diffuse freely in and out of cells, unlike Hb. In particular, the NO group of RSNOs possesses nitrosonium (NO.sup.+) character that distinguishes it from NO itself. It is increasingly appreciated that RSNO's have the capacity to elicit certain functions that NO is incapable of (DeGroote, M. A. et al., Proc. Natl. Acad. Sci. USA 92:6399-6403 (1995); Stamler, J. S., Cell 78:931-936 (1994)). Moreover, consideration has been given to the possibility that --SNO groups in proteins serve a signaling function, perhaps analagous to phosphorylation (Stamler, J. S. et al., Proc. Natl. Acad. Sci. USA 89:444-448 (1992); Stamler, J. S. Cell 78:931-926 (1994)). Although S-nitrosylation of proteins can regulate protein function (Stamler, J. S. et al., Proc. Natl. Acad. Sci. USA 89:444-448 (1992); Stamler, J. S., Cell 78:931-936 (1994)), the identification of S-

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nitrosoproteins within cells--the sine qua non of a regulatory posttranslational modification--has heretofore not been demonstrated. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Selective complex of lipoprotein with hemoglobin or hemoglobin analog, and assay method and assaying kit using the complex Inventor(s): Nakano, Hajime; (Kyoto, JP), Okamoto, Masashi; (Kyoto, JP) Correspondence: Sughrue Mion, Pllc; 2100 Pennsylvania Avenue, NW; Washington; DC; 20037-3213; US Patent Application Number: 20030109050 Date filed: December 20, 2002 Abstract: A selective complex of a lipoprotein with hemoglobin or a hemoglobin analogue; a method of assaying hemoglobin or a hemoglobin analogue in a sample, comprising reacting the sample with a lipoprotein which is capable of selectively forming a complex with hemoglobin or a hemoglobin analogue; and a kit for assaying hemoglobin or a hemoglobin analogue, comprising a lipoprotein which is capable of selectively forming a complex with hemoglobin or a hemoglobin analogue. Excerpt(s): The present invention relates to a selective complex of a lipoprotein with hemoglobin or a hemoglobin analogue; a method of assaying hemoglobin or a hemoglobin analogue in a sample, using the selective complex, and a kit for assaying hemoglobin or a hemoglobin analogue, using the selective complex in clinical examinations. In clinical examinations, it is required to selectively assay a target substance from a sample containing various coexisting substances. Accordingly, there have been employed a number of substances that specifically binds to target substances to form a pair just like a key and a keyhole, for example, antigen (including hapten)antibody, ligand-receptor, substrate-enzyme, inhibitor-enzyme, or the like. For example, the sandwich method is an immunoassay method using antibodies which is frequently employed. In this method, an antigen to be assayed is sandwiched between two kinds of antibodies. One of these antibodies is immobilized on a solid phase for capturing the antigen, while the other antibody is labeled. Then, the antigen to be assayed is allowed to react with the antibodies to thereby form a sandwich complex of immobilized antibody-antigen-labeled antibody. After removing the unreacted labeled antibody, the amount of the antigen is determined by measuring the label. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Sensor calibration and blood volume determination Inventor(s): Krivitski, Nikolai M.; (Ithaca, NY), Starostin, Dimitry M.; (Ithaca, NY) Correspondence: Stephen B. Salai, ESQ.; Harter, Secrest & Emery Llp; 1600 Bausch & Lomb Place; Rochester; NY; 14604-2711; US Patent Application Number: 20030130570 Date filed: December 9, 2002 Abstract: A method and device for the continuous real-time monitoring of relative blood volume change, based on registration of blood hemoglobin concentration, during long periods of time, such as dialysis session. A method and device for cardiac output

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measurement during dialysis, surgeries, intensive care procedure is provided. Calibration of a sensor in response to a change in a measureable blood property is determined from a coefficient corresponding to a change in the measured blood property. Excerpt(s): The present application claims priority as a continuation in part of U.S. Ser. No. 09/528,880 filed Mar. 20, 2000, now U.S. Pat. No. 6,493,567, which is a divisional of U.S. Ser. No. 08/950,244, now U.S. Pat. No. 6,041,2446, each of which is hereby expressly incorporated by reference. The present invention relates to the photometric analysis of blood properties to monitor changes in blood volume, blood proteins concentration, cardiac output and other hemodynamic parameters. More particularly, the invention includes a method and apparatus for employing a single light emitter and a single photodetector, the single photodetector is oriented with respect to the emitter to minimize a scattering effect of the light from the electrolyte composition of the blood, blood flow rate, blood hematocrit level and other factors. The optical density of blood corresponds to a number of factors and the measurement of the optical density of the blood has been used to determine certain blood parameters. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Simplified and lightweight system for enhanced visualization of subcutaneous hemoglobin-containing structures Inventor(s): Kimble, Allan Wayne; (Jacksonville, FL) Correspondence: Allan Wayne Kimble; 5085 Bradford Road; Jacksonville; FL; 32217; US Patent Application Number: 20030018271 Date filed: June 28, 2002 Abstract: A simplified, lightweight and inexpensive system and method for enhancing visualization of veins or other subcutaneous natural or foreign structures of the body containing hemoglobin is provided. This system will facilitate intravenous insertion or extraction of fluids, medication or other treatments in hospital or emergency settings. Excerpt(s): This invention claims the benefit of earlier filed U.S. Provisional Application No. 60/302,284 filed Jul. 2, 2001, incorporated herein by reference. The invention described herein relates generally to medical devices and procedures, and more particularly to a simplified system and method for enhancing visualization of veins and other subcutaneous hemoglobin-containing features of the body. Such visualization will aid in fluid insertion into or extraction from the body. Subcutaneous blood or hemoglobin containing areas can provide useful information for diagnosis of the medical condition of a patient or administration of medical treatment to a patient. The earliest efforts to use infrared to locate veins and blood were led by Eastman Kodak Company.TM. and used photography to accomplish venous visualization. "Medical Infrared Photography," published by them is incorporated into this patent by reference. (Eastman Kodak Co; ISBN: 0879850256; 3rd edition, June 1973.) Other prior art devices and procedures for enhancing visualization of veins, arteries and other blood or hemoglobin containing subcutaneous structures of the body have included the following techniques: applying tourniquets, flashlights, direct application of liquid crystalline materials, dual fiber optic sources, ultrasonic imaging and nuclear magnetic resonance imaging. The tourniquet method is the traditional approach in which the venous return is restricted to cause the major superficial venous vessels to engorge with blood for enhancing their visibility This is the standard approach used in all medical

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facilities. However, this technique is compromised in conditions of poor ambient illumination, and inpatients with low blood pressure, racial pigmentation, skin bums, etc. Flashlights are limited to transilluminating very thin sections of tissue. The liquid crystal technique is based on the thermal sensitivity of liquid crystal materials. By applying a thin liquid crystal film over the vein, it is possible to map out the venous structure from the surrounding tissue based on relative temperature differences. The dual fiber-optic source is a method by which both sides of the venous structure are simultaneously illuminated with visible light to eliminate shadows and to provide enhanced visualization. Ultrasonic images can be taken of vascular and surrounding tissue. This technique is based on the reflection of ultrasonic waves due to the impedance mismatch at the various tissue interfaces found within the body. Lastly, the nuclear magnetic resonance (NMR) imaging technique relies on the magnetic relaxation times of various chemical species specific to blood within the body. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Stabilized hemoglobin solutions Inventor(s): Avella, Anthony; (Crystal Lake, IL), Chavez, Gabriel; (Chicago, IL), DeWoskin, Richard; (St. Charles, IL), Doubleday, Marc; (Cary, IL), McGinnis, Robert; (Park Ridge, IL) Correspondence: Mcdonnell Boehnen Hulbert & Berghoff; 32nd Floor; 300 S. Wacker Drive; Chicago; IL; 60606; US Patent Application Number: 20030065149 Date filed: April 18, 2002 Abstract: A hemoglobin solution packaged in a flexible oxygen-impermeable container system. The container system includes a multi-layer film having at least a product contact layer, an oxygen and moisture barrier layer and an exterior layer. The flexible container system further includes an interface port for filling the flexible container with the hemoglobin solution and delivering the hemoglobin solution. The hemoglobin solution comprises a substantially stroma and tetramer free, cross linked, pyridoxylated hemoglobin solution including preservatives such as ascorbic acid, glycine and dextrose. Excerpt(s): The invention relates to stabilized oxygen carrying solutions. More specifically, it relates to a hemoglobin solution packaged in an oxygen and water vapor impermeable flexible container, and to the storage and preservation of a deoxygenated hemoglobin solution. There is a consistent need for ready blood products for an everincreasing surgical and trauma load, and to supplement blood bank shortages. Oxygen carrying solutions, such as hemoglobin-derived solutions can be used in place of whole blood or red blood cells for patients having a need for augmented oxygen carrying capacity. Because they are not dependent upon donor availability, such solutions can be made readily available in an emergency situation or during a blood bank shortage. Also, due to risk of infection of blood borne pathogens as a result of a blood transfusion, a patient may prefer a hemoglobin-derived solution for transfusion in place of whole blood or red blood cells. In particular, such solutions may include, but are not limited to, oxygen carriers, blood substitutes, and hemoglobin-derived compositions such as those disclosed in U.S. Pat. Nos. 6,133,425, 5,464,814, 5,438,041, 5,217,648, 5,194,590, 5,061,688, and 4,826,811, the teachings of which are incorporated herein by reference in their entirety. Active hemoglobin is an oxygen (O.sub.2) transporting protein found in red blood cells. Each hemoglobin molecule is comprised of four protein chains and four

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porphyrin molecules known as heme. In the middle of each heme is an iron atom that is partially oxidized to the (+2) state. When oxygen is transported under normal conditions in vivo, oxygen is bound to the heme without a change in valence of the iron ion; the hemoglobin thus becomes oxyhemoglobin. To indicate that this binding occurs without a change in valence, the reaction is called oxygenation (rather than oxidation), and the reverse process is deoxygenation. Hemoglobin is called deoxyhemoglobin to emphasize its oxygen free state. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Substituted chiral allosteric hemoglobin modifiers Inventor(s): Abraham, Donald J.; (Midlothian, VA), Danso-Danquah, Richmond; (Richmond, VA), Grella, Melissa; (Columbia, MD), Hoffman, Stephen J.; (Carlisle, MA), Joshi, Gajanan S.; (Glen Allen, VA), Kulkarni, Sanjeev; (Richmond, VA), Safo, Martin; (Richmond, VA), Yousseff, Amal; (Richmond, VA) Correspondence: Whitham, Curtis & Christofferson, P.C.; 11491 Sunset Hills Road; Suite 340; Reston; VA; 20190; US Patent Application Number: 20030130523 Date filed: September 10, 2002 Abstract: A family of substituted chiral allosteric effectors of hemoglobin is useful for delivering more oxygen to hypoxic and ischemic tissues by reducing the oxygen affinity of hemoglobin in whole blood. Excerpt(s): This application is based on U.S. Prov. App. Nos. 60/150,351, filed on Aug. 24, 1999 and 60/176,635 filed Jan. 19, 2000, incorporated by reference in its entirety. The present invention generally relates to a family of allosteric effectors of hemoglobin and more specifically to chirality affects of allosteric effectors where the chiral carbon has a substituted carbon ring, a heteroatom ring, or different substituents. The invention includes several new potent enantiomers that are superior than their racemic mixture and other enantiomeric isomer, possessing different degrees of allosteric potency. Human hemoglobin (Hb) is a tetrameric allosteric protein comprised of two alpha and two beta chains and functions to deliver oxygen from the lungs to the many tissues of the body. The four subunits are arranged around a molecular two fold axis creating a central water cavity. As an allosteric protein, Hb exists in an equilibrium between two states, the relaxed (R) or oxy-state and the tense (T) or deoxy-state. In the oxy-state, the water cavity is narrow and the subunits have fewer and weaker bonds between them (i.e., relaxed). However, in the deoxy-state, the water cavity is larger, and the subunits are tightly tethered together by salt bridges (i.e., tense). The allosteric equilibrium can be influenced by allosteric modifiers. Such molecules can increase the oxygen affinity of Hb shifting the allosteric equilibrium toward oxy-Hb or decrease the affinity of oxygen, shifting the equilibrium to the deoxy-Hb. Modifiers that decrease the oxygen affinity act by adding constraints to the T-state. Oxygen affinity decreasing agents have several potential applications including radiosensitization of tumors, enhancement of oxygen delivery to hypoxic and ischemic tissues, and shelf-life prolongation of stored blood. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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System and method for closed loop controlled inspired oxygen concentration Inventor(s): Bancalari, Eduardo H.; (Miami, FL), Claure, Nelson R.; (Miami, FL) Correspondence: Kit M. Stetina; Stetina Brunda Garred & Brucker; Suite 250; 75 Enterprise; Aliso Viejo; CA; 92656; US Patent Application Number: 20030078480 Date filed: November 27, 2002 Abstract: A system and method for delivering fractionally inspired oxygen (FiO.sub.2) to a patient in response to receiving an arterial hemoglobin oxygen saturation signal (SpO.sub.2) are disclosed. The SpO.sub.2 is measured, for example, by using a pulse oximeter. An algorithm receives a signal indicating the SpO.sub.2. The algorithm determines wither the SpO.sub.2 is in the normoxemia range, hypoxemia range or hyperoxemia range. The algorithm also determines trends by calculating a slope of second-to-second changes in the SpO.sub.2. Based on the current SpO.sub.2 and the trend, the algorithm determines the appropriate FiO.sub.2 for the patient and instructs a device, such as a mechanical ventilator or an air oxygen mixer as to the appropriate FiO.sub.2 to be delivered to the patient. The system initializes various parameters with default values, but a user (e.g., a nurse) can also update the settings at any time. The system also provides alerts for various conditions, for example, standard pulse oximeter alarms, as well as notification when an episode of hyperoxemia or hypoxemia occurs, when it lasts for more than a specified period of time (e.g., two minutes) in spite of FiO.sub.2 adjustments and when the adjustments set the FiO.sub.2 at certain levels. The user is also alerted when SpO.sub.2 signal is lost. Excerpt(s): The present invention relates generally to oxygen delivery systems and more particularly to a closed loop system and method for automatically delivering fractionally inspired oxygen (FiO.sub.2). Very low birth weight infants often present with episodes of hypoxemia. These episodes are detected by arterial oxygen saturation monitoring by pulse oximetry (SpO.sub.2) and are usually assisted with a transient increase in the fraction of inspired oxygen (FiO.sub.2). Given the rapid onset and frequency at which most of these episodes of hypoxemia occur, maintaining SpO.sub.2 within a normal range by manual FiO.sub.2 adjustment during each episode is a difficult and time-consuming task. Nurses and respiratory therapists respond to high/low SpO.sub.2 alarms. Under routine clinical conditions, the response time is variable and the FiO.sub.2 adjustment is not well defined. This exposes the infants to periods of hypoxemia and hyperoxemia which may increase the risk of neonatal chronic lung disease and retinopathy of prematurity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Test device for detecting human blood and method of use Inventor(s): Bagaria, Padma S.; (West Hills, CA) Correspondence: Timothy T. Tyson; Freilich, Hornbaker & Rosen; Suite 1220; 10960 Wilshire BLVD.; Los Angeles; CA; 90024; US Patent Application Number: 20030027222 Date filed: July 23, 2001 Abstract: A test device (20) for detecting human blood includes a strip (22) having an introduction station (24), a test station (26), and a control station (28) disposed in spaced

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apart relationship. The test sample introduction station (24) has labeled antihuman Hb antibodies, the test station (26) has immobilized antihuman Hb antibodies, and the control station has immobilized polyclonal antibodies. A test sample (500) is deposited at the introduction station (24). If human hemoglobin is present in the test sample (500), a colored line will appear at the test station (26) and at the control station (28). If no human hemoglobin is present in the test sample (500), a colored line will only appear at the control station (28). Excerpt(s): The present invention pertains generally to immunoassays for determining the presence of a particular analyte, and, in particular, to a test device which may be used to detect the presence of human blood. Immunoassay test devices are well known in the art. These devices are employed to detect a wide variety of substances. For example, U.S. Pat. No. 4,313,734 shows a method, test kit, and labeled component for the detection and/or determination of one or more components of the reaction between a specific binding protein and the corresponding bindable substance, in which one or more labeled components are used, that are obtained by coupling particles of a dispersion of a metal, metal compound or polymer nuclei, coated with a metal or metal compound, having a particle size of at least 5 nm, directly or indirectly to the desired component of the reaction. During the reaction or after an adequate reaction time, the physical properties and/or the amount of the metal and/or the formed metal containing agglomerate, is/are determined in the test sample, or optionally after a separation of the bound and free metal labeled components in one of the derived fractions. U.S. Pat. No. 4,376,110 illustrates "two-site" or "sandwich" immunometric assay techniques for determination of the presence and/or concentration of antigenic substances in fluids using monoclonal antibodies. One monoclonal antibody is presented in a soluble labeled form and a second monoclonal antibody is presented bound to a solid carrier; the soluble and bound monoclonal antibodies may be the products of either the same or different cell lines. Each monoclonal antibody has an affinity for the antigenic substances of at least about 108 liters/mole. 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 hemoglobin, 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 “hemoglobin” (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 hemoglobin. You can also use this procedure to view pending patent applications concerning hemoglobin. 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 7. BOOKS ON HEMOGLOBIN Overview This chapter provides bibliographic book references relating to hemoglobin. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on hemoglobin 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: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “hemoglobin” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on hemoglobin: •

Clinical Practice Guidelines for the Treatment of Anemia of Chronic Renal Failure Source: New York, NY: National Kidney Foundation. 1997. 174 p. Contact: Available from National Kidney Foundation. 30 East 33rd Street, New York, NY 10016. (800) 622-9010. Fax (212) 689-9261. PRICE: $13.00. ISBN: 0962972177. Summary: In March 1995, the National Kidney Foundation Dialysis Outcomes Quality Initiative (NKF-DOQI) was established, with the objective of improving patient outcomes and survival by providing recommendations for optimal clinical practices in four areas: hemodialysis adequacy, peritoneal dialysis adequacy, vascular access, and the treatment of anemia of chronic renal failure (CRF). This document presents 28 clinical practice guidelines for anemia. They are categorized in seven sections: anemia workup, target hematocrit and hemoglobin, iron support, administration of Epoetin (erythropoietin), inadequate epoetin response, the role of red blood cell transfusions, and possible adverse effects related to epoetin therapy. Each guideline is accompanied

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by a rationale, enabling dialysis caregivers to make informed decisions about the proper care plan for each individual patient. This document also includes a list of acronyms and abbreviations, a description of the guideline development methodology, endnotes, references, biographical sketches of the NKF-DOQI anemia work group members, and a complete listing of the articles reviewed by the anemia work group. 1 figure. 9 tables. 349 references. (AA-M). •

Beating the Blood Sugar Blues Source: Alexandria, VA: American Diabetes Association. 2001. 159 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $12.95 plus shipping and handling. ISBN: 1580400485. Summary: This book offers first hand knowledge from two doctors who have more than 100 years of combined experienced with the day-to-day balancing act of blood glucose (sugar) and diabetes. The authors, both of whom have type 1 diabetes, share their own stories as well as those of over 40 of their patients. The book includes 20 chapters that cover an overview of hypoglycemia (low blood glucose levels), the risks associated with high and low blood glucose levels, monitoring blood glucose levels (SMBG), monitoring blood levels over time (glycosylated hemoglobin levels), treating low blood glucose at home, adjusting insulin to avoid hypoglycemia, using a meal plan to control blood glucose, the impact of exercise on blood glucose, handling low blood glucose at school, teenagers and the blood sugar blues, sex and pregnancy and their impact on hypoglycemia, sleep, driving or flying safely, traveling and hypoglycemia, alcohol and hypoglycemia, prescription drugs and hypoglycemia, the effects of hypoglycemia on nerves and vision, psychological insights, losing awareness of hypoglycemia, and managing one's own diabetes. The book concludes with a subject index.

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American Diabetes Association Guide to Raising a Child with Diabetes. 2nd ed Source: Alexandria, VA: American Diabetes Association. 2000. 165 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $16.95 plus shipping and handling. ISBN: 1580400272. Summary: This book presents up to date information on diabetes to help parents and other family members care for a child who has diabetes. The book begins with a chapter that explains the causes of type 1 diabetes, identifies the signs and symptoms of diabetes, and discusses the management of blood glucose levels. The next chapter focuses on caring for the child who has diabetes. Topics include new thinking about treating children with diabetes, the role of health care providers, and ways to keep a child's best interests a top priority. Chapter three discusses the use of insulin to manage diabetes, focusing on insulin types, insulin dosages, insulin administration, site rotation, insulin delivery devices, needle disposal, insulin adjustment, and self injection. This is followed by a chapter that explains blood glucose testing. Topics include determining the number of times per day to test blood glucose, recording blood glucose test results, making sure a blood glucose meter is accurate, testing urine for glucose and ketones, helping a child test regularly, and understanding the glycated hemoglobin test. The fifth chapter deals with meal planning, focusing on planning balanced meals; using exchanges and carbohydrate counting to plan meals; helping a child accept meal

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planning; coping with schedule changes, holidays, and parties; and eating out. The next chapter offers guidelines for playing games and sports safely. This is followed by a chapter that explains how to prevent and treat hypoglycemia, hyperglycemia, and ketoacidosis and how to handle sick days and infections. Chapter eight deals with diabetes care during various stages of development, focusing on care of infants, preschoolers, school age children, and adolescents. The final chapter offers advice for living with diabetes, focusing on budgeting, traveling, solving the day to day challenges of diabetes, coping with diabetes, and asking for help. The book provides problem solving examples and easy to read tables throughout. In addition, the book includes a glossary, a list of resources, and an index. 44 figures. 2 tables. •

Diabetes Sourcebook. 3rd ed Source: Detroit, MI: Omnigraphics. 2003. 621 p. Contact: Available from Omnigraphics. 615 Griswold Street, Detroit, MI 48226. (800) 234-1340. Fax (800) 875-1340. Website: www.omnigraphics.com. ISBN: 780806298. Summary: This book provides information for people seeking to understand the risk factors, complications, and management of type 1 diabetes, type 2 diabetes, and gestational diabetes. The book offers 67 chapters in seven sections: diabetes types and diagnosis; lifestyle and related diabetes management concerns; exercise and nutrition for diabetes management; medication management of diabetes; complications of diabetes; treatment of end stage renal disease (ESRD); and diabetes-related research and statistics. Specific topics include risk factors, impaired glucose tolerance (IGT), insulin resistance, HbA1c (glycosylated hemoglobin) testing, blood glucose testing, urine testing, SMBG (self monitoring of blood glucose), non-invasive blood glucose monitors, preventing complications, how stress affect diabetes, alternative therapies for diabetes, exercise, exchange lists, carbohydrate counting, eating at restaurants, insulin administration and dosage, oral medications, amputation, kidney disease (diabetic nephropathy), diabetic retinopathy (eye disease), diabetic neuropathy (nerve disease), gastroparesis (reduced motility of stomach contents), hypoglycemia (low blood glucose levels), hyperglycemia (high blood glucose levels), erectile dysfunction (ED formerly called impotence), research advances in diabetes, and diabetes in ethnic and racial groups. The book includes a glossary of related terms, information about locating financial help for diabetes care, and a list of resources, including organizations, recipes and cookbooks.

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Mayo Clinic on Managing Diabetes Source: Rochester, MN: Mayo Clinic. 2001. 194 p. Contact: Available from Mayo Clinic Health Information. 200 First Street, S.W., Fifth Floor Centerplace Building, Rochester, MN 55905. (800) 430-9699. Website: www.mayoclinic.com. PRICE: $14.95 plus shipping and handling. ISBN: 1893005062. Summary: This book provides practical and easy to understand information on controlling diabetes and preventing complications of the disease. Part one provides facts about diabetes. Topics include types of diabetes, the signs and symptoms of diabetes, the risk factors for diabetes, and the criteria and tests for diagnosing diabetes. In addition, the issue of diabetic complications is addressed, focusing on hypoglycemia, diabetic hyperosmolar syndrome, diabetic ketoacidosis, neuropathy, nephropathy, retinopathy, heart and blood vessel disease, and increased risk of infection. Part two deals with the components involved in controlling the disease. Chapters discuss monitoring blood glucose, eating a healthy diet, getting daily exercise, and maintaining

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a healthy weight. Part three examines medical therapies for managing diabetes. Chapters provide information on the use of insulin to manage type 1 and type 2 diabetes; the use of sulfonylureas, meglinitides, biguanides, alpha glucosidase inhibitors, thiazolidinediones, and drug combinations to manage type 2 diabetes; and pancreas and islet cell transplantation as possible cures for diabetes. Part four addresses issues related to living well with diabetes. One chapter focuses on important tests every person who has diabetes should be getting, including the glycosylated hemoglobin test, lipid tests, the serum creatinine test, and the urine microalbumin test. Another chapter discusses self care issues, including having annual physical examinations, visiting a dentist regularly, caring for feet, avoiding smoking, monitoring blood pressure, and managing stress. A third chapter explores sexual health issues for both men and women. Topics include the affect of the menstrual cycle and menopause on blood glucose, hormone replacement therapy, pregnancy, and impotence. Each chapter concludes with a question and answer section. The book also includes a list of additional resources. 17 figures. 1 table. •

Medical Management of Pregnancy Complicated by Diabetes. 3rd ed Source: Alexandria, VA: American Diabetes Association. 2000. 176 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $39.95 plus shipping and handling. ISBN: 1580400132. Summary: This book, which is part of the American Diabetes Association's Clinical Education Series, provides health professionals with protocols that have resulted in healthy infants in pregnancies complicated by type 1, type 2, or gestational diabetes. The first section focuses on prepregnancy counseling and management of women with preexisting diabetes or previous gestational diabetes. The next section discusses contraceptive methods, including oral contraceptives, the norplant system, barrier methods, intrauterine devices, the rhythm method, and permanent sterilization. This is followed by a section that examines the psychological impact of diabetes and pregnancy. Topics include the response to pregnancy in women with preexisting diabetes, the response to a diagnosis of gestational diabetes, long term adaptation, personality types and individualizing treatment, pregnancy crises, and the importance of a team approach and a support system. The fourth section focuses on blood glucose monitoring. Topics include glycosylated hemoglobin measurements in pregnancy for women with preexisting or gestational diabetes, self monitoring of blood glucose and urine ketones, and medical tests to evaluate maternal status in women with preexisting or gestational diabetes. The next section offers guidelines for managing morning sickness with dietary remedies, insulin adjustments, and medical management. The sixth section discusses nutritional management during pregnancy in women with preexisting diabetes. Topics include patient responsibility; the nutrient needs of pregnancy; diet and eating habits; vitamin and mineral supplementation; calorie level; weight gain; meal planning; recordkeeping; use of sodium, caffeine, and artificial sweeteners; the management of hypoglycemia; and postpartum nutritional management. Section seven focuses on the use of insulin during pregnancy in women with preexisting diabetes. Topics include metabolic alterations during normal gestation, therapeutic insulin use, dosage adjustment, insulin during labor and delivery, postpartum insulin requirements, and oral hypoglycemic agents. The next section describes diagnostic tests and methods of fetal surveillance, including ultrasonography, alpha fetoprotein testing, genetic testing, fetal monitoring, and amniocentesis. The ninth

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section discusses gestational diabetes, focusing on epidemiology, screening, diagnosis, nutritional management, insulin therapy, exercise, and obstetric management. Section ten addresses the issue of neonatal care of infants of women with diabetes. Topics include perinatal mortality and morbidity, resuscitation, nursery care, and long term followup. The final section discusses postpartum followup of women with gestational diabetes. The book includes an index and resources for health care professionals. 3 figures. 39 tables. Numerous references. •

Healing Handbook for Persons with Diabetes Source: Worcester, MA: University of Massachusetts Medical School. 1998. [141 p.]. Contact: Available from University of Massachusetts Medical School Bookstore. 55 Lake Avenue, Worcester, MA 01655. (508) 856-3213. Website: http://www.umassmed.edu/diabeteshandbook/. PRICE: $14.95 plus $5.00 for shipping and handling. Summary: This handbook, available in both English and Spanish, provides people who have diabetes with an overview of the disease. Chapter one defines diabetes and provides information on the causes and history of the disease, as well as an overview of insulin, the pancreas, and kidney functioning. Chapter two offers practical advice for accepting diabetes and living with it day to day. Topics include psychological and social aspects, coping skills, life and health insurance, diabetes identification, legal rights, treatment plans, regular assessments, and continuing education. Chapters three and four describe type 1 and type 2 diabetes, respectively. Topics include goals and management. Chapter five focuses on blood glucose monitoring. Topics include self monitoring of blood glucose (SMBG), equipment for SMBG, glycosylated hemoglobin, and urine tests for ketones and glucose. Chapter six deals with diet, focusing on basic nutrition, meal planning at home or when dining out, and exchange lists. Chapter seven offers advice on exercise programs for people who have diabetes. Topics include aerobic exercise options, exercise for the overweight person with type 2 diabetes, exercise for the person with type 1 diabetes, food exchanges for exercise, easy exercises for beginners, and blood glucose monitoring during exercise. Chapter eight provides an overview of insulin, focusing on types of insulin, how to buy and store insulin, how to inject insulin, and how to avoid and treat insulin reactions. Chapter nine describes oral medications that are used to treat type 2 diabetes, including sulfonylurea compounds, biguanides, thiazolidinediones, and alpha glucosidase inhibitors. Chapter 10 serves as a guide to diabetes management during an illness. Chapter 11 offers tips for preventing some common skin and foot problems experienced by people who have diabetes. Chapter 12 describes complications associated with diabetes and provides advice on how to avoid them. Complications discussed include those affecting the eyes, kidneys, nerves, blood vessels, feet, and teeth. Chapter 13 addresses special concerns of families coping with diabetes. Sections discuss the special needs of women with diabetes during pregnancy, provide advice for parents of children with diabetes, and offer information for school personnel who have contact with students who have diabetes. Chapter 14 offers tips that help ensure safe, healthy travel for people who have diabetes. Chapter 15 highlights current research activities into the causes and prevention of and potential treatments for diabetes. Some chapters end with a series of questions and answers that may help clarify information about the chapter. Several chapters list products for people with diabetes or refer to other publications on diabetes. A glossary of diabetes related terms is included at the end of the handbook.

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Diabetes Ready-Reference Guide for Health Care Professionals Source: Alexandria, VA: American Diabetes Association. 2000. 56 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $29.95 plus shipping and handling. ISBN: 1580400116. Summary: This reference guide provides health professionals with clear, concise guidelines for effective direct or indirect care of patients who have diabetes. The guide is tabbed for quick access to the various topics. Sections focus on the causes, characteristics, and treatment of type 1, type 2, and gestational diabetes; the diagnosis of diabetes; monitoring blood glucose through the use of self monitoring and the glycated hemoglobin and fructosamine test; the dietary management of diabetes and the meal planning approaches for obtaining optimal glucose and weight management; and the benefits of exercise and ways to start an exercise program. Other sections deal with the dosage, duration of action, and side effects of oral agent medications; types of insulin and the dosing and administration of insulin; the effects of nonprescription and prescription medications on diabetes control; acute complications such as hypoglycemia, diabetic ketoacidosis, and hyperglycemic hyperosmolar nonketotic syndrome; chronic complications such as cardiovascular disease, diabetic retinopathy, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, and autonomic dysfunction; foot care; sick day rules; and travel guidelines. The guide also includes a glossary and a bibliography.

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American Diabetes Association Complete Guide to Diabetes: The Ultimate Home Diabetes Reference. 2nd ed Source: Alexandria, VA: American Diabetes Association. 1999. 514 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $23.95 plus shipping and handling. ISBN: 1580400388. Summary: This sourcebook provides people who have diabetes with expert advice, written in clear, easy to understand language, on every aspect of type 1, type 2, and gestational diabetes. The book begins with a chapter that provides an overview of type 1, type 2, and gestational diabetes. This is followed by a chapter that offers guidelines for designing a diabetes plan and describes options for treating diabetes, including insulin therapy, pancreas and islet transplantation, diet therapy, and oral diabetes medications. The third chapter provides suggestions for selecting a diabetes care team and answers questions about the glycated hemoglobin test. The next chapter describes types of insulin; explains how to buy, store, and administer insulin; and discusses various insulin plans. This is followed by a chapter that focuses on achieving glucose control. Topics include the impact of food, insulin, exercise, stress, and illness on blood glucose; self monitoring of blood glucose; and the causes and treatment of hypoglycemia and hyperglycemia. Chapter six provides information on diabetes tools, including blood glucose meters, test strips, lancets, and miscellaneous supplies. The focus of chapter seven is on intensive diabetes management. Topics include standard diabetes control versus tight control, goals for type 1 and type 2 diabetes, and intensive management techniques. Chapter eight discusses healthy eating in terms of creating a healthy meal plan using the food pyramid and using medical nutrition therapy. The next chapter offers suggestions for beginning an exercise program, exercising safely, and

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finding a desirable exercise. Other topics include the impact of exercise on blood glucose levels and exercise during pregnancy. Chapter 10 examines diabetes complications and their prevention and treatment. Complications include cardiovascular disease, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, and infections. Other chapters discuss the impact of diabetes on sexual health and pregnancy, the psychological impact of diabetes, and the effect of diabetes on other family members. Remaining chapters examine diabetes in the workplace, in the military, and at school and offer advice for working with the health care system. The book includes a glossary, an index, and lists of resources and helpful websites. 1 appendix. 9 figures. •

Type II Diabetes Sourcebook Source: Los Angeles, CA: Lowell House, and Chicago, IL: Contemporary Books. 1997. 336 p. Contact: Available from Contemporary Books, Inc. 2 Prudential Plaza, Suite 1200, Chicago, IL 60601. Also available from Lowell House, 2020 Avenue of the Stars, Suite 300, Los Angeles, CA 90067. (310) 552-7555. Fax (310) 552-7573. PRICE: $25.00 (cloth). ISBN: 1565656466. Summary: This sourcebook provides people with diabetes a comprehensive manual of self care for noninsulin-dependent diabetes mellitus (NIDDM, or Type II). The authors stress the importance of active patient participation and self management in caring for diabetes and in preventing complications. Sixteen chapters cover an introduction to diabetes, self empowerment, the patient care team and elements of a good treatment plan, the biology of diabetes and the role of insulin, stress management, blood glucose and its monitoring, food and nutrition, exercise, medications, laboratory tests and why each is important, daily hygiene and self care steps to prevent complications, pregnancy, the social and psychological aspects of diabetes, financial considerations, complications, and research being undertaken in this area. The chapter on laboratory tests covers blood pressure, hemoglobin A1C testing, lipid profile, urine tests, oral glucose tolerance test (OGTT), and the fructosamine assay. The chapter on mental health covers family problems, social support, communication skills, professional counseling, support groups, and diabetes burnout. The book includes two appendices: a listing of resources and a glossary of common terms. A subject index concludes the volume.

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 “hemoglobin” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “hemoglobin” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “hemoglobin” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

Advances in hemoglobin analysis : proceedings of a workshop held in Ann Arbor, Michigan, on September 28, 1980; ISBN: 0845100602; http://www.amazon.com/exec/obidos/ASIN/0845100602/icongroupinterna

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Biochemical and Clinical Aspects of Hemoglobin Abnormalities by Winslow S. Caughey; ISBN: 0121643506; http://www.amazon.com/exec/obidos/ASIN/0121643506/icongroupinterna

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Blood gases: hemoglobin, base excess and maldistribution; nomograms for normal and abnormal bloods, effects of maldistribution by Albert J. Olszowka; ISBN: 0812104137; http://www.amazon.com/exec/obidos/ASIN/0812104137/icongroupinterna

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Can't Live Without It: The Story of Hemoglobin in Sickness and in Health by Loren F. Hazelwood (2001); ISBN: 1560729074; http://www.amazon.com/exec/obidos/ASIN/1560729074/icongroupinterna

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Cellular and molecular regulation of hemoglobin switching; ISBN: 0808911597; http://www.amazon.com/exec/obidos/ASIN/0808911597/icongroupinterna

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Computation of the unsteady facilitated transport of oxygen in hemoglobin (SuDoc NAS 1.15:102251) by Sanford Davis; ISBN: B000105D5Q; http://www.amazon.com/exec/obidos/ASIN/B000105D5Q/icongroupinterna

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Data on the Abnormal Hemoglobins and Glucose-Six-Phosphate Dehydrogenase Deficiency in Human Populations by Frank B. Livingstone (1973); ISBN: 0932206123; http://www.amazon.com/exec/obidos/ASIN/0932206123/icongroupinterna

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Determination of hemoglobin adducts following acrylamide exposure (SuDoc EP 1.89/2:600/SR-93/226) by L. G. Costa; ISBN: B00010NWZ4; http://www.amazon.com/exec/obidos/ASIN/B00010NWZ4/icongroupinterna

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Developmental control of globin gene expression : proceedings of the Fifth Conference on Hemoglobin Switching, held in Airlie, Virginia, September 28October 1, 1986; ISBN: 0845151010; http://www.amazon.com/exec/obidos/ASIN/0845151010/icongroupinterna

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Disorders of Hemoglobin: Genetics, Pathophysiology and Clinical Management by Martin H. Steinberg (Editor), et al; ISBN: 0521632668; http://www.amazon.com/exec/obidos/ASIN/0521632668/icongroupinterna

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Distribution and Evolution of Hemoglobin and Globin Loci: Proceedings by James E. Bowman (Editor); ISBN: 0444007938; http://www.amazon.com/exec/obidos/ASIN/0444007938/icongroupinterna

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Experimental Approaches for the Study of Hemoglobin Switching (Progress in Clinical and Biological Research, Volume 191) by George Stamatoyannopoulos (Editor), et al; ISBN: 0471843873; http://www.amazon.com/exec/obidos/ASIN/0471843873/icongroupinterna

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Experimental approaches for the study of hemoglobin switching : proceedings of the Fourth Conference on Hemoglobin Switching, October 1-3, 1984; ISBN: 0845150413; http://www.amazon.com/exec/obidos/ASIN/0845150413/icongroupinterna

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Frequencies of Hemoglobin Variants: Thalassemia, the Glucose-6-Phosphate Dehydrogenase Deficiency, G6Pd Variants & Ovalocytosis in Human Populations by Frank B. Livingstone; ISBN: 0195036344; http://www.amazon.com/exec/obidos/ASIN/0195036344/icongroupinterna

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Globin gene expression and hematopoietic differentiation : proceedings of the Third Conference on Hemoglobin Switching, September 12-15, 1982; ISBN: 084510134X; http://www.amazon.com/exec/obidos/ASIN/084510134X/icongroupinterna

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Glycosylated Hemoglobins: Methods of Analysis and Clinical Applications by E.C. Abraham; ISBN: 082477356X; http://www.amazon.com/exec/obidos/ASIN/082477356X/icongroupinterna

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HANSASH ADVANCES IN HEMOGLOBIN ANALYSIS by SM HANSASH; ISBN: 0471564206; http://www.amazon.com/exec/obidos/ASIN/0471564206/icongroupinterna

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Hemoglobin and myoglobin in their reactions with ligands by Eraldo Antonini; ISBN: 0444100962; http://www.amazon.com/exec/obidos/ASIN/0444100962/icongroupinterna

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Hemoglobin and Oxygen Binding by Chien Ho; ISBN: 0333340485; http://www.amazon.com/exec/obidos/ASIN/0333340485/icongroupinterna

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Hemoglobin and Oxygen Binding: Electron Transport and Oxygen Utilization by Ho Chien; ISBN: 0444007172; http://www.amazon.com/exec/obidos/ASIN/0444007172/icongroupinterna

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Hemoglobin and red cell structure and function; proceedings; ISBN: 0306390280; http://www.amazon.com/exec/obidos/ASIN/0306390280/icongroupinterna

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Hemoglobin Disorders: Molecular Methods and Protocols by R. L. Nagel (Editor) (2003); ISBN: 0896039625; http://www.amazon.com/exec/obidos/ASIN/0896039625/icongroupinterna

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Hemoglobin Function in Vertebrates: Molecular Adaptation in Extreme and Temperate Environments by Guido Di Prisco (Editor), et al (2000); ISBN: 8847001072; http://www.amazon.com/exec/obidos/ASIN/8847001072/icongroupinterna

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Hemoglobin Lab Site License Package by Desharnais; ISBN: 0805368914; http://www.amazon.com/exec/obidos/ASIN/0805368914/icongroupinterna

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Hemoglobin switching : proceedings of the Sixth Conference on Hemoglobin Switching, held in Airlie, Virginia, September 24-27, 1988; ISBN: 0845151665; http://www.amazon.com/exec/obidos/ASIN/0845151665/icongroupinterna

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Hemoglobin Switching, Part A: Transcriptional Regulation: Proceedings of the Sixth Conference on Hemoglobin Switching Held in Airlie, Virginia, sept by George Stomatoyannopoulos, Arthur W. Nienhuis (Editor); ISBN: 0845154028; http://www.amazon.com/exec/obidos/ASIN/0845154028/icongroupinterna

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Hemoglobin Switching, Part B: Cellular and Molecular Mechanisms (Progress in Clinical and Biological Research, Vol 316B) by George Stomatoyannpoulos, Arthur W. Nienhuis (Editor); ISBN: 0845154036; http://www.amazon.com/exec/obidos/ASIN/0845154036/icongroupinterna

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Hemoglobin Switching: Part B: Cellular and Molecular Mechanisms by George Stamatoyannopoulos, Arthur W. Nienhuis; ISBN: 0471562459; http://www.amazon.com/exec/obidos/ASIN/0471562459/icongroupinterna

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Hemoglobin Variants in Human Populations by Winter (1986); ISBN: 0849361834; http://www.amazon.com/exec/obidos/ASIN/0849361834/icongroupinterna

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Hemoglobin: Cooperativity and Electronic Properties (Molecular Biology, Biochemistry and Biophysics, Vol 15) by M. Weissbluth (1974); ISBN: 0387065822; http://www.amazon.com/exec/obidos/ASIN/0387065822/icongroupinterna

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Hemoglobin: Molecular, Genetic and Clinical Aspects by H. Franklin Bunn, et al; ISBN: 0721621813; http://www.amazon.com/exec/obidos/ASIN/0721621813/icongroupinterna

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Hemoglobin: Structure, Function, Evolution, and Pathology by Richard Earl Dickerson, Irving Geis; ISBN: 0805324119; http://www.amazon.com/exec/obidos/ASIN/0805324119/icongroupinterna

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Hemoglobin-Based Red Cell Substitutes (1991); ISBN: 0808142453; http://www.amazon.com/exec/obidos/ASIN/0808142453/icongroupinterna

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Hemoglobin-Based Red Cell Substitutes (The Johns Hopkins Series in Contemporary Medicine and Public Health) by Robert M. Winslow; ISBN: 080184245X; http://www.amazon.com/exec/obidos/ASIN/080184245X/icongroupinterna

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Hemoglobinopathies by H. Franklin Bunn; ISBN: 0721621791; http://www.amazon.com/exec/obidos/ASIN/0721621791/icongroupinterna

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Hemoglobinopathies (Methods in Hematology, Vol 15) by T.H.J. Huisman (Editor); ISBN: 0443033099; http://www.amazon.com/exec/obidos/ASIN/0443033099/icongroupinterna

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Hemoglobins : Volume 76: Hemoglobins by Sidney P. Colowick (Editor), Eraldo Antonini (Editor) (1981); ISBN: 0121819760; http://www.amazon.com/exec/obidos/ASIN/0121819760/icongroupinterna

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Hemoglobins in development and differentiation; ISBN: 0845102133; http://www.amazon.com/exec/obidos/ASIN/0845102133/icongroupinterna

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Hemoglobins in Genetics and Evolution by Vernon M. Ingram; ISBN: 0231025858; http://www.amazon.com/exec/obidos/ASIN/0231025858/icongroupinterna

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Hemoglobins Part C: Biophysical Methods by Johannes Everse (Editor), et al; ISBN: 0121821331; http://www.amazon.com/exec/obidos/ASIN/0121821331/icongroupinterna

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Human Hemoglobin Genetics by George R. Honig, Junius G., III Adams (1986); ISBN: 0387818723; http://www.amazon.com/exec/obidos/ASIN/0387818723/icongroupinterna

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Human Hemoglobin Genetics (1985); ISBN: 3211818723; http://www.amazon.com/exec/obidos/ASIN/3211818723/icongroupinterna

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Human hemoglobins by H. Franklin Bunn; ISBN: 0721621783; http://www.amazon.com/exec/obidos/ASIN/0721621783/icongroupinterna

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International Symposium on Stabilized Hemoglobin; ISBN: 0936022299; http://www.amazon.com/exec/obidos/ASIN/0936022299/icongroupinterna

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Molecular Biology of Hemoglobin Switching by G. Stamatoyannopoulos (Editor); ISBN: 1898298351; http://www.amazon.com/exec/obidos/ASIN/1898298351/icongroupinterna

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Organization and expression of globin genes : [proceedings of the Second Conference on Hemoglobin Switching, held at Airlie House, Virginia, June 22-26, 1980]; ISBN: 0845102117; http://www.amazon.com/exec/obidos/ASIN/0845102117/icongroupinterna

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Organization and Expression of Globin Genes: Proceedings of the Second Conference on Hemoglobin Switching, Held at Airlie House, Virginia, June 22-26 by Conference

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on Hemoglobin Switching; ISBN: 0471566519; http://www.amazon.com/exec/obidos/ASIN/0471566519/icongroupinterna •

Oxygen affinity of hemoglobin and red cell acid base status; proceedings; ISBN: 0120653508; http://www.amazon.com/exec/obidos/ASIN/0120653508/icongroupinterna

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Physiology and disorders of hemoglobin degradation; ISBN: 0808907913; http://www.amazon.com/exec/obidos/ASIN/0808907913/icongroupinterna

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Reference Procedure for the Quantitative Determination of Hemoglobin in Blood: Approved Standard; ISBN: 1562380451; http://www.amazon.com/exec/obidos/ASIN/1562380451/icongroupinterna

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Regulation of Hemoglobin Biosynthesis by Eugene Goldwasser (Editor); ISBN: 0444007687; http://www.amazon.com/exec/obidos/ASIN/0444007687/icongroupinterna

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Sickle Cell Hemoglobin: Molecule to Man by Makio, Murayama; ISBN: 0316589519; http://www.amazon.com/exec/obidos/ASIN/0316589519/icongroupinterna

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STAMAT'OULOS HEMOGLOBINS DEV DIF by STAMAT'OULOS; ISBN: 0471566500; http://www.amazon.com/exec/obidos/ASIN/0471566500/icongroupinterna

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The Chromatography of Hemoglobin by Walter Adolph Schroeder; ISBN: 0824769414; http://www.amazon.com/exec/obidos/ASIN/0824769414/icongroupinterna

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The detection of hemoglobinopathies; [working papers]; ISBN: 0878191240; http://www.amazon.com/exec/obidos/ASIN/0878191240/icongroupinterna

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The Handbook on the Psychology of Hemoglobin-S: A Perspicacious View of Sickle Cell Disease by Samuel Rayford. McElroy; ISBN: 0819111325; http://www.amazon.com/exec/obidos/ASIN/0819111325/icongroupinterna

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The molecular basis of mutant hemoglobin dysfunction; ISBN: 0444006311; http://www.amazon.com/exec/obidos/ASIN/0444006311/icongroupinterna

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The Regulation of Hemoglobin Switching: Proceedings (Johns Hopkins Series in Contemporary Medicine and Public Health) by George Stamatoyannopoulos, Arthur W. Nienhuis (Editor); ISBN: 0801842530; http://www.amazon.com/exec/obidos/ASIN/0801842530/icongroupinterna

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “hemoglobin” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:11 11

In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found.

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Chromatographic (microcolumn) determination of hemoglobin A2. (approved standard) Author: Schneider, R. G.; Year: 1981; Villanova, PA: NCCLS, 1989

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Clinical disorders of hemoglobin structure and synthesis [by] Thomas F. Necheles, Donald M. Allen [and] Harvey E. Finkel. Author: Necheles, Thomas F.,; Year: 1973; New York, Appleton-Century-Crofts [c1969]

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Glycohemoglobin analyzers Author: ECRI (Organization); Year: 1995; Plymouth Meeting, PA: ECRI, c2003

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Glycosylated hemoglobin testing in the Department of Veterans Affairs: status & recommendations. Author: National Center for Cost Containment (U.S.); Year: 1989; Milwaukee, WI: National Center for Cost Containment, Dept. of Veterans Affairs, [1994]

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Harmonization of glycohemoglobin measurements: approved guideline Author: Goldstein, David E.; Year: 1996; Wayne, Pa.: NCCLS, c2002; ISBN: 1562384783

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Hemoglobin synthesis. Editors: Kaj Gert Jensen & Sven-Aage Killmann. Author: Jensen, Kaj Gert.; Year: 1956; Baltimore, Williams; Wilkins [c1971]

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Physical performance and hematological parameters; with special reference to hemoglobin and maximal oxygen uptake, by Odd D. Vellar and Lars Hermansen. Author: Vellar, Odd D.; Year: 1974; [Stockholm, Distributed by Almqvist; Wiksell, c1971]

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Quantitative measurement of fetal hemoglobin using the alkali denaturation method (approved guideline) Author: Schneider, R. G.; Year: 1998; Villanova, PA: NCCLS, 1989

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Sickle cell hemoglobin; molecule to man [by] Makio Murayama [and] Robert M. Nalbandian. Author: Murayama, Makio.; Year: 1990; Boston, Little, Brown [c1973]; ISBN: 031658951

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Solubility test to confirm the presence of sickling hemoglobins - second edition; approved standard Author: Fairbanks, V. F.; Year: 1980; Villanova: NCCLS, 1995; ISBN: 1562382748

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The dynamic equilibrium of body proteins: hemoglobin, plasma proteins, organ and tissue proteins. Author: Whipple, George Hoyt,; Year: 1988; Springfield, Ill., Thomas [c1956]

Chapters on Hemoglobin In order to find chapters that specifically relate to hemoglobin, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and hemoglobin using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “hemoglobin” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on hemoglobin: •

Anaemia Source: in Scully, C. and Cawson, R.A. Medical Problems in Dentistry. 4th ed. Woburn, MA: Butterworth-Heinemann. 1998. p. 106-122.

Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

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Contact: Available from Butterworth-Heinemann. 225 Wildwood Avenue, Woburn, MA 01801-2041. (800) 366-2665 or (781) 904-2500. Fax (800) 446-6520 or (781) 933-6333. E-mail: [email protected]. Website: www.bh.com. PRICE: $110.00. ISBN: 0723610568. Summary: Anemia is not a disease in itself but may be a feature of many diseases. The essential feature of anemia is a hemoglobin level below normal for the age and sex of the patient. This chapter on anemia is from a text that covers the general medical and surgical conditions relevant to the oral health care sciences. Topics include the classification of anemias, laboratory investigations, general dental aspects of anemia, iron deficiency anemia, Vitamin B12 (cobalamin) deficiency, pernicious (Addisonian) anemia, folate (folic acid) deficiency, anemia associated with systemic disease, aplastic anemia, hemolytic anemia, sickle cell disease, the thalassemias, erythrocyte membrane defects, erythrocyte metabolic defects, and acquired hemolytic anemia. For each disorder, the authors discuss general aspects, diagnosis and management issues, dental aspects, and patient care strategies. The chapter includes a lengthy summary of the points covered. 1 appendix. 2 figures. 12 tables. 49 references. •

Disorders of Bilirubin Metabolism Source: in Arias, I.M., et al. Liver: Biology and Pathobiology, Fourth Edition. Philadelphia, PA: Lippincott Williams and Wilkins. 2001. p.291-309. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-3030 or (301) 223-2300. Fax (301) 223-2365. PRICE: $249.00 plus shipping and handling. ISBN: 0781723906. Summary: Bilirubin is the end product of degradation of the heme moiety of hemoproteins. Hemoglobin, derived from senescent erythrocytes (aging red blood cells), is the major source of bilirubin. Hyperbilirubinemia (high levels of bilirubin in the blood) is commonly considered a marker of liver dysfunction. This chapter on bilirubin is from a textbook on the pathobiology and biology of the liver. Bilirubin is potentially toxic, but is normally rendered harmless by tight binding to albumin, and rapid detoxification and excretion by the liver. The authors discusses the formation of bilirubin, the chemistry of bilirubin, the quantification of bilirubin in body fluids, the toxicity of bilirubin, the disposition of bilirubin, disorders of bilirubin metabolism that result in unconjugated hyperbilirubinemia, and disorders of bilirubin metabolism that result in predominantly conjugated hyperbilirubinemia. 5 figures. 5 tables. 147 references.

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Approach to the Patient with Occult Gastrointestinal Bleeding Source: in Textbook of Gastroenterology. 4th ed. [2-volume set]. Hagerstown, MD: Lippincott Williams and Wilkins. 2003. p. 724-738. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-6423. Fax: (301) 223-2400. Website: www.lww.com. PRICE: $289.00. ISBN: 781728614. Summary: Occult gastrointestinal (GI) bleeding is hidden and not apparent on stool inspection. It occurs commonly, but a test is required for its detection. This chapter on the approach to patients with occult GI bleeding is from a lengthy, two-volume textbook that integrates the various demands of science, technology, expanding information, good judgment, and common sense into the diagnosis and management of gastrointestinal patients. Topics include quantifying blood loss, gastrointestinal hemoglobin metabolism, iron metabolism and deficiency, etiology (causes) of blood

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loss, clinical manifestations of blood loss, assessment and diagnostic strategies, fecal blood screening for colorectal neoplasia, and therapeutic considerations. The author notes that fecal occult blood testing is widely used to screen for colorectal cancer and to evaluate iron deficiency and anemia. A rational assessment and treatment of occult GI bleeding are based on an appreciation of the pathophysiology of occult blood loss, available diagnostic tools, and therapeutic principles. 5 figures. 5 tables. 219 references. •

Monitoring Source: in Franz, M.J., et al, eds. Core Curriculum for Diabetes Education. 4th ed.: (Volume 2) Diabetes Management Therapies. Chicago, IL: American Association of Diabetes Educators (AADE). 2001. p. 151-172. Contact: Available from American Association of Diabetes Educators. AADE Member Service Center, 100 W. Monroe Street, Suite 400, Chicago, IL 60603. (800) 338-3633. Fax (312) 424-2427. Website: www.diabeteseducator.org. PRICE: Individual volume $45.00 for members and $60.00 for nonmembers; complete 4-volume set $149.95 for members and $199.95 for nonmembers; plus shipping and handling. ISBN: 1881876063 (Volume 2); 1881876098 (4-volume set). Summary: Regular monitoring is an essential component of any diabetes management program. Monitoring by the patient includes self monitoring of blood glucose (SMBG), serum ketones, urine ketones, and urine glucose, if recommended. Monitoring also includes assessment of metabolic control by the health care team. This chapter on monitoring is from a book in a series of four texts that make up a Core Curriculum, designed primarily to help educators prepare for the Certified Diabetes Educator (CDE) exam. Topics include factors that affect the accuracy of SMBG results; the most common user error related to SMBG; critical uses of SMBG data by patients; how educators can use SMBG results to teach abstract principles of diabetes management; required psychosocial adaptations to SMBG; the SMBG needs of special populations; the measurement methods and target ranges for glycosylated hemoglobin, fructosamine, and urinary protein; the indications for tests of ketonemia, ketonuria, and glycosuria; and how to use documentation of weight patterns as a monitoring tool. The chapter lists the learning objectives for that chapter, presents information in outline and bulleted format, summarizes the key educational considerations, offers self review questions and questions for discussion, presents an illustrative case report, and concludes with a list of references. A post-test and the answers to the post-test questions are appended to the chapter. 4 tables. 30 references.

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Intensive Insulin Therapy for Patients with Type II Diabetes Source: in LeRoith, D.; Taylor, S.I.; Olefsky, J.M., eds. Diabetes Mellitus: A Fundamental and Clinical Text. Philadelphia, PA: Lippincott-Raven Publishers. 1996. p. 647-660. Contact: Available from Lippincott-Raven Publishers. 12107 Insurance Way, Hagerstown, MD 21740-5184. (800) 777-2295. Fax (301) 824-7390. PRICE: $199.00. ISBN: 0397514565. Summary: The benefits of normalizing glycosylated hemoglobin in patients with Type I diabetes mellitus (insulin-dependent, or IDDM) have been clearly demonstrated by the results of the Diabetes Control and Complications Trial (DCCT). This chapter, from a medical textbook on diabetes, explores the use of intensive insulin therapy for patients with Type II (noninsulin-dependent, or NIDDM) diabetes. The authors cover the different insulin therapeutic regimens available to normalize glycemia and glycosylated hemoglobin in patients with Type II diabetes mellitus; for each therapy, the authors

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review their application, possible benefits, and adverse effects. They note that the area of major concern when insulin therapy is used to achieve tight glucose control in Type II diabetes is the association of hyperinsulinemia with weight gain and accelerated atherosclerosis. In addition, when a meal plan, exercise, and oral antidiabetic agents fail to control glycemia, then the lowest possible dose of insulin should be used. Topics include intensive management goals, tools used to monitor glycemic control, intensive insulin strategies, the application of intensive insulin therapy, combination therapy, multiple-injection regimens, external subcutaneous insulin infusion pumps, implantable intraperitoneal insulin infusion pumps, insulin analogs, human insulin-like growth factor, the benefits of normoglycemia, insulin therapy and weight gain, and hypoglycemia. 8 figures. 5 tables. 89 references. •

Porphyrias Source: in Arias, I.M., et al. Liver: Biology and Pathobiology, Fourth Edition. Philadelphia, PA: Lippincott Williams and Wilkins. 2001. p.311-329. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-3030 or (301) 223-2300. Fax (301) 223-2365. PRICE: $249.00 plus shipping and handling. ISBN: 0781723906. Summary: The porphyries are a group of metabolic disorders that result from defects of specific enzymes of the heme (the iron-containing part of the hemoglobin molecule) synthetic pathway. Clinically, they may be characterized by a propensity to acute neurovisceral crises, photosensitive skin disease, or both. This chapter on the porphyrias is from a textbook on the pathobiology and biology of the liver. The authors discuss the chemistry and biochemistry of porphyrins and heme, heme biosynthesis, the enzymology and molecular biology of heme biosynthesis, clinical disorders associated with defects in heme biosynthesis, and the specific syndromes of porphyria. Specific syndromes covered are: 5-aminolevulinic acid dehydratase deficiency, porphobilinogen deaminase deficiency, uroporphyrinogen III cosynthetase deficiency, uroporphyrinogen decarboxylase deficiency, coproporphyrinogen oxidase deficiency, protoporphyringoen oxidase deficiency, and ferrochelatase deficiency. 1 table. 196 references.

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Management of Type 2 Diabetes in the Elderly Patient Source: in Cooper, J.W. Diabetes Mellitus in the Elderly. Binghamton, NY: Pharmaceutical Products Press. 1999. p. 21-45. Contact: Available from Pharmaceutical Products Press. 10 Alice Stret, Binghamton, NY 13904-1580. (800)429-6784. E-mail: [email protected]. Website: www.haworthpressinc.com. PRICE: $49.95 plus shipping and handling. ISBN: 0789006820. Summary: This article on the management of type 2 diabetes in the elderly patient is from a volume that is devoted to the diagnosis and treatment of diabetes mellitus in the elderly. The authors evaluate the various available pharmacologic (drug) agents and combinations of these agents in the management of type 2 diabetes in this population. Currently, the incidence of type 2 diabetes in the elderly is on the rise. While goals of glycemic control may be similar in the elderly to the younger type 2 patients, nuances in the pharmacology of the four groups of oral agents and in insulin products may make some regimens preferable in the elderly population. The positive benefits of euglycemia (optimal levels of glucose, or sugar, in the blood) in all patients with diabetes has been conclusively demonstrated. Currently in the United States, sulfonylureas, alpha glucosidase inhibitors, biguanides, thiazolidinediones, and various insulin products are

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available for management of hyperglycemia (high levels of blood glucose). When choosing an agent, the practitioner must consider efficacy of the medication (blood glucose lowering potential), current and goal blood glucose, and glycosylated hemoglobin measures (a monitor of long term blood glucose levels), contraindications, side effects, and effect on other metabolic parameters such as insulin concentration, lipids (fats), and body weight. Additionally, in the elderly, remaining life expectancy, presence of diabetes complications, presence of coexisting medical or neuropsychiatric disorders, and the patient's willingness and ability to comply with the proposed diabetes treatment plan must be considered when developing treatment goals and therapeutic regimens. While cost of medication must be considered, it is incidental (less than 2 percent) when compared to the overall cost of diabetes. 6 tables. 39 references. •

Testing for Gestational Diabetes Source: in Reece, E.A. and Coustan, D.R., eds. Diabetes Mellitus in Pregnancy. 2nd ed. New York, NY: Churchill Livingstone. 1995. p. 261-275. Contact: Available from Churchill Livingstone. 300 Lighting Way, Secaucus, NJ 07094. (800) 553-5426. PRICE: $92.00. ISBN: 0443089795. Summary: This chapter covers diagnostic criteria for the oral glucose tolerance test and for the intravenous glucose tolerance test (IVGTT) in testing for gestational diabetes. In addition, the author examines proposed screening tests, including historical factors, glycosylated hemoglobin and other blood protein levels, and other oral challenge tests. The diagnostic use of amniotic fluid glucose, insulin, and C-peptide, as well as postpartum evaluation of women with suspected diabetic fetopathy, are also discussed. 6 tables. 90 references. (AA-M).

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Solving Oral Medication Problems Source: in Touchette, N. Diabetes Problem Solver. Alexandria, VA: American Diabetes Association. 1999. p. 149-159. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $19.95 for members; plus shipping and handling. ISBN: 1570400091. Summary: This chapter deals with solving oral medication problems in people who have type 2 diabetes. Oral agents may be used when diet and exercise alone are no longer controlling blood glucose levels. A physician may recommend pharmacological intervention if a patient's blood glucose level is over 140 milligrams per deciliter before breakfast, if the bedtime blood glucose level is over 160 milligrams per deciliter, or if the glycosylated hemoglobin level is over 8 percent. There are two kinds of oral agents. One type increases the supply of insulin, and the other makes insulin more effective. Common side effects of oral agents are gastrointestinal problems, allergic reactions, alcohol intolerance, hypoglycemia, and lactic acidosis. The chapter provides information on recognizing, handling, and preventing hypoglycemia and lactic acidosis. In addition, the chapter explains how people who are taking oral agents can determine if other drugs are interfering with oral agents, as well as how they can determine if oral agents are not working and how to deal with this failure. 2 tables.

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Well-Child Care and the Next Steps in Diabetes Management Source: in Plotnick, L. and Henderson, R. Clinical Management of the Child and Teenager with Diabetes. Baltimore, MD: The Johns Hopkins University Press. 1998. p. 49-61. Contact: Johns Hopkins University Press. 2715 North Charles Street, Baltimore, MD 21218-4363. (410) 516-6900. Fax (410) 516-6998. Website: www.press.jhu.edu. PRICE: $24.95 for paperback; $55.00 for hardcover; plus shipping and handling. ISBN: 0801859093. Summary: This chapter discusses general health care for children and adolescents who have diabetes. They should receive health care that meets all American Academy of Pediatrics recommendations for preventive pediatric health care. One of the main goals in treating children and adolescents who have diabetes is to help maintain normal physical growth, including normal growth in height and weight and normal timing of the onset and progression of puberty. Blood glucose monitoring is the foundation of good diabetes management. Daily self monitoring of blood glucose is the responsibility of the children and adolescents themselves and their families, whereas the measurement of glycohemoglobin is the responsibility of the health care provider. A clinician should compare the patient's glycohemoglobin level with reported blood glucose levels obtained from self monitoring. Glycohemoglobin measurements help the clinician, the patient, and the family plan and to adjust their goals. Monitoring can also be used to detect acute and chronic complications. Monitoring the urine for ketones can prevent ketoacidosis. The earliest sign of nephropathy, a long term complication of diabetes, is the spilling of small amounts of albumin in the urine. Urine dipsticks can be used to detect protein in the urine. Blood pressure and vision should be checked at least once a year. Weight should be monitored at every clinic visit for early detection of deviations from normal patterns. Children and adolescents should also receive all immunizations recommended by the American Academy of Pediatrics. The chapter also discusses the implications of the Diabetes Control and Complications Trial for the medical management of diabetes. 2 figures. 1 table.

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Diabetes Control Source: in Betschart, J. Diabetes Care for Babies, Toddlers, and Preschoolers: A Reassuring Guide. Somerset, NJ: John Wiley and Sons, Inc. 1999. p. 57-70. Contact: Available from John Wiley and Sons. One Wiley Drive, Somerset, NJ 08875. (800) 225-5945 or (732) 469-4400. Fax (732) 302-2300. E-mail: [email protected]. Website: www.wiley.com. PRICE: $14.95 plus shipping and handling. ISBN: 0471346764. Summary: This chapter explains how to prevent, detect, and treat hypoglycemia. Although no specific guidelines for blood glucose control have been set for young children, diabetes control is generally looked at in three different ways. One way is by determining glycosylated hemoglobin level. Another way is evaluating the daily blood glucose numbers, and the third way is assessing clinical signs. Most pediatric diabetes specialists believe that the before meal target blood glucose range for children younger than six years old should be at or around 100 to 200 milligrams per deciliter. Hypoglycemia occurs when there is too little glucose in the bloodstream, and hyperglycemia occurs when there is too much glucose in the bloodstream. The chapter presents the symptoms of hypoglycemia; suggests ways to treat the first signs of low blood glucose in infants, toddlers, and preschoolers; discusses the use of glucagon to treat hypoglycemia; explains how to prevent hypoglycemia in a young child; suggests supplies to pack for short and long trips; and offers tips for managing nighttime

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hypoglycemia. In addition, the chapter provides suggestions for managing hyperglycemia in a young child, handling ketoacidosis, and coping with sick days. •

Survival Skills for Patients and Parents Source: in Plotnick, L. and Henderson, R. Clinical Management of the Child and Teenager with Diabetes. Baltimore, MD: The Johns Hopkins University Press. 1998. p. 32-48. Contact: Johns Hopkins University Press. 2715 North Charles Street, Baltimore, MD 21218-4363. (410) 516-6900. Fax (410) 516-6998. Website: www.press.jhu.edu. PRICE: $24.95 for paperback; $55.00 for hardcover; plus shipping and handling. ISBN: 0801859093. Summary: This chapter explains the survival skills of preparing for and giving insulin injections, monitoring blood glucose and urine ketones, keeping records, planning meals, managing exercise, and handling complications. These skills should be taught in the hospital before the patient is discharged from an inpatient program or in the first days of an outpatient program. At least one parent and the child, if old enough, will need to learn how to inject insulin. The first step in injecting insulin is to gather the necessary supplies. Once the supplies have been gathered, the next step is to measure insulin into the syringe. This is followed by selecting and cleaning the injection site and administering the injection. Blood glucose monitoring is the foundation of diabetes management. Blood glucose can be monitored through self monitoring or through the glycohemoglobin measurement. Self monitoring, which should be performed about four times a day, involves lancing the finger for a drop of blood, placing the blood on a blood glucose monitor test strip, and obtaining a measure of glucose in the blood. Ketone monitoring is also important because ketones in the urine are an early sign of impending problems. Keeping records of blood glucose levels and insulin doses is important because this information allows quick detection of developing problems, accurate troubleshooting, and informed choices on necessary adjustments. Meal planning is a central element of diabetes control, which encompasses a spectrum of philosophies about food. Although exercise is a beneficial activity, it is a factor that must be weighed in calculations about insulin doses. Families learning about diabetes survival skills must also know how to guard against and recognize acute complications such as hypoglycemia and know about the risk of chronic complications. 2 figures.

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What Happens at the First Visit to the Doctor? Source: in Hirsch, I.B. 12 Things You Must Know About Diabetes Care Right Now!. Alexandria, VA: American Diabetes Association. 2000. p. 33-48. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $14.95 plus shipping and handling. ISBN: 1580400612. Summary: This chapter explains what happens at the first visit to the doctor following a diagnosis of diabetes. The medical history is the foundation of diabetes care, so the doctor will ask the patient about symptoms of hypoglycemia and hyperglycemia, the use of diabetes related medications, self monitoring of blood glucose data, glycosylated hemoglobin test results, meal plans and nutrition education, exercise, and complications. Other aspects of the medical history include asking the patient about eye examinations and treatments; high blood pressure; neuropathy symptoms; circulation, heart, and thyroid problems; gestational diabetes, for female patients; cultural issues

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affecting diabetes management; and financial considerations. The physical examination should focus on height, weight, blood pressure, eyes, internal organs, pulse, and feet. Once the doctor has obtained a medical history, conducted a physical examination, and performed laboratory tests, a management plan can be developed. This plan is tailored to the individual patient, and it should be shared with any other doctors caring for the patient. •

Checking Your Levels Source: in Lincoln, T.A.; Eaddy, J.A. Beating the Blood Sugar Blues. Alexandria, VA: American Diabetes Association. 2001. p.16-25. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $12.95 plus shipping and handling. ISBN: 1580400485. Summary: This chapter is from a book that offers first hand knowledge from two doctors who have more than 100 years of combined experienced with the day-to-day balancing act of blood glucose (sugar) and diabetes. The authors, both of whom have type 1 diabetes, share their own stories as well as those of over 40 of their patients. In this chapter, the authors describe the use of self monitoring of blood glucose (SMBG), emphasizing the importance of monitoring blood glucose levels every day. The authors cover learning to use a blood glucose meter, how the meters work, why urine testing is not reliable enough to use for monitoring, how to use the information gained from SMBG, why people do not monitor their blood glucose levels (pain, needing assistance, time involved, cost, lack of understanding about how to use the results), what to expect from the health care provider, what to expect from a home glucose meter, how to avoid getting frustrated with readings that seem out of sync with the pattern, the role of glycosylated hemoglobin (HbA1c) testing, and the future of SMBG.

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Dietary Recommendations for Active and Inactive Ulcerative Colitis Source: in Bayless, T.M. and Hanauer, S.B. Advanced Therapy of Inflammatory Bowel Disease. Hamilton, Ontario: B.C. Decker Inc. 2001. p. 161-164. Contact: Available from B.C. Decker Inc. 20 Hughson Street South, P.O. Box 620, L.C.D. 1 Hamilton, Ontario L8N 3K7. (905) 522-7017 or (800) 568-7281. Fax (905) 522-7839. Email: [email protected]. Website: www.bcdecker.com. PRICE: $129.00 plus shipping and handling. ISBN: 1550091220. Summary: This chapter on dietary recommendations for active and inactive ulcerative colitis (UC) is from the second edition of a book devoted to the details of medical, surgical, and supportive management of patients with Crohn's disease (CD) and UC, together known as inflammatory bowel disease (IBD). This chapter discusses the role of diet and nutritional support in ulcerative colitis (UC) in which the catabolic effect (breakdown or loss of body tissue) of inflammation, impaired nutrient absorption, and gastrointestinal (GI) dysfunction can rapidly lead to malnutrition. Inactive UC is a chronic disorder and may be associated with malnutrition, specific elemental deficiencies, and specific food intolerances. Patients may not eat enough to meet their nutritional requirements because of anorexia, drug side effects (eg, nausea, headache, and anorexia), food-induced diarrhea, or pain. In lactose intolerant people, production of hydrogen produces bloating, nausea, and flatulence and unabsorbed short-chain fatty acids produce diarrhea. Lactose intolerance may be primary (racial or congenital) or secondary (eg, due to bacterial overgrowth or intestinal mucosal disease or injury). The

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incidence of UC is not increased in lactose intolerant people, and the incidence of lactose intolerance is not increased in patients with UC. In UC in remission, lactose restriction is important to control symptoms only in those patients documented to have lactose intolerance, presumably on a genetic basis. Active UC involves pathologic and physiologic changes both within the colonic mucosa and systemically. The colonic mucosa is inflamed and associated with loss of fluid, electrolytes, proteins and immunoglobulins, albumin (protein), and hemoglobin (red blood cells). Systemic manifestations of fever and anorexia are associated with reduced oral intake of nutrients. However, the body is in a catabolic state, with increased nutritional requirements and increased energy needs as a result of fever, associated infections, and steroid therapy. In these situations, nutritional support is essential. In such cases, parental or enteral nutrition not only may be of value but may be essential in patient management. 2 tables. 10 references. •

Improving Diabetes Control in Adolescents With Type I Diabetes Source: in Anderson, B.J. and Rubin, R.R., eds. Practical Psychology for Diabetes Clinicians: How to Deal with the Key Behavioral Issues Faced by Patients and Health Care Teams. Alexandria, VA: American Diabetes Association. 1996. p. 23-33. Contact: Available from American Diabetes Association. Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (404) 442-9742. PRICE: $19.95 (members); $24.95 (nonmembers). ISBN: 0945448732. Summary: This chapter on improving diabetes control in adolescents with IDDM is from a guidebook on behavioral issues for diabetes clinicians. The author introduces the information gained from the DCCT and discusses how that information can be applied to adolescence. Topics include adolescent developmental considerations; endocrinologic effects of puberty; insulin regimens; nutrition; exercise; monitoring diabetes control; the biochemical goals of therapy; hypoglycemia; and issues of responsibility for diabetes care, including cognitive maturity, family functioning, and the adherence problem. The author encourages readers to maintain their emphasis on glycemic control, even during the difficult adolescent years, as any sustained reduction in the level of glycosylated hemoglobin lowers the risk of complications. 8 references.

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Insulin Therapy Source: in Edelman, S.V. and Henry, R.R. Diagnosis and Management of Type 2 Diabetes. Caddo, OK: Professional Communications, Inc. 2002. p. 121-148. Contact: Available from Professional Communications, Inc., Fulfillment Center, PO Box 10, Caddo, OK 74729-0010. (800)337-9838. Fax (580)367-9989. E-mail: [email protected]. ISBN: 1884735754. PRICE: $21.95, plus shipping and handling. Summary: This chapter on the use of insulin therapy is from a handbook for primary care providers that offers a concise overview of the diagnosis and management of type 2 diabetes. Insulin therapy most commonly is reserved for patients who have failed an adequate trial of diet, exercise, and oral antidiabetes agents. However, institution of insulin therapy is commonly delayed inappropriately in patients failing oral antidiabetes agents. The authors encourage early use of insulin soon after it is evident that oral antidiabetes agents are failing. The authors focus on the different insulin regimens commonly used to normalize glucose levels and glycosylated hemoglobin (HbA1c, a measure of blood glucose levels over time) in patients with type 2 diabetes mellitus. Topics include selecting an insulin preparation, the application of intensive

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insulin therapy, combination therapy, multiple injection regimens, insulin pump therapy, alternative insulin delivery systems, complications of insulin therapy, and the use of islet cell transplantation. 2 figures. 5 tables. 5 references. •

Therapy for Diabetes Source: in Harris, M.I., et al., eds., for the National Diabetes Data Group (NDDG). Diabetes in America. 2nd ed. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. 1995. p. 519-540. Contact: Available from National Diabetes Information Clearinghouse (NDIC). 1 Information Way, Bethesda, MD 20892-3560. (800) 860-8747 or (301) 654-3327. Fax (301) 634-0716. E-mail: [email protected]. Also available at http://www.niddk.nih.gov/. PRICE: Full-text book and chapter available online at no charge; book may be purchased for $20.00. Order number: DM-96 (book). Summary: This chapter on therapy for diabetes is from a compilation and assessment of data on diabetes and its complications in the United States. The authors note that the most recent information about use of diet, oral agents, and insulin by people with diabetes in the United States is from the 1989 National Health Interview Survey (NHIS). For all diabetes patients older than 18 years, 43 percent were treated with insulin, 49 percent were treated with oral agents, and 64 percent reported they were following a diet for their diabetes. Two or more insulin injections daily were taken by 61 percent of insulin-dependent diabetes (IDDM) patients and 48 percent of insulin-treated NIDDM patients; use of an insulin pump was rare. Nutritional therapy is a challenging but crucial element in the management of diabetes. For children with IDDM, a goal is to match diet to insulin requirements to ensure normal growth and development. By contrast, in obese NIDDM patients, it is important to achieve and maintain a reasonable or realistic body weight. The authors outline recommendations for dietary intake for patients with diabetes. When optimal diet with weight reduction and exercise fail to restore adequate glycemic control in NIDDM patients, pharmacologic treatment should be considered. The sulfonylureas are the major group of oral hypoglycemic agents currently used, with the biguanide drug metformin recently approved for use. The Diabetes Control and Complications Trial (DCCT) evaluated the effect of intensive insulin therapy in IDDM and found a 40 to 70 percent risk reduction in retinopathy, nephropathy, and neuropathy, compared with conventionally treated subjects. The authors report that favorable effects of patient education, notably increased self management skills, such as self glucose monitoring (SMBG), compliance with overall management, improved glycemia for insulin-treated diabetes, and reduction in complications. The authors conclude with a brief discussion of pancreatic transplantation. Pancreatic transplant is the only treatment for IDDM capable of establishing an insulin-independent state with euglycemia and normal glycosylated hemoglobin. 2 appendices. 10 figures. 14 tables. 152 references. (AA-M).

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Diabetes Mellitus Source: in Wilson, J.D., et al., eds. Williams Textbook of Endocrinology. 9th ed. Philadelphia, PA: W.B. Saunders Company. 1998. p. 973-1059. Contact: Available from W.B. Saunders Company. Book Order Fulfillment Department. 11830 Westline Industrial Drive, Saint Louis, MO 63146-9988. (800) 545-2522 or (314) 4537010. Fax (800) 568-5136 or (314) 453-7095. E-mail: [email protected]. Website: www.wbsaunders.com. PRICE: $150.00 plus shipping and handling. ISBN: 0721661521.

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Summary: This chapter provides an overview of diabetes mellitus. This condition comprises a heterogenous group of hyperglycemic disorders. The chapter begins with a description of the tests used to diagnose diabetes, including measurement of fasting plasma glucose, glycosylated hemoglobin, and the muscle capillary basement membrane; the oral glucose tolerance test; and the intravenous glucose tolerance test. This is followed by a discussion of nomenclature and definitions. The chapter then provides detailed information on type 1 and type 2 diabetes. Topics related to both types of diabetes include their prevalence, incidence, genetics, and clinical features. Other topics relevant to type 1 diabetes include environmental-genetic interactions, islet antibodies, and superantigens. In addition, the natural history, prevention, and hormonal pathophysiology of type 1 diabetes are discussed. Topics related to the prevention of type 1 diabetes include potential prophylactic agents, immunomodulation in autoimmune diabetes, and the pathology of the Islets of Langerhans in type 1 diabetes. Topics concerning type 2 diabetes include islet cell function, hormonal pathophysiology, and molecular genetics. Molecular genetic topics include mutations in genes involved in insulin resistance, mutations in genes encoding beta cell proteins involved in the quality and quantity of secreted insulin, mutations in genes involved in lipid metabolism and obesity, mutations in genes relevant to insulin action, miscellaneous mutations in genes without known diabetogenicity, the current state of candidate genes, the inheritance of type 2 diabetes, and autoimmune type 2 diabetes. The chapter continues with a discussion of insulin resistance, management of the diabetic pregnancy, gestational diabetes, and surgery in diabetic patients. Information is provided on the complications of diabetes, including the role of metabolic control in preventing complications and the potential mechanisms in the pathogenesis of complications. Complications discussed include cardiomyopathy, dermopathy, diabetic foot syndrome, nephropathy, retinopathy, cataracts, neuropathy, and peripheral vascular disease. The issue of treatment is also addressed. Topics include the treatment of type 1 diabetes with insulin, diet, and exercise; the treatment of type 2 diabetes with diet, oral antihyperglycemic drugs, and insulin; the treatment of diabetic ketoacidosis and nonketotic hyperosmolar coma; the prevention and treatment of vascular complications; and pancreas and islet transplantation. 49 figures. 28 tables. 1207 references. •

General Information About Medications Used To Treat Diabetes Source: in Carlisle, B.A.; Kroon, L.A.; Koda-Kimble, M.A. 101 Medication Tips for People with Diabetes. Alexandria, VA: American Diabetes Association. 1999. p. 1-13. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $14.95 plus shipping and handling. ISBN: 1580400329. Order number 483301. Summary: This chapter provides general information on medications used to treat type 2 diabetes. Different medications are used because this form of diabetes can be caused by many factors. In some people, these medications are used in combination with each other or with insulin. Oral medications help the pancreas release more insulin or help the body's insulin work better. Classes of medications available to treat type 2 diabetes include alpha-glucosidase inhibitors, biguanides, meglitinides, sulfonylureas, thiazolidinediones, and insulin. All of these medications work in different ways to lower blood glucose. Alpha-glucosidase inhibitors slow the breakdown of starches to glucose. Biguanides and meglitinides decrease production of glucose by the liver. Sulfonylureas stimulate the pancreas to release insulin in response to a meal. Thiazolidinediones

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enhance glucose uptake by muscle. Generally, the sulfonylureas, meglitinides, and biguanides are more potent in lowering blood glucose than thiazolidinediones or alphaglucosidase inhibitors used as single agents. Many factors are involved in determining which medication is best for a particular patient. Effectiveness is determined by blood glucose testing. A target blood glucose level between 80 and 120 milligrams per deciliter is recommended by the American Diabetes Association. Glycosylated hemoglobin is a measure of overall blood glucose control over the past 2 to 3 months. Blood glucose testing will also tell people whether their diabetes is in good control on a daily basis. People taking medications should continue their prescribed diet and exercise therapy. Combination therapy may be needed to achieve blood glucose control when a single medication is no longer effective. Although insulin therapy may be delayed by taking a combination of medications and following a diet and exercise program, over time, the pancreas of many people who have type 2 diabetes stops producing insulin, thus necessitating insulin injections. In some people, triple medication therapy may delay the use of insulin. 3 tables. •

Chapter 159: Hematologic Diseases Source: in Freedberg, I.M., et al., eds. Fitzpatrick's Dermatology in General Medicine. 5th ed., Vol. 2. New York, NY: McGraw-Hill. 1999. p. 1867-1881. Contact: Available from McGraw-Hill Customer Services. P.O. Box 548, Blacklick, OH 43004-0548. (800) 262-4729 or (877) 833-5524. Fax (614) 759-3749 or (614) 759-3641. E-mail: [email protected]. PRICE: $395.00 plus shipping and handling. ISBN: 0070219435. Summary: This chapter provides health professionals with information on hematologic diseases. The chapter begins with a discussion of the cutaneous signs and symptoms associated with hematologic diseases, including pallor, flushing and erythroderma, cyanosis, jaundice, and infiltrative lesions. Cutaneous pallor occurs as a result of a drop in the hemoglobin content of the cutaneous microvascular. This decrease can occur either with a drop in the overall cutaneous blood flow due to emotion, epinephrine, cold exposure, shock, or with physiologic adjustment to severe anemia. The symptoms of iron-deficiency anemia include pallor, fatigue, irritability, and headaches. Megaloblastic anemias result from impaired deoxyribonucleic acid synthesis. The most common causes of this type of anemia are folate or vitamin B12 deficiency. Folate deficiency usually results from poor nutrition, decreased absorption, or increased metabolic requirements. The most common disorder of impaired vitamin B12 absorption is pernicious anemia. Various endocrine disorders may also lead to anemia, including pituitary deficiency, adrenal dysfunction, gonadal dysfunction, and thyroid dysfunction. Emotion or heat may stimulate vasodilation and flushing. Central cyanosis indicates arterial deoxygenation or altered hemoglobin. Jaundice results from staining of the skin by bile pigment. The chapter continues with a discussion of the differential diagnosis of purpura with an emphasis on those subsets of purpura with important underlying hematologic abnormalities, including nonpalpable purpura and palpable or retiform purpura. 7 figures, 6 tables, and 148 references.

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What Should Happen at Each Doctor's Appointment? Source: in Hirsch, I.B. 12 Things You Must Know About Diabetes Care Right Now!. Alexandria, VA: American Diabetes Association. 2000. p. 49-59. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 442-

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9742. Website: www.diabetes.org. PRICE: $14.95 plus shipping and handling. ISBN: 1580400612. Summary: This chapter provides people who have diabetes with information on what should happen at each doctor's appointment. The American Diabetes Association recommends that people who treat their diabetes with insulin should visit their health care provider at least four times a year and those who do not use insulin should visit their health care provider two to four times per year. At each visit, the doctor and patient will review blood glucose control, consider any changes that may need to be made to the diabetes care plan, and discuss symptoms of developing complications and other health concerns. A physical examination should also be repeated at all visits. At every visit, weight and blood pressure should be measured, feet should be examined, and eyes checked for retinopathy. Ongoing laboratory work includes tests for glycated hemoglobin level, fasting blood glucose level, lipid levels, and urine albumin. In addition, the patient and doctor should review the patient's management plan to find problems and check the patient's progress in meeting goals. The chapter includes a list of questions a patient may ask a doctor and questions a doctor may ask a patient. •

Good Health Care and Your Health Care Team Source: in American Diabetes Association. American Diabetes Association Complete Guide to Diabetes: The Ultimate Home Diabetes Reference. 2nd ed. Alexandria, VA: American Diabetes Association. 1999. p. 55-92. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $23.95 plus shipping and handling. ISBN: 1580400388. Summary: This chapter provides suggestions for selecting diabetes care team members. People with diabetes should look for health professionals who recognize the patient as an individual, respond to the patient's questions and concerns, and recommend the best possible strategies for the care and management of diabetes. The patient is the team captain, so the patient is responsible for choosing the other members of the patient care team. The patient can think of his or her primary care physician as the team co-captain. Other health professionals that may be part of the patient care team include a diabetes educator, a dietitian or nutritional counselor, an eye doctor, a podiatrist, a counselor, a pharmacist, a dentist, a dermatologist, and an exercise physiologist. The chapter offers guidelines for choosing these health care professionals and getting the most out of the health care team by communicating with other team members, meeting with the primary care physician, and getting a physical examination. The chapter also provides tips for caring for the eyes, feet, mouth, and skin and answers questions about the glycated hemoglobin test.

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Comprehensive Monitoring for Evaluating Diabetes Therapy Source: in Powers, M.A., ed. Handbook of Diabetes Medical Nutrition Therapy. Gaithersburg, MD: Aspen Publishers, Inc. 1996. p. 134-149. Contact: Available from Aspen Publishers. P.O. Box 990, Frederick, MD 21705-9727. (800) 638-8437. Fax (301) 695-7931. PRICE: $89.00. ISBN: 0834206315. Summary: This chapter, from a handbook on diabetes medical nutrition therapy (MNT), discusses comprehensive monitoring for evaluating diabetes therapy. The authors provide an overview of monitoring tests and methods that are used to assess nutrition-

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related problems and to evaluate the success of nutrition intervention in diabetes. Clinical cases are presented to illustrate how information obtained from monitoring can be used to improve the quality of nutrition care. Topics include patient monitoring of physiologic parameters (blood glucose, urinary ketones, blood pressure, weight), quality assurance considerations, laboratory tests (blood glucose, glycated hemoglobin, lipids, renal function), and nutrition monitoring for NIDDM, IDDM, and gestational diabetes. 5 figures. 2 tables. 17 references. •

Diabetic Retinopathy Source: in Reece, E.A.; Coustan, D.R., eds. Diabetes Mellitus in Pregnancy. 2nd ed. New York, NY: Churchill Livingstone. 1995. p. 303-314. Contact: Available from Churchill Livingstone. 300 Lighting Way, Secaucus, NJ 07094. (800) 553-5426. PRICE: $92.00. ISBN: 0443089795. Summary: This chapter, from a medical textbook on diabetes mellitus in pregnancy, covers the literature on pregnancies complicated by diabetic retinopathy (eye disease). The authors focus on the variables that influence the natural history of retinopathy during pregnancy. Topics include the natural history of retinopathy in nonpregnant individuals; the role of hyperglycemia as a cause of retinopathy; the effects of rapid normalization of glucose levels, for example, after institution of insulin pump therapy, on diabetic retinopathy; how increased hormone levels in pregnancy may accelerate retinopathy; and determining when to treat pregnant women with retinopathy and the controversy about photocoagulation therapy during pregnancy. The authors conclude with a list of five risk factors that accelerate the natural progression of retinopathy during pregnancy: pregnancy per se as an independent risk factor; hypertension; hyperglycemia at the start of pregnancy; rapid normalization of blood glucose; and the duration of diabetes and state of the retina at the beginning of the pregnancy. The authors recommend prudent therapy that allows normalization of blood glucose slowly, bringing the glycosylated hemoglobin to less than six standard deviations above the mean of a normal population over a period of at least 6 to 9 months before conception. In addition, until more definitive research information is available, the authors conclude that photocoagulation treatment for proliferative retinopathy that presents during pregnancy is recommended, despite the possibility that retinopathy may regress spontaneously postpartum. 5 figures. 2 tables. 71 references.

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Urine and Urinary Sediment Source: in Barakat, A.Y. Renal Disease in Children: Clinical Evaluation and Diagnosis. Secaucus, NJ: Springer-Verlag. 1990. p. 31-54. Contact: No longer available from publisher. Summary: This chapter, from an extensive desk reference book about the clinical evaluation and diagnosis of renal disease in children, discusses the urine and urinary sediment. The authors note that a carefully performed urinalysis using physical, chemical, and microscopic examination offers very important information regarding the kidney. Seven sections cover: specimen collection and preservation; quality control and instrumentation; physical examination; specific gravity; chemical examination; other studies; and microscopic examination. Specific chemical examinations are used to test the urine for pH and the presence of protein; glucose and reducing substances; ketones; blood; hemoglobin and myoglobin; bilirubin; bacteria; and electrolytes. 2 figures. 7 references.

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Nitty-Gritty 2: Glucose Testing Source: in Siminerio, L.M. and Betschart, J. American Diabetes Association Guide to Raising a Child with Diabetes. 2nd ed. Alexandria, VA: American Diabetes Association. 2000. p. 43-52. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $16.95 plus shipping and handling. ISBN: 1580400272. Summary: This chapter, part of a book on raising a child with diabetes, focuses on blood glucose testing. Regular blood glucose testing is important because it is the only way to know if the child's blood glucose level is in the target range. Glucose testing involves using a meter to measure the amount of glucose in a drop of capillary blood. Topics include determining the number of times per day to test blood glucose, recording blood glucose test results, making sure a blood glucose meter is accurate, testing urine for glucose and ketones, helping a child test regularly, and understanding the glycated hemoglobin test. 1 figure.

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Urine Tests: Examining the Body's Excess Fluids Source: in Shaw, M., et al., eds. Everything You Need to Know About Medical Tests. Springhouse, PA: Springhouse Corporation. 1996. p. 549-616. Contact: Available from Springhouse Publishing. Attention: Trade and Textbook Department, 1111 Bethlehem Pike, P.O. Box 908, Springhouse, PA 19477-0908. (800) 3313170 or (215) 646-4670 or (215) 646-4671. Fax (215) 646-8716. PRICE: $24.95 (as of 1995). ISBN: 0874348234. Summary: This lengthy chapter, from a consumer handbook about medical practice and disease, presents information on urine tests used for diagnosis. Written in a question and answer format, the chapter discusses urine tests for these functions, diseases, and substances: kidney stones, kidney function, phosphate reabsorption by the kidneys, amylase, arysulfatase A, lysozyme, aldosterone, Cushing's syndrome, epinephrine, norepinephrine, dopamine, estrogens, pregnancy, placental estriol, pregnanetriol, vanillylmandelic acid, homovanillic acid, hydroxyindoleacetic acid, pregnanediol, proteins, Bence Jones protein, amino acid disorders, creatinine, creatinine clearance by the kidneys, urea clearance by the kidneys, uric acid, hemoglobin, myoglobin, porphyrins, delta-aminolevulinic acid, bilirubin, urobilinogen, sugar, glucose, ketones, vitamin B6, vitamin C, sodium, chloride, potassium, calcium, phosphates, magnesium, and iron. For each test discussed, the authors provide information about why the test is done, how the test is performed, what to do before the test, and what the results indicate.

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Hypoglycemic Disorders Source: in Hall, J.E.; Nieman, L.K., eds. Handbook of Diagnostic Endocrinology. Totowa, NJ: The Humana Press, Inc. 2003. p. 193-211. Contact: Humana Press, Inc. 999 Riverview Dr., Suite 208 Totowa, NJ 07512. (973) 2561699. Fax (973) 256-8341. E-mail: [email protected] PRICE: $99.50 plus shipping and handling. ISBN: 0896037576. Summary: With the rapid development of new and more reliable diagnostic tests, and aided by the molecular and genetic approaches that continue to deepen the

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understanding of these diseases, the ability to diagnose patients with endocrine disease has dramatically increased. This chapter on hypoglycemic (low blood glucose) disorders is from a book that explains the pathophysiology and clinical manifestations of endocrine disorders and surveys all the latest laboratory tests used in their diagnosis. The author discusses classification of hypoglycemic disorders, and then considers the tests available for their diagnostic evaluation. The author notes that a healthy-appearing patient with no coexisting disease who has a history of neuroglycopenic spells requires an approach quite different from that taken for a patient with concurrent illness or a hospitalized patient with acute hypoglycemia (low levels of blood glucose). Tests discussed include serum glucose levels, the prolonged (72 hour) fast, the mixed meal test, the C-peptide suppression test, insulin antibodies, glycated hemoglobin, and imaging studies. 6 figures. 4 tables. 84 references.

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CHAPTER 8. MULTIMEDIA ON HEMOGLOBIN Overview In this chapter, we show you how to keep current on multimedia sources of information on hemoglobin. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.

Video Recordings An excellent source of multimedia information on hemoglobin is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “hemoglobin” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Videorecording (videotape, videocassette, etc.).” Type “hemoglobin” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on hemoglobin: •

Preventing Long Term Complications of Diabetes Source: Timonium, MD: Milner-Fenwick. 2000. (videocassette). Contact: Available from Milner-Fenwick, Inc. 2125 Greenspring Drive, Timonium, MD 21093-3100. (800) 432-8433. Fax (410) 252-6316. PRICE: $125.00; bulk orders available; plus shipping and handling. Summary: The goal of this video program is to help patients with diabetes understand and prevent the long term complications of their disease. Viewers learn how high blood sugar (hyperglycemia) and the associated damage to blood vessels can possibly lead to heart attack, stroke, loss of vision (diabetic retinopathy), kidney disease (diabetic nephropathy), nerve damage (diabetic neuropathy), and amputation. Information is included about damage to both large and small blood vessels, updated terminology, HbA1c (glycosylated hemoglobin) testing (used to monitor blood glucose levels over time), heart disease risk factors, and erectile dysfunction (impotence). The video stresses that improving blood glucose (sugar) levels can help reduce the patient's risk of

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complications over time. The videotape was produced in cooperation with the American Association of Diabetes Educators (AADE), which defined the content of the video, selected the program consultants, and approved production at each stage of development. The program is closed-captioned. •

Strategies for the Prevention and Treatment of Macrovascular Complications of Type 2 Diabetes Source: Kansas City, MO: American Academy of Family Physicians. 1998. (videocassette). Contact: Available from American Academy of Family Physicians. 8880 Ward Parkway, Kansas City, MO 64114-2797. (800) 274-2237. PRICE: $17.95 for members; $25.00 for nonmembers, plus shipping and handling. Summary: The macrovascular (large blood vessel) complications of diabetes account for the majority of the morbidity (related illness) and mortality (death) associated with the disease. In particular, people with type 2 diabetes are at increased risk for cardiovascular disease, since they exhibit many independent risk factors for heart disease, including obesity, hypertension (high blood pressure), and dyslipidemia (disordered levels of fats in the blood). This continuing education program features a videocassette and study guide that discuss why people with diabetes are at increased risk for macrovascular complications and how to reduce the patient's risk of cardiovascular disease. Topics include hyperglycemia (high blood glucose levels) and cardiovascular disease, insulin resistance and cardiovascular disease, the benefits of improved glycemic control, recommended target glycemic goals, nonpharmacologic therapies for diabetes (diet, exercise, patient education), pharmacologic (drug) therapies for diabetes (insulin secretagogues, insulin sensitizers, alpha-glucosidase inhibitors, and insulin), determining the optimal drug treatment regimen for individual patients, and treating cardiovascular risk factors. The program recommends that patients should be seen quarterly or more often, depending upon the severity of their disease, and target goals for HbA1c (glycosylated hemoglobin, a measurement of blood glucose levels over time) and fasting blood glucose should be established at the initial visit and discussed directly with the patient. Patients should be reminded at every office visit that weight loss and regular exercise are the most important aspects of controlling their diabetes and reducing the risk of macrovascular disease. A sample patient education hand out is included in the study guide. Through this program, users can qualify for one credit hour of Continuing Medical Education (CME) in category 1; the appropriate posttest is provided. 5 figures. 14 tables. 15 references.

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HGB E, anemia and basic genetics Source: Providence, RI: Providence Ambulatory Health Care Foundation. n.d. 1 videotape. Contact: Available from Media Consultants, 18 Stillwater Road, Smithfield, RI 02917. Telephone: (401) 232-0412 / fax: (401) 231-4462. $8.00 plus $2.00 shipping and handling. Summary: This videotape provides information on hemoglobin E, anemia, and basic genetics. It is supplemented by three pamphlets: 'Questions about Thalassemia,' Questions about Hemoglobin E,' and 'Genetics: The story of genes.' The tapes and pamphlets are available in English, Laotian, and Cambodian. [Funded by the Maternal and Child Health Bureau].

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Bibliography: Multimedia on Hemoglobin The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in hemoglobin (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on hemoglobin: •

[Hematology, hemoglobin electrophoresis and rare hemoglobins] [slide] Source: [Communications in Learning, Inc.]; Year: 1972; Format: Hematology, hemoglobin electrophoresis and rare hemoglobins; Buffalo, NY: CIL, [1972]

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Diagnosis of hemoglobin abnormalities [videorecording] Source: Faculty of Health Sciences, McMaster University. [et al.]; Year: 1975; Format: Videorecording; [Hamilton, Ont.]: The University, 1975

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Hemoglobin: standard curve [videorecording] Source: University of California at Davis, School of Veterinary Medicine; Year: 1977; Format: Videorecording; [Berkeley, Calif.]: Regents of the University; [Davis, Calif.: for loan and sale by the University of California, Davis, Health Sciences Television], 1977

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Hemoglobin determination [videorecording]: cyanmethemoglobin method Source: University of California at Davis, School of Veterinary Medicine; Year: 1977; Format: Videorecording; Davis: The University: [for loan or sale by its Health Sciences Television], c1977

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Hemoglobin determination using cyanmethemoglobin standards [motion picture] Source: Laboratory Branch, Communicable Disease Center; produced by Public Health Service Audiovisual Facility; Year: 1965; Format: Motion picture; Atlanta: The Center: [for loan by National Medical Audiovisual Center, 1965]

•

Hemoglobin determination utilizing the Spencer hemoglobinometer [videorecording] Source: Dept. of Pathology, College of Veterinary Medicine, Michigan State University; produced by Instructional Television Services; Year: 1977; Format: Videorecording; East Lansing: The University: [for loan and sale by its Instructional Media Center, Marketing Division], c1977

•

Hemoglobin determinations [videorecording] Source: Brooke Army Medical Center. Television Division; Year: 1970; Format: Videorecording; San Antonio, Tex.: The Division: [for loan by Academy of Health Sciences, 1970]

•

Manual determination of hemoglobin by the cyanmethemoglobin method [slide] Source: Brain Vickery; Year: 1976; Format: Slide; [Washington]: AIBS; [Tarrytown, N. Y.: for sale by Prentice-Hall Media], c1976

•

New advances in establishing norms and diagnostic levels of hemoglobin [videorecording] Source: University of Texas, System Cancer Center, M. D. Anderson Hospital and Tumor Institute; Year: 1973; Format: Videorecording; Houston: The Center, 1973

•

The Role of hemoglobin in hydrogen ion metabolism [slide] Source: American Physiological Society; Year: 1977; Format: Slide; [Rockville, Md.]: The Society; [New York: for sale by Audio Visual Medical Marketing], p1977

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CHAPTER 9. PERIODICALS AND NEWS ON HEMOGLOBIN Overview In this chapter, we suggest a number of news sources and present various periodicals that cover hemoglobin.

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

Effects of cell-free hemoglobin on nitric oxide may explain sickle-cell pain crisis Source: Reuters Medical News Date: November 11, 2002

•

Bovine hemoglobin spares transfusions, but adverse events are significant Source: Reuters Medical News Date: October 16, 2002

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•

Bovine hemoglobin spares needs for transfusion, but adverse events more common Source: Reuters Industry Breifing Date: October 16, 2002

•

Nateglinide effectively lowers hemoglobin a1c in type 2 diabetics Source: Reuters Industry Breifing Date: June 18, 2002

•

Protein protects alpha-hemoglobin stability in normal erythropoiesis Source: Reuters Medical News Date: June 14, 2002 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 “hemoglobin” (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. 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 “hemoglobin” (or synonyms). If you know the name of a company that is relevant to hemoglobin, 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/.

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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 “hemoglobin” (or synonyms).

Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “hemoglobin” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on hemoglobin: •

National Diabetes Education Program Adopts A1C Names for the Hemoglobin A1C Test Source: IHS Primary Care Provider. 26(10): 154-155. October 2001. Contact: Available from Indian Health Service Clinical Support Center. Two Renaissance Square, Suite 780, 40 North Central Avenue, Phoenix, AZ 85004. (602) 3647777. Fax (602) 364-7788. E-mail: [email protected]. Website: www.ihs.gov. Summary: This brief article reports that the National Diabetes Education Program (NDEP) Steering Committee has agreed to adopt a simple name for the hemoglobin A1c test, a test that is used to monitor long term blood glucose (glycosylated hemoglobin) levels. The new name A1C will be used in NDEP communications with people with diabetes. As NDEP partners, the NDEP American Indian Subcommittee and the Association of American Indian Physicians encourage their members and Indian health providers to use the name A1C. The author notes that every person with diabetes should know their A1C level, and work with their health providers to take control of their diabetes and prevent complications. The second page of the article is a patient education handout about the A1C. The handout describes the A1C test and explains the target values, how often to have the test, home testing for A1C, and the importance of recordkeeping. 1 figure.

Academic Periodicals covering Hemoglobin Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to hemoglobin. In addition to these sources, you can search for articles covering hemoglobin 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.

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At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

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CHAPTER 10. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for hemoglobin. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI® Advice for the Patient® can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with hemoglobin. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The

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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to hemoglobin: Ascorbic Acid (Vitamin C) •

Systemic - U.S. Brands: Ascorbicap; Cecon; Cee-500; Cemill; Cenolate; Cetane; Cevi-Bid; Flavorcee; Ortho/CS; Sunkist http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202071.html

Repaglinide •

Systemic - U.S. Brands: Prandin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203463.html

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

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

Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to hemoglobin by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/.

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Scroll down the page, and on the left toolbar, click on “Orphan Drug Designation Database.” On this page (http://www.rarediseases.org/search/noddsearch.html), type “hemoglobin” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for hemoglobin: •

Isobutyramide (trade name: Isobutyramide oral solution) http://www.rarediseases.org/nord/search/nodd_full?code=157

•

Sodium phenylbutyrate http://www.rarediseases.org/nord/search/nodd_full?code=191

•

Arginine butyrate http://www.rarediseases.org/nord/search/nodd_full?code=673

•

Hydroxyurea (trade name: Droxia) http://www.rarediseases.org/nord/search/nodd_full?code=771

If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

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APPENDICES

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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 Institute12: •

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

12

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

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•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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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.13 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:14 •

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

13

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 14 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 Combined Health Information Database

A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to one of the following: Brochure/Pamphlet, Fact Sheet, or Information Package, and “hemoglobin” using the “Detailed Search” option. Go directly to the following hyperlink: 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 the publication date, select “All Years.” Select your preferred language and the format option “Fact Sheet.” Type “hemoglobin” (or synonyms) into the “For these words:” box. The following is a sample result: •

West Virginia Pediatric Nutrition Surveillance System (PedNSS): 1996 annual summary Source: [Charleston, WV]: West Virginia WIC Program, West Virginia Department of Health and Human Resources. [1997]. 29 pp. Contact: Available from Librarian, National Center for Education in Maternal and Child Health, 2000 15th Street, North, Suite 701, Arlington, VA 22201-2617. Telephone: (703) 524-7802 / fax: (703) 524- 9335 / e-mail: [email protected] / Web site: http://www.ncemch.org. Photocopy available at no charge. Summary: This annual summary reports West Virginia's participation in the Pediatric Nutrition Surveillance System (PedNSS), through which the Centers for Disease Control and Prevention monitor the prevalence of specific health indicators of nutrition risk in infants, children, and adolescents in families with low incomes. This allows for the evaluation of health indicators for this population over time. The data are then used to supply information for planning health priorities and policies and for guiding, improving, and supporting decisions regarding nutrition interventions at state and local levels. The nutrition risk indicators collected in PedNSS are short stature (low height for age), underweight (low weight for height), overweight (high weight for height), anemia (low hemoglobin), and low birthweight (< 2,500 grams). Infant feeding practices data are also collected for children under 2 to assess the prevalence and duration of breastfeeding. West Virginia statewide data, regional data, and selected local clinic data are presented in this report. Healthy People 2000 objectives for nutrition are presented (as appropriate).

The NLM Gateway15 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, 15

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

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providing one-stop searching for many of NLM’s information resources or databases.16 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “hemoglobin” (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 99106 840 42 432 16 100436

HSTAT17 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.18 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.19 Simply search by “hemoglobin” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists20 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.21 Each report is about 400 words and is usually based on a discovery reported in one or

16

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

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

19

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 20 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 21

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story.

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more articles from recently published, peer-reviewed literature.22 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

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

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/.

The Genome Project and Hemoglobin In the following section, we will discuss databases and references which relate to the Genome Project and hemoglobin. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).23 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “hemoglobin” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for hemoglobin: •

22

Fetal Hemoglobin Quantitative Trait Locus on Chromosome 8 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?606789

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. 23 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

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•

Hemoglobin F, Hereditary Persistence Of, Pancellular Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?141749

•

Hemoglobin H-related Mental Retardation Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?141750

•

Hemoglobin, Gamma a Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?142200

•

Hemoglobin, Gamma G Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?142250

•

Hemoglobin--alpha Locus 1 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?141800

•

Hemoglobin--alpha Locus 2 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?141850

•

Hemoglobin--alpha Locus 3 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?141860

•

Hemoglobin--beta Locus Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?141900

•

Hemoglobin--delta Locus Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?142000

•

Hemoglobin--epsilon Locus Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?142100

•

Hemoglobin--theta-1 Locus Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?142240

•

Hemoglobin--variants for Which the Chain Carrying the Mutation Is Unknown or Uncertain Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?142309

•

Hemoglobin--zeta Locus Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?142310

•

Hereditary Persistence of Fetal Hemoglobin, Heterocellular, Indian Type Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?142335

•

Heterocellular Hereditary Persistence of Fetal Hemoglobin Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?142470

•

Methemoglobinemia due to Deficiency of Cytochrome B5 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?250790

•

Methemoglobinemia due to Deficiency of Methemoglobin Reductase Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?250800

•

Sulfhemoglobinemia, Congenital Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?185460 Genes and Disease (NCBI - Map)

The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to

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http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •

Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html

•

Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html

•

Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html

•

Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html

•

Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html

•

Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html

•

Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez

Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide

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sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •

3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

•

Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

•

NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

•

Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

•

OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

•

PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

•

ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

•

PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

•

Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

•

Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “hemoglobin” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database24 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form.

24

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html.

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At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database25 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “hemoglobin” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).

25

Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

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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 hemoglobin 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 hemoglobin. 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 hemoglobin. 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 “hemoglobin”:

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•

Other guides Anemia http://www.nlm.nih.gov/medlineplus/anemia.html Blood Transfusion and Donation http://www.nlm.nih.gov/medlineplus/bloodtransfusionanddonation.html Diabetes http://www.nlm.nih.gov/medlineplus/diabetes.html Juvenile Diabetes http://www.nlm.nih.gov/medlineplus/juvenilediabetes.html Sickle Cell Anemia http://www.nlm.nih.gov/medlineplus/sicklecellanemia.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 hemoglobin. 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: •

Hemoglobin A1c Testing (HbA1c): Bayer Care Health Facts Source: Tarrytown, NY: Bayer Corporation. 2000. [7 p.]. Contact: Available from Bayer Corporation. Diagnostics Division, 511 Benedict Avenue, Tarrytown, NY 10591-5097. (800) 445-5901. PRICE: Single copy free. Summary: This brochure uses a question and answer format to provide people who have diabetes with information on glycosylated hemoglobin (HbA1c) testing. This test, which measures how much glucose is stuck to hemoglobin, determines average blood glucose for the past 2 to 3 months. Both the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) have demonstrated the importance of good blood glucose control and the importance of having the HbA1c test performed on a regular basis. The brochure explains how HbA1c readings compare with daily blood glucose levels, how HbA1c testing can help people who have diabetes, where people who have diabetes should go for HbA1c testing, and how often HbA1c should be tested. 1 table.

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Glycated Hemoglobin Test: A long-Term Picture of Diabetes Control Source: Princeton, NJ: Novo Nordisk Pharmaceuticals, Inc. 1990. 2 p. Contact: Available from Novo Nordisk Pharmaceuticals, Inc. 100 Overlook Center, Suite 200, Princeton, NJ 08540-7810. (800) 727-6500. PRICE: Single copy free. Summary: This brochure, written for the person with diabetes, describes the glycated hemoglobin test, a measurement of overall diabetes control for the previous 2 to 3 months. Topics include the test itself, target test results that would show optimal blood glucose control, the role of the laboratory that is performing the procedure, and a discussion of how self-monitoring of blood glucose (SMBG) can work in tandem with regular glycated hemoglobin tests to help manage diabetes. A blank chart is provided for the health care provider to fill in normal ranges of glycated hemoglobin and to fill in the test results for the individual. 4 references.

•

Glycated Hemoglobin: The Test That Never Forgets Source: Alexandria, VA: American Diabetes Association. 199x. 4 p. Contact: Available from American Diabetes Association, Inc. Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. PRICE: $9.95 (members), $11.95 (nonmembers) for 50 copies; single copy free. Order number CDBD19. Summary: This fact sheet, which is one in a series of 42 fact sheets about daily living and coping with diabetes, provides information on the glycated hemoglobin (HbA1c) test. The test is done by a laboratory and gives an idea of how well a diabetes treatment plan is working. Topics include how the test works, how it aids in diabetes control, and its limitations. Glycated hemoglobin tests, which provide an overview of average blood glucose control over the previous several months, can help confirm self testing results or the results of blood tests given by the doctor, identify whether a treatment plan is working, and demonstrate how healthy choices can make a difference in diabetes control. However, glycated hemoglobin tests do not measure daily control and should not replace daily self testing of blood glucose. The fact sheet includes one graph. (AAM). 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 hemoglobin. 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.

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Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

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

•

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

•

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

•

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

•

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

•

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

•

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

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to hemoglobin. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with hemoglobin. 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 hemoglobin. 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 “hemoglobin” (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

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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 “hemoglobin”. 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 “hemoglobin” (or synonyms) into the “For these words:” 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 “hemoglobin” (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.26

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

26

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)27: •

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

•

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

•

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

•

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

•

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

•

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

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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/

27

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

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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

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

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

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

•

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

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

•

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

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 hemoglobin: •

Basic Guidelines for Hemoglobin Hemoglobin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003645.htm Hemoglobin - serum Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003677.htm Hemoglobin derivatives Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003371.htm Hemoglobin electrophoresis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003639.htm Hemoglobinuria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003363.htm

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Signs & Symptoms for Hemoglobin Anemia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000560.htm Anemias Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000560.htm Anxiety Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Cyanosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm Fainting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003092.htm Headache Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003024.htm Lethargy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Shortness of breath Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm Skin rash Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Stupor Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003202.htm Tension Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm

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Diagnostics and Tests for Hemoglobin Albumin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003480.htm Blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003398.htm CBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm CO2 Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003469.htm Complete blood count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm

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Erythropoietin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003683.htm Glycosylated hemoglobin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003640.htm Haptoglobin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003634.htm Hb Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003645.htm Hemoglobin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003645.htm Hemoglobin electrophoresis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003639.htm Hemoglobinuria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003363.htm Serum hemoglobin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003677.htm Venipuncture Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003423.htm •

Nutrition for Hemoglobin Folate Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002408.htm Protein Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002467.htm Vitamin B12 Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002403.htm Vitamin B6 Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002402.htm

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Background Topics for Hemoglobin 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 Burns Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000030.htm

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Carbon monoxide Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002804.htm Cytochrome b5 reductase Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002315.htm Heart disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000147.htm Hemolysis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002372.htm Infant test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002055.htm Lead poisoning Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002473.htm Penis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002279.htm Peripheral Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002273.htm Preschooler test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002057.htm Proximal Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002287.htm Renal disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000457.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 Vagina Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002342.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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HEMOGLOBIN DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 3-dimensional: 3-D. A graphic display of depth, width, and height. Three-dimensional radiation therapy uses computers to create a 3-dimensional picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Ablation: The removal of an organ by surgery. [NIH] Abscess: Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. [NIH] Absolute risk: The observed or calculated probability of an event in a population under study, as contrasted with the relative risk. [NIH] Acanthosis Nigricans: A circumscribed melanosis consisting of a brown-pigmented, velvety verrucosity or fine papillomatosis appearing in the axillae and other body folds. It occurs in association with endocrine disorders, underlying malignancy, administration of certain drugs, or as in inherited disorder. [NIH] Acatalasia: A rare autosomal recessive disorder resulting from the absence of catalase activity. Though usually asymptomatic, a syndrome of oral ulcerations and gangrene may be present. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetone: A colorless liquid used as a solvent and an antiseptic. It is one of the ketone bodies produced during ketoacidosis. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Acrylamide: A colorless, odorless, highly water soluble vinyl monomer formed from the hydration of acrylonitrile. It is primarily used in research laboratories for electrophoresis, chromatography, and electron microscopy and in the sewage and wastewater treatment industries. [NIH] Acrylonitrile: A highly poisonous compound used widely in the manufacture of plastics, adhesives and synthetic rubber. [NIH]

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Actin: Essential component of the cell skeleton. [NIH] Activities of Daily Living: The performance of the basic activities of self care, such as dressing, ambulation, eating, etc., in rehabilitation. [NIH] Acuity: Clarity or clearness, especially of the vision. [EU] Acute myelogenous leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute nonlymphocytic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Diphosphate: Adenosine 5'-(trihydrogen diphosphate). An adenine nucleotide containing two phosphate groups esterified to the sugar moiety at the 5'-position. [NIH] Adenosine Triphosphate: Adenosine 5'-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adhesives: Substances that cause the adherence of two surfaces. They include glues (properly collagen-derived adhesives), mucilages, sticky pastes, gums, resins, or latex. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [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]

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Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal 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] Adsorption: The condensation of gases, liquids, or dissolved substances on the surfaces of solids. It includes adsorptive phenomena of bacteria and viruses as well as of tissues treated with exogenous drugs and chemicals. [NIH] Adsorptive: It captures volatile compounds by binding them to agents such as activated carbon or adsorptive resins. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerobic Exercise: A type of physical activity that includes walking, jogging, running, and dancing. Aerobic training improves the efficiency of the aerobic energy-producing systems that can improve cardiorespiratory endurance. [NIH] Aerobic Metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, oxidative metabolism, or cell respiration. [NIH] Aerobic Respiration: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as oxidative metabolism, cell respiration, or aerobic metabolism. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]

Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

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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] 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 serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by the adrenal cortex that functions in the regulation of electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. [NIH] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [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] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allografts: A graft of tissue obtained from the body of another animal of the same species but with genotype differing from that of the recipient; tissue graft from a donor of one genotype to a host of another genotype with host and donor being members of the same species. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] 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

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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] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Aminolevulinic Acid: A compound produced from succinyl-CoA and glycine as an intermediate in heme synthesis. [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] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH]

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Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Amylase: An enzyme that helps the body digest starches. [NIH] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [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] Analgesics: Compounds capable of relieving pain without the loss of consciousness or without producing anesthesia. [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]

Anaphylactic: Pertaining to anaphylaxis. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anaphylaxis: An acute hypersensitivity reaction due to exposure to a previously encountered antigen. The reaction may include rapidly progressing urticaria, respiratory distress, vascular collapse, systemic shock, and death. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anemia, Sickle Cell: A disease characterized by chronic hemolytic anemia, episodic painful crises, and pathologic involvement of many organs. It is the clinical expression of homozygosity for hemoglobin S. [NIH] Anemic: Hypoxia due to reduction of the oxygen-carrying capacity of the blood as a result of a decrease in the total hemoglobin or an alteration of the hemoglobin constituents. [NIH] Anergy: Absence of immune response to particular substances. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH]

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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] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH] Angiotensin converting enzyme inhibitor: A drug used to decrease pressure inside blood vessels. [NIH] 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] Ankle: That part of the lower limb directly above the foot. [NIH] Anode: Electrode held at a positive potential with respect to a cathode. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Anthropometric measurements: Measurements of human body height, weight, and size of component parts, including skinfold measurement. Used to study and compare the relative proportions under normal and abnormal conditions. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU]

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Antidiabetic: An agent that prevents or alleviates diabetes. [EU] Antidiabetic Agent: A substance that helps a person with diabetes control the level of glucose (sugar) in the blood so that the body works as it should. [NIH] Antidote: A remedy for counteracting a poison. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] 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] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]

Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiseptic: A substance that inhibits the growth and development of microorganisms without necessarily killing them. [EU] Antisickling Agents: Agents used to prevent or reverse the pathological events leading to sickling of erythrocytes in sickle cell conditions. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Apathy: Lack of feeling or emotion; indifference. [EU] Aperture: A natural hole of perforation, especially one in a bone. [NIH] Aplasia: Lack of development of an organ or tissue, or of the cellular products from an organ or tissue. [EU] Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [NIH]

Apnea: A transient absence of spontaneous respiration. [NIH] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to

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which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aptitude: The ability to acquire general or special types of knowledge or skill. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Argon: A noble gas with the atomic symbol Ar, atomic number 18, and atomic weight 39.948. It is used in fluorescent tubes and wherever an inert atmosphere is desired and nitrogen cannot be used. [NIH] Aromatic: Having a spicy odour. [EU] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriosus: Circle composed of anastomosing arteries derived from two long posterior ciliary and seven anterior ciliary arteries, located in the ciliary body about the root of the iris. [NIH]

Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Arthropathy: Any joint disease. [EU] Arthroplasty: Surgical reconstruction of a joint to relieve pain or restore motion. [NIH] Ascites: Accumulation or retention of free fluid within the peritoneal cavity. [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] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH]

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Aspiration: The act of inhaling. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Asynchronous: Pacing mode where only one timing interval exists, that between the stimuli. While the duration of this interval may be varied, it is not modified by any sensed event once set. As no sensing occurs, the upper and lower rate intervals are the same as the pacema. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atrial: Pertaining to an atrium. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] 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] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Aurothioglucose: (1-Thio-D-glucopyranosato)gold. A thioglucose derivative used as an antirheumatic and experimentally to produce obesity in animals. [NIH] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autologous bone marrow transplantation: A procedure in which bone marrow is removed

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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] Autonomic Neuropathy: A disease of the nerves affecting mostly the internal organs such as the bladder muscles, the cardiovascular system, the digestive tract, and the genital organs. These nerves are not under a person's conscious control and function automatically. Also called visceral neuropathy. [NIH] Avian: A plasmodial infection in birds. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Bacteremia: The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Bacteriuria: The presence of bacteria in the urine with or without consequent urinary tract infection. Since bacteriuria is a clinical entity, the term does not preclude the use of urine/microbiology for technical discussions on the isolation and segregation of bacteria in the urine. [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] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU]

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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 and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Belching: Noisy release of gas from the stomach through the mouth. Also called burping. [NIH]

Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Benzocaine: A surface anesthetic that acts by preventing transmission of impulses along nerve fibers and at nerve endings. [NIH] Benzodiazepines: A two-ring heterocyclic compound consisting of a benzene ring fused to a diazepine ring. Permitted is any degree of hydrogenation, any substituents and any Hisomer. [NIH] Benzoic Acid: A fungistatic compound that is widely used as a food preservative. It is conjugated to glycine in the liver and excreted as hippuric acid. [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] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU]

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Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] 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] 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] Biotype: A group of individuals having the same genotype. [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] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [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 Coagulation Factors: Endogenous substances, usually proteins, that are involved in the blood coagulation process. [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 Proteins: Proteins that are present in blood serum, including serum albumin, blood

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coagulation factors, and many other types of proteins. [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 vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood Viscosity: The internal resistance of the blood to shear forces. The in vitro measure of whole blood viscosity is of limited clinical utility because it bears little relationship to the actual viscosity within the circulation, but an increase in the viscosity of circulating blood can contribute to morbidity in patients suffering from disorders such as sickle cell anemia and polycythemia. [NIH] Blood Volume: Volume of circulating blood. It is the sum of the plasma volume and erythrocyte volume. [NIH] Blood Volume Determination: Method for determining the circulating blood volume by introducing a known quantity of foreign substance into the blood and determining its concentration some minutes later when thorough mixing has occurred. From these two values the blood volume can be calculated by dividing the quantity of injected material by its concentration in the blood at the time of uniform mixing. Generally expressed as cubic centimeters or liters per kilogram of body weight. [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 Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bolus: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus infusion. [NIH] Bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus. [NIH] Bolus injection: The injection of a drug (or drugs) in a high quantity (called a bolus) at once, the opposite of gradual administration (as in intravenous infusion). [EU] 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] 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]

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Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradycardia: Excessive slowness in the action of the heart, usually with a heart rate below 60 beats per minute. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Breast Feeding: The nursing of an infant at the mother's breast. [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] Bronchospasm: Spasmodic contraction of the smooth muscle of the bronchi, as occurs in asthma. [EU] Bulimia: Episodic binge eating. The episodes may be associated with the fear of not being able to stop eating, depressed mood, or self-deprecating thoughts (binge-eating disorder) and may frequently be terminated by self-induced vomiting (bulimia nervosa). [NIH] Burns: Injuries to tissues caused by contact with heat, steam, chemicals (burns, chemical), electricity (burns, electric), or the like. [NIH] Burns, Electric: Burns produced by contact with electric current or from a sudden discharge of electricity. [NIH] Butyrates: Salts and esters of butyric acid [NIH] Butyric Acid: A four carbon acid, CH3CH2CH2COOH, with an unpleasant odor that occurs in butter and animal fat as the glycerol ester. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [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

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many enzymatic processes. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] 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] 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] Carboxy: Cannabinoid. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiopulmonary Bypass: Diversion of the flow of blood from the entrance of the right atrium directly to the aorta (or femoral artery) via an oxygenator thus bypassing both the heart and lungs. [NIH] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH]

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Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] 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] Catalase: An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Cataracts: In medicine, an opacity of the crystalline lens of the eye obstructing partially or totally its transmission of light. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Catheters: A small, flexible tube that may be inserted into various parts of the body to inject or remove liquids. [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] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Degranulation: The process of losing secretory granules (secretory vesicles). This occurs, for example, in mast cells, basophils, neutrophils, eosinophils, and platelets when secretory products are released from the granules by exocytosis. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing

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specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell Lineage: The developmental history of cells as traced from the first division of the original cell or cells in the embryo. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] 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] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] 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 Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH]

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Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Chancroid: Acute, localized autoinoculable infectious disease usually acquired through sexual contact. Caused by Haemophilus ducreyi, it occurs endemically almost worldwide, especially in tropical and subtropical countries and more commonly in seaports and urban areas than in rural areas. [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] 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] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Cholecystokinin: A 33-amino acid peptide secreted by the upper intestinal mucosa and also found in the central nervous system. It causes gallbladder contraction, release of pancreatic exocrine (or digestive) enzymes, and affects other gastrointestinal functions. Cholecystokinin may be the mediator of satiety. [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] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or

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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] Circulatory system: The system that contains the heart and the blood vessels and moves blood throughout the body. This system helps tissues get enough oxygen and nutrients, and it helps them get rid of waste products. The lymph system, which connects with the blood system, is often considered part of the circulatory system. [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] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] Citrus: Any tree or shrub of the Rue family or the fruit of these plants. [NIH] C-kit receptor: A protein on the surface of some cells that binds to stem cell factor (a substance that causes certain types of cells to grow). Altered forms of this receptor may be associated with some types of cancer. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Clot Retraction: Retraction of a clot resulting from contraction of platelet pseudopods attached to fibrin strands that is dependent on the contractile protein thrombosthenin. Used as a measure of platelet function. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cod Liver Oil: Oil obtained from fresh livers of the cod family, Gadidae. It is a source of vitamins A and D. [NIH]

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Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognitive restructuring: A method of identifying and replacing fear-promoting, irrational beliefs with more realistic and functional ones. [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] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Community Health Centers: Facilities which administer the delivery of health care services to people living in a community or neighborhood. [NIH] Comorbidity: The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with

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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] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH] Compress: A plug used to occludate an orifice in the control of bleeding, or to mop up secretions; an absorbent pad. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computer Simulation: Computer-based representation of physical systems and phenomena such as chemical processes. [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] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confounder: A factor of confusion which blurs a specific connection between a disease and a probable causal factor which is being studied. [NIH] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU]

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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] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Contraceptive: An agent that diminishes the likelihood of or prevents conception. [EU] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Conus: A large, circular, white patch around the optic disk due to the exposing of the sclera as a result of degenerative change or congenital abnormality in the choroid and retina. [NIH] Conventional therapy: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment. [NIH] Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [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] Coproporphyrinogen Oxidase: One of the enzymes active in heme biosynthesis. It catalyzes

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the oxidative decarboxylation of coproporphyrinogen III to protoporphyrinogen III by the conversion of two propionic acid groups to two vinyl groups. It can act under both aerobic and anaerobic conditions. EC 1.3.3.3. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [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] Corpuscle: A small mass or body; a sensory nerve end bulb; a cell, especially that of the blood or the lymph. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cost Savings: Reductions in all or any portion of the costs of providing goods or services. Savings may be incurred by the provider or the consumer. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH]

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Creatinine clearance: A test that measures how efficiently the kidneys remove creatinine and other wastes from the blood. Low creatinine clearance indicates impaired kidney function. [NIH] Criterion: A standard by which something may be judged. [EU] Culture Media: Any liquid or solid preparation made specifically for the growth, storage, or transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as agar or gelatin. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyanide: An extremely toxic class of compounds that can be lethal on inhaling of ingesting in minute quantities. [NIH] Cyanosis: A bluish or purplish discoloration of the skin and mucous membranes due to an increase in the amount of deoxygenated hemoglobin in the blood or a structural defect in the hemoglobin molecule. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

Cystoscope: A thin, lighted instrument used to look inside the bladder and remove tissue samples or small tumors. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytochrome A: One of a group of proteins involved in electron transport systems. [NIH] Cytochrome b: Cytochromes (electron-transporting proteins) with protoheme or a related heme as the prosthetic group. The prosthetic group is not covalently bound to the protein moiety. [NIH] Cytochrome b5: A cytochrome occurring in the endoplasmic reticulum that acts as an intermediate electron carrier in some reactions catalyzed by mixed function oxidases, e.g., fatty acid desaturation. It further activates molecular oxygen for an attack on the substrate. MW 16kDa. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they

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produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [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] Cytoplasmic Structures: Components of the cytoplasm excluding the cytosol. [NIH] 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] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] 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] Decision Making: The process of making a selective intellectual judgment when presented with several complex alternatives consisting of several variables, and usually defining a course of action or an idea. [NIH] Decitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Deferoxamine: Natural product isolated from Streptomyces pilosus. It forms iron complexes and is used as a chelating agent, particularly in the form of its mesylate. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydration: The condition that results from excessive loss of body water. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delivery of Health Care: The concept concerned with all aspects of providing and distributing health services to a patient population. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH]

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Deoxycytidine: A drug that protects healthy tissues from the toxic effects of anticancer drugs. [NIH] Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleic acid: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleotides: A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. [NIH] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermal: Pertaining to or coming from the skin. [NIH] Dermatologist: A doctor who specializes in the diagnosis and treatment of skin problems. [NIH]

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] Dexamethasone: (11 beta,16 alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4diene-3,20-dione. An anti-inflammatory glucocorticoid used either in the free alcohol or esterified form in treatment of conditions that respond generally to cortisone. [NIH] Diabetes Insipidus: A metabolic disorder due to disorders in the production or release of vasopressin. It is characterized by the chronic excretion of large amounts of low specific gravity urine and great thirst. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Foot: Ulcers of the foot as a complication of diabetes. Diabetic foot, often with infection, is a common serious complication of diabetes and may require hospitalization and disfiguring surgery. The foot ulcers are probably secondary to neuropathies and vascular problems. [NIH] Diabetic Ketoacidosis: Complication of diabetes resulting from severe insulin deficiency coupled with an absolute or relative increase in glucagon concentration. The metabolic acidosis is caused by the breakdown of adipose stores and resulting increased levels of free fatty acids. Glucagon accelerates the oxidation of the free fatty acids producing excess ketone bodies (ketosis). [NIH] Diabetic Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [NIH] Diagnostic Imaging: Any visual display of structural or functional patterns of organs or tissues for diagnostic evaluation. It includes measuring physiologic and metabolic responses to physical and chemical stimuli, as well as ultramicroscopy. [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

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peritoneal dialysis. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diastolic blood pressure: The minimum pressure that remains within the artery when the heart is at rest. [NIH] Diastolic pressure: The lowest pressure to which blood pressure falls between contractions of the ventricles. [NIH] Diathesis: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the person more than usually susceptible to certain diseases. [EU] Dietary Fats: Fats present in food, especially in animal products such as meat, meat products, butter, ghee. They are present in lower amounts in nuts, seeds, and avocados. [NIH]

Dietitian: An expert in nutrition who helps people plan what and how much food to eat. [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] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilator: A device used to stretch or enlarge an opening. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Disabled Persons: Persons with physical or mental disabilities that affect or limit their activities of daily living and that may require special accommodations. [NIH] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH]

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Disposition: A tendency either physical or mental toward certain diseases. [EU] Dissection: Cutting up of an organism for study. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Diuresis: Increased excretion of urine. [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] 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-blinded: A clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. [NIH] Doxycycline: A synthetic tetracycline derivative with a range of antimicrobial activity and mode of action similar to that of tetracycline, but more effective against many species. Animal studies suggest that it may cause less tooth staining than other tetracyclines. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Delivery Systems: Systems of administering drugs through controlled delivery so that an optimum amount reaches the target site. Drug delivery systems encompass the carrier, route, and target. [NIH] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Evaluation: Any process by which toxicity, metabolism, absorption, elimination, preferred route of administration, safe dosage range, etc., for a drug or group of drugs is determined through clinical assessment in humans or veterinary animals. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH]

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Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duodenum: The first part of the small intestine. [NIH] Dwell time: In peritoneal dialysis, the amount of time a bag of dialysate remains in the patient's abdominal cavity during an exchange. [NIH] 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] Dyslipidemia: Disorders in the lipoprotein metabolism; classified as hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and low levels of high-density lipoprotein (HDL) cholesterol. All of the dyslipidemias can be primary or secondary. Both elevated levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol predispose to premature atherosclerosis. [NIH] Dyspepsia: Impaired digestion, especially after eating. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Echocardiography: Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. [NIH] 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] 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] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrochemistry: The study of chemical changes resulting from electrical action and electrical activity resulting from chemical changes. [NIH] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] 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] 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

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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] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]

Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said 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] Endocrinologist: A doctor that specializes in diagnosing and treating hormone disorders. [NIH]

Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH]

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Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [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] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energetic: Exhibiting energy : strenuous; operating with force, vigour, or effect. [EU] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Energy Intake: Total number of calories taken in daily whether ingested or by parenteral routes. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enteral Nutrition: Nutritional support given via the alimentary canal or any route connected to the gastrointestinal system (i.e., the enteral route). This includes oral feeding, sip feeding, and tube feeding using nasogastric, gastrostomy, and jejunostomy tubes. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Environmental Medicine: Medical specialty concerned with environmental factors that may impinge upon human disease, and development of methods for the detection, prevention, and control of environmentally related disease. [NIH] Environmental Pollutants: Substances which pollute the environment. Use environmental pollutants in general or for which there is no specific heading. [NIH] Enzymatic: Phase where enzyme cuts the precursor protein. [NIH]

for

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Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] 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] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epoetin alfa: A colony-stimulating factor that is made in the laboratory. It increases the production of red blood cells. [NIH] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythema Nodosum: An erythematous eruption commonly associated with drug reactions or infection and characterized by inflammatory nodules that are usually tender, multiple, and bilateral. These nodules are located predominantly on the shins with less common occurrence on the thighs and forearms. They undergo characteristic color changes ending in temporary bruise-like areas. This condition usually subsides in 3-6 weeks without scarring or atrophy. [NIH] Erythroblasts: Immature, nucleated erythrocytes occupying the stage of erythropoiesis that follows formation of erythroid progenitor cells and precedes formation of reticulocytes. Popularly called normoblasts. [NIH] Erythrocyte Membrane: The semipermeable outer portion of the red corpuscle. It is known as a 'ghost' after hemolysis. [NIH] Erythrocyte Volume: Volume of circulating erythrocytes. It is usually measured by radioisotope dilution technique. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH]

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Erythroid Progenitor Cells: Committed, erythroid stem cells derived from myeloid stem cells. The progenitor cells develop in two phases: erythroid burst-forming units (BFU-E) followed by erythroid colony-forming units (CFU-E). BFU-E differentiate into CFU-E on stimulation by erythropoietin, and then further differentiate into erythroblasts when stimulated by other factors. [NIH] 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] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophageal Varices: Stretched veins in the esophagus that occur when the liver is not working properly. If the veins burst, the bleeding can cause death. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estriol: (16 alpha,17 beta)-Estra-1,3,5(10)-triene-3,16,17-triol. A metabolite of estradiol and usually the predominant estrogenic metabolite in urine. During pregnancy, large amounts of estriol are produced by the placenta. It has also been obtained from plant sources. The 16 beta-isomer has also been isolated from the urine of pregnant women. [NIH] Estrogen: One of the two female sex hormones. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evacuation: An emptying, as of the bowels. [EU] Evaluable patients: Patients whose response to a treatment can be measured because enough information has been collected. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excrete: To get rid of waste from the body. [NIH] Exercise Therapy: Motion of the body or its parts to relieve symptoms or to improve function, leading to physical fitness, but not physical education and training. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exocytosis: Cellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU]

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Expander: Any of several colloidal substances of high molecular weight. used as a blood or plasma substitute in transfusion for increasing the volume of the circulating blood. called also extender. [NIH] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Extender: Any of several colloidal substances of high molecular weight, used as a blood or plasma substitute in transfusion for increasing the volume of the circulating blood. [NIH] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]

External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracorporeal: Situated or occurring outside the body. [EU] Extraction: The process or act of pulling or drawing out. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Extravasation: A discharge or escape, as of blood, from a vessel into the tissues. [EU] Extravascular: Situated or occurring outside a vessel or the vessels. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Febrile: Pertaining to or characterized by fever. [EU] Fecal occult blood test: A test to check for blood in stool. (Fecal refers to stool; occult means hidden.) [NIH] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated

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from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Femoral: Pertaining to the femur, or to the thigh. [EU] Femoral Artery: The main artery of the thigh, a continuation of the external iliac artery. [NIH] Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Ferrochelatase: An enzyme widely distributed in cells and tissues. It is located in the inner mitochondrial membrane and catalyzes the formation of heme from protoporphyrin IX and ferrous ions during the terminal step in the heme biosynthetic pathway. EC 4.99.1.1. [NIH] Fetal Development: Morphologic and physiologic growth and development of the mammalian embryo or fetus. [NIH] Fetal Hemoglobin: The major component of hemoglobin in the fetus. This hemoglobin has two alpha and two gamma polypeptide subunits in comparison to normal adult hemoglobin, which has two alpha and two beta polypeptide subunits. Fetal hemoglobin concentrations can be elevated (usually above 0.5%) in children and adults affected by leukemia and several types of anemia. [NIH] Fetal Monitoring: Physiologic or biochemical monitoring of the fetus. It is usually done during labor and may be performed in conjunction with the monitoring of uterine activity. It may also be performed prenatally as when the mother is undergoing surgery. [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] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibronectin: An adhesive glycoprotein. One form circulates in plasma, acting as an opsonin; another is a cell-surface protein which mediates cellular adhesive interactions. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Flank Pain: Pain emanating from below the ribs and above the ilium. [NIH] Flatulence: Production or presence of gas in the gastrointestinal tract which may be expelled through the anus. [NIH] Flatus: Gas passed through the rectum. [NIH] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering,

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the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fluid Therapy: Therapy whose basic objective is to restore the volume and composition of the body fluids to normal with respect to water-electrolyte balance. Fluids may be administered intravenously, orally, by intermittent gavage, or by hypodermoclysis. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Flushing: A transient reddening of the face that may be due to fever, certain drugs, exertion, stress, or a disease process. [NIH] Focus Groups: A method of data collection and a qualitative research tool in which a small group of individuals are brought together and allowed to interact in a discussion of their opinions about topics, issues, or questions. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] 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] Follicles: Shafts through which hair grows. [NIH] Food Exchange: See: Exchange lists. [NIH] Foot Care: Taking special steps to avoid foot problems such as sores, cuts, bunions, and calluses. Good care includes daily examination of the feet, toes, and toenails and choosing shoes and socks or stockings that fit well. People with diabetes have to take special care of their feet because nerve damage and reduced blood flow sometimes mean they will have less feeling in their feet than normal. They may not notice cuts and other problems as soon as they should. [NIH] Foot Ulcer: Lesion on the surface of the skin of the foot, usually accompanied by inflammation. The lesion may become infected or necrotic and is frequently associated with diabetes or leprosy. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Fructosamine: An amino sugar formed when glucose non-enzymatically reacts with the Nterminal amino group of proteins. The fructose moiety is dervied from glucose by the "classical" Amadori rearrangement. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has

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calories. [NIH] Functional magnetic resonance imaging: A noninvasive tool used to observe functioning in the brain or other organs by detecting changes in chemical composition, blood flow, or both. [NIH]

Fundus: The larger part of a hollow organ that is farthest away from the organ's opening. The bladder, gallbladder, stomach, uterus, eye, and cavity of the middle ear all have a fundus. [NIH] Fungemia: The presence of fungi circulating in the blood. Opportunistic fungal sepsis is seen most often in immunosuppressed patients with severe neutropenia or in postoperative patients with intravenous catheters and usually follows prolonged antibiotic therapy. [NIH] 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] Fungistatic: Inhibiting the growth of fungi. [EU] Galago: A genus of the family Lorisidae having four species which inhabit the forests and bush regions of Africa south of the Sahara and some nearby islands. The four species are G. alleni, G. crassicaudatus, G. demidovii, and G. senegalensis. There is another genus, Euoticus, containing two species which some authors have included in the Galago genus. [NIH]

Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized 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] Gastric: Having to do with the stomach. [NIH] Gastric Emptying: The evacuation of food from the stomach into the duodenum. [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] Gastroparesis: Nerve or muscle damage in the stomach. Causes slow digestion and emptying, vomiting, nausea, or bloating. Also called delayed gastric emptying. [NIH] Gastrostomy: Creation of an artificial external opening into the stomach for nutritional support or gastrointestinal compression. [NIH]

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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] Gels: Colloids with a solid continuous phase and liquid as the dispersed phase; gels may be unstable when, due to temperature or other cause, the solid phase liquifies; the resulting colloid is called a sol. [NIH] Gelsolin: A 90-kD protein produced by macrophages that severs actin filaments and forms a cap on the newly exposed filament end. Gelsolin is activated by calcium ions and participates in the assembly and disassembly of actin, thereby increasing the motility of some cells. [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] Gene Silencing: Interruption or suppression of the expression of a gene at transcriptional or translational levels. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Screening: Searching a population or individuals for persons possessing certain genotypes or karyotypes that: (1) are already associated with disease or predispose to disease; (2) may lead to disease in their descendants; or (3) produce other variations not known to be associated with disease. Genetic screening may be directed toward identifying phenotypic expression of genetic traits. It includes prenatal genetic screening. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] 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] Globins: The protein constituents of hemoglobin.The term is used for proteins attached to iron-porphyrin molecules such as hemoglobin and myoglobin proteins. [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] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus.

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[EU]

Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucokinase: A group of enzymes that catalyzes the conversion of ATP and D-glucose to ADP and D-glucose 6-phosphate. They are found in invertebrates and microorganisms and are highly specific for glucose. (Enzyme Nomenclature, 1992) EC 2.7.1.2. [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] Glucosidases: Enzymes that hydrolyze O-glucosyl-compounds. (Enzyme Nomenclature, 1992) EC 3.2.1.-. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glyburide: An antidiabetic sulfonylurea derivative with actions similar to those of chlorpropamide. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosuria: The presence of glucose in the urine; especially the excretion of an abnormally large amount of sugar (glucose) in the urine, i.e., more than 1 gm. in 24 hours. [EU] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Governing Board: The group in which legal authority is vested for the control of health-

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related institutions and organizations. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] 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] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Halitosis: An offensive, foul breath odor resulting from a variety of causes such as poor oral hygiene, dental or oral infections, or the ingestion of certain foods. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache,

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paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Health Planning: Planning for needed health and/or welfare services and facilities. [NIH] Health Priorities: Preferentially rated health-related activities or functions to be used in establishing health planning goals. This may refer specifically to PL93-641. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heartbeat: One complete contraction of the heart. [NIH] Heartburn: Substernal pain or burning sensation, usually associated with regurgitation of gastric juice into the esophagus. [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] Hematologic Diseases: Disorders of the blood and blood forming tissues. [NIH] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hematoma: An extravasation of blood localized in an organ, space, or tissue. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic Stem Cell Transplantation: The transference of stem cells from one animal or human to another (allogeneic), or within the same individual (autologous). The source for the stem cells may be the bone marrow or peripheral blood. Stem cell transplantation has been used as an alternative to autologous bone marrow transplantation in the treatment of a variety of neoplasms. [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] 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] Hemodilution: Reduction of blood viscosity usually by the addition of cell free solutions. Used clinically l) in states of impaired microcirculation, 2) for replacement of intraoperative blood loss without homologous blood transfusion, and 3) in cardiopulmonary bypass and hypothermia. [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

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glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin A: Normal adult human hemoglobin. The globin moiety consists of two alpha and two beta chains. [NIH] Hemoglobin C: A commonly occurring abnormal hemoglobin in which lysine replaces a glutamic acid residue at the sixth position of the beta chains. It results in reduced plasticity of erythrocytes. [NIH] Hemoglobin E: An abnormal hemoglobin that results from the substitution of lysine for glutamic acid at position 26 of the beta chain. It is most frequently observed in southeast Asian populations. [NIH] Hemoglobin H: An abnormal hemoglobin composed of four beta chains. It is caused by the reduced synthesis of the alpha chain. This abnormality results in alpha-thalassemia. [NIH] Hemoglobin M: A group of abnormal hemoglobins in which amino acid substitutions take place in either the alpha or beta chains but near the heme iron. This results in facilitated oxidation of the hemoglobin to yield excess methemoglobin which leads to cyanosis. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemorrhoids: Varicosities of the hemorrhoidal venous plexuses. [NIH] Hepatic: Refers to the liver. [NIH] Hepatic Encephalopathy: A condition that may cause loss of consciousness and coma. It is usually the result of advanced liver disease. Also called hepatic coma. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatitis Viruses: Any of the viruses that cause inflammation of the liver. They include both DNA and RNA viruses as well viruses from humans and animals. [NIH] 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] 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] Heritability: The proportion of observed variation in a particular trait that can be attributed

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to inherited genetic factors in contrast to environmental ones. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Heterogenic: Derived from a different source or species. Also called heterogenous. [NIH] Heterogenous: Derived from a different source or species. Also called heterogenic. [NIH] Hexokinase: An enzyme that catalyzes the conversion of ATP and a D-hexose to ADP and a D-hexose 6-phosphate. D-Glucose, D-mannose, D-fructose, sorbitol, and D-glucosamine can act as acceptors; ITP and dATP can act as donors. The liver isoenzyme has sometimes been called glucokinase. (From Enzyme Nomenclature, 1992) EC 2.7.1.1. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Histone Deacetylase: Hydrolyzes N-acetyl groups on histones. [NIH] Holidays: Days commemorating events. Holidays also include vacation periods. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of hormone deficiency. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Human papillomavirus: HPV. A virus that causes abnormal tissue growth (warts) and is often associated with some types of cancer. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH]

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Hydration: Combining with water. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [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] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. [NIH] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperlipidemia: An excess of lipids in the blood. [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] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypoglycemia: Abnormally low blood sugar [NIH] Hypoglycemic: An orally active drug that produces a fall in blood glucose concentration. [NIH]

Hypoglycemic Agents: Agents which lower the blood glucose level. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypothermia: Lower than normal body temperature, especially in warm-blooded animals; in man usually accidental or unintentional. [NIH] Hypovolemia: An abnormally low volume of blood circulating through the body. It may result in hypovolemic shock. [NIH]

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Hypoxemia: Deficient oxygenation of the blood; hypoxia. [EU] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

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

effects

of

foreign

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] Immunodiffusion: Technique involving the diffusion of antigen or antibody through a semisolid medium, usually agar or agarose gel, with the result being a precipitin reaction. [NIH]

Immunoelectrophoresis: A technique that combines protein electrophoresis and double immunodiffusion. In this procedure proteins are first separated by gel electrophoresis (usually agarose), then made visible by immunodiffusion of specific antibodies. A distinct elliptical precipitin arc results for each protein detectable by the antisera. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH]

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Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indigestion: Poor digestion. Symptoms include heartburn, nausea, bloating, and gas. Also called dyspepsia. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate 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]

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]

Information Systems: Integrated set of files, procedures, and equipment for the storage, manipulation, and retrieval of information. [NIH] Infuse: To pour (a liquid) into something. [EU] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Infusion Pumps: Fluid propulsion systems driven mechanically, electrically, or osmotically that are used to inject (or infuse) over time agents into a patient or experimental animal; used routinely in hospitals to maintain a patent intravenous line, to administer antineoplastic agents and other drugs in thromboembolism, heart disease, diabetes mellitus (insulin infusion systems is also available), and other disorders. [NIH] Infusion Pumps, Implantable: Implanted fluid propulsion systems with self-contained power source for providing long-term controlled-rate delivery of drugs such as chemotherapeutic agents or analgesics. Delivery rate may be externally controlled or osmotically or peristaltically controlled with the aid of transcutaneous monitoring. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU]

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Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inotropic: Affecting the force or energy of muscular contractions. [EU] Inpatients: Persons admitted to health facilities which provide board and room, for the purpose of observation, care, diagnosis or treatment. [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 Infusion Systems: Portable or implantable devices for infusion of insulin. Includes open-loop systems which may be patient-operated or controlled by a pre-set program and are designed for constant delivery of small quantities of insulin, increased during food ingestion, and closed-loop systems which deliver quantities of insulin automatically based on an electronic glucose sensor. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]

Intensive Care Units: Hospital units providing continuous surveillance and care to acutely ill patients. [NIH] 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 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-18: Cytokine which resembles IL-1 structurally and IL-12 functionally. It enhances the cytotoxic activity of NK cells and CTLs, and appears to play a role both as neuroimmunomodulator and in the induction of mucosal immunity. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which

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regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] 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] Intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Intubation: Introduction of a tube into a hollow organ to restore or maintain patency if obstructed. It is differentiated from catheterization in that the insertion of a catheter is usually performed for the introducing or withdrawing of fluids from the body. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Invertebrates: Animals that have no spinal column. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ion Exchange: Reversible chemical reaction between a solid, often an ION exchange resin, and a fluid whereby ions may be exchanged from one substance to another. This technique is used in water purification, in research, and in industry. [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

352 Hemoglobin

may be transported in the same (symport) or opposite (antiport) direction. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] 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] Irritable Bowel Syndrome: A disorder that comes and goes. Nerves that control the muscles in the GI tract are too active. The GI tract becomes sensitive to food, stool, gas, and stress. Causes abdominal pain, bloating, and constipation or diarrhea. Also called spastic colon or mucous colitis. [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] Isoelectric: Separation of amphoteric substances, dissolved in water, based on their isoelectric behavior. The amphoteric substances are a mixture of proteins to be separated and of auxiliary "carrier ampholytes". [NIH] Isoelectric Focusing: Electrophoresis in which a pH gradient is established in a gel medium and proteins migrate until they reach the site (or focus) at which the pH is equal to their isoelectric point. [NIH] Isoelectric Point: The pH in solutions of proteins and related compounds at which the dipolar ions are at a maximum. [NIH] Isoenzyme: Different forms of an enzyme, usually occurring in different tissues. The isoenzymes of a particular enzyme catalyze the same reaction but they differ in some of their properties. [NIH] Isotonic: A biological term denoting a solution in which body cells can be bathed without a net flow of water across the semipermeable cell membrane. Also, denoting a solution having the same tonicity as some other solution with which it is compared, such as physiologic salt solution and the blood serum. [EU] Isozymes: The multiple forms of a single enzyme. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

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Jejunostomy: Surgical formation of an opening through the abdominal wall into the jejunum, usually for enteral hyperalimentation. [NIH] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [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] Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [NIH] Ketone Bodies: Chemicals that the body makes when there is not enough insulin in the blood and it must break down fat for its energy. Ketone bodies can poison and even kill body cells. When the body does not have the help of insulin, the ketones build up in the blood and then "spill" over into the urine so that the body can get rid of them. The body can also rid itself of one type of ketone, called acetone, through the lungs. This gives the breath a fruity odor. Ketones that build up in the body for a long time lead to serious illness and coma. [NIH] Ketonuria: Having ketone bodies in the urine; a warning sign of diabetic ketoacidosis (DKA). [NIH] Ketosis: A condition of having ketone bodies build up in body tissues and fluids. The signs of ketosis are nausea, vomiting, and stomach pain. Ketosis can lead to ketoacidosis. [NIH] Keyhole: A carrier molecule. [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]

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Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lactation: The period of the secretion of milk. [EU] Lactose Intolerance: The disease state resulting from the absence of lactase enzyme in the musocal cells of the gastrointestinal tract, and therefore an inability to break down the disaccharide lactose in milk for absorption from the gastrointestinal tract. It is manifested by indigestion of a mild nature to severe diarrhea. It may be due to inborn defect genetically conditioned or may be acquired. [NIH] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] 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] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]

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] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from fat cells in the feedback system that controls body fat stores. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] 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] Leukocytosis: A transient increase in the number of leukocytes in a body fluid. [NIH] Leukopenia: A condition in which the number of leukocytes (white blood cells) in the blood is reduced. [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] 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] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Life Expectancy: A figure representing the number of years, based on known statistics, to which any person of a given age may reasonably expect to live. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH]

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Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC 3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipid Peroxides: Peroxides produced in the presence of a free radical by the oxidation of unsaturated fatty acids in the cell in the presence of molecular oxygen. The formation of lipid peroxides results in the destruction of the original lipid leading to the loss of integrity of the membranes. They therefore cause a variety of toxic effects in vivo and their formation is considered a pathological process in biological systems. Their formation can be inhibited by antioxidants, such as vitamin E, structural separation or low oxygen tension. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Lipoxygenase: An enzyme of the oxidoreductase class that catalyzes reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives. Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5lipoxygenase, arachidonate 12-lipoxygenase, and arachidonate 15-lipoxygenase. EC 1.13.11.12. [NIH] 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 Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Locus Control Region: A regulatory region first identified in the human beta-globin locus

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but subsequently found in other loci. The region is believed to regulate transcription by opening and remodeling chromatin structure. It may also have enhancer activity. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lumen: The cavity or channel within a tube or tubular organ. [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] 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] 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 Count: A count of the number of lymphocytes in the blood. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lymphoproliferative: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macronutrients: Nutrients in the diet that are the key sources of energy, namely protein, fat, and carbohydrates. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes

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dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] 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] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammography: Radiographic examination of the breast. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Mean blood pressure: The average blood pressure, taking account of the rise and fall that occurs with each heartbeat. It is often estimated by multiplying the diastolic pressure by two, adding the systolic pressure, and then dividing this sum by three. [NIH] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH]

Meat Products: Articles of food which are derived by a process of manufacture from any portion of carcasses of any animal used for food (e.g., head cheese, sausage, scrapple). [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU]

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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 Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Megacolon: Pathological enlargement of the colon. [NIH] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melanosis: Disorders of increased melanin pigmentation that develop without preceding inflammatory disease. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menorrhagia: Excessive menstrual flow. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] 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

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atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH] 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] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Methanol: A colorless, flammable liquid used in the manufacture of formaldehyde and acetic acid, in chemical synthesis, antifreeze, and as a solvent. Ingestion of methanol is toxic and may cause blindness. [NIH] Methemoglobin Reductase: An erythrocyte enzyme which catalyzes the reduction of methemoglobin (ferrihemoglobin) to hemoglobin (ferrohemoglobin). Deficiency produces the inherited disease familial methemoglobinemia. In the absence of methemoglobin, the enzyme can also reduce methylene blue. [NIH] Methylene Blue: A compound consisting of dark green crystals or crystalline powder, having a bronze-like luster. Solutions in water or alcohol have a deep blue color. Methylene blue is used as a bacteriologic stain and as an indicator. It inhibits Guanylate cyclase, and has been used to treat cyanide poisoning and to lower levels of methemoglobin. [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] Mice Minute Virus: The type species of parvovirus prevalent in mouse colonies and found as a contaminant of many transplanted tumors or leukemias. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Micronutrients: Essential dietary elements or organic compounds that are required in only small quantities for normal physiologic processes to occur. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microscopy: The application of microscope magnification to the study of materials that

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cannot be properly seen by the unaided eye. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] 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] Mixed Function Oxidases: Catalyse the insertion of one oxygen atom of molecular oxygen into the organ substrate. Require a second substrate to donate electrons for the reduction of the second atom in the oxygen molecule to water. [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] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] 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] Monogenic: A human disease caused by a mutation in a single gene. [NIH] Monophosphate: So called second messenger for neurotransmitters and hormones. [NIH]

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Monotherapy: A therapy which uses only one drug. [EU] Monounsaturated fat: An unsaturated fat that is found primarily in plant foods, including olive and canola oils. [NIH] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Mouth Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscle Relaxation: That phase of a muscle twitch during which a muscle returns to a resting position. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] Mutagenicity: Ability to damage DNA, the genetic material; the power to cause mutations. [NIH]

Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelofibrosis: A disorder in which the bone marrow is replaced by fibrous tissue. [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

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within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]

Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myoglobin: A conjugated protein which is the oxygen-transporting pigment of muscle. It is made up of one globin polypeptide chain and one heme group. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Narcosis: A general and nonspecific reversible depression of neuronal excitability, produced by a number of physical and chemical aspects, usually resulting in stupor. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nasogastric: The process of passing a small, flexible plastic tube through the nose or mouth into the stomach or small intestine. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH]

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Neonatal: Pertaining to the first four weeks after birth. [EU] Neonatal period: The first 4 weeks after birth. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Neoplastic Processes: The pathological mechanisms and forms taken by tissue during degeneration into a neoplasm and its subsequent activity. [NIH] 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 Endings: Specialized terminations of peripheral neurons. Nerve endings include neuroeffector junction(s) by which neurons activate target organs and sensory receptors which transduce information from the various sensory modalities and send it centrally in the nervous system. Presynaptic nerve endings are presynaptic terminals. [NIH] Nerve Fibers: Slender processes of neurons, especially the prolonged axons that conduct nerve impulses. [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] Neural tube defects: These defects include problems stemming from fetal development of the spinal cord, spine, brain, and skull, and include birth defects such as spina bifida, anencephaly, and encephalocele. Neural tube defects occur early in pregnancy at about 4 to 6 weeks, usually before a woman knows she is pregnant. Many babies with neural tube defects have difficulty walking and with bladder and bowel control. [NIH] Neurologist: A doctor who specializes in the diagnosis and treatment of disorders of the nervous system. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neurotransmitters: Endogenous signaling molecules that alter the behavior of neurons or effector cells. Neurotransmitter is used here in its most general sense, including not only messengers that act directly to regulate ion channels, but also those that act through second messenger systems, and those that act at a distance from their site of release. Included are neuromodulators, neuroregulators, neuromediators, and neurohumors, whether or not acting at synapses. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier

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nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Niche: The ultimate unit of the habitat, i. e. the specific spot occupied by an individual organism; by extension, the more or less specialized relationships existing between an organism, individual or synusia(e), and its environment. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nitrogen Oxides: Inorganic oxides that contain nitrogen. [NIH] Nitrosamines: A class of compounds that contain a -NH2 and a -NO radical. Many members of this group have carcinogenic and mutagenic properties. [NIH] Nitrosation: Conversion into nitroso compounds. An example is the reaction of nitrites with amino compounds to form carcinogenic N-nitrosamines. [NIH] Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [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 magnetic resonance imaging: NMRI. A procedure in which a magnet linked to a computer is used to create detailed pictures of areas inside the body. Also called magnetic resonance imaging (MRI). [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] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nurse Practitioners: Nurses who are specially trained to assume an expanded role in providing medical care under the supervision of a physician. [NIH]

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Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Nutritional Support: The administration of nutrients for assimilation and utilization by a patient by means other than normal eating. It does not include fluid therapy which normalizes body fluids to restore water-electrolyte balance. [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] Occult: Obscure; concealed from observation, difficult to understand. [EU] Occult Blood: Chemical, spectroscopic, or microscopic detection of extremely small amounts of blood. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odour: A volatile emanation that is perceived by the sense of smell. [EU] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Operating Rooms: Facilities equipped for performing surgery. [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] Ophthalmic: Pertaining to the eye. [EU] Ophthalmic Artery: Artery originating from the internal carotid artery and distributing to the eye, orbit and adjacent facial structures. [NIH] Ophthalmoscope: A lighted instrument used to examine the inside of the eye, including the retina and the optic nerve. [NIH] Opsin: A visual pigment protein found in the retinal rods. It combines with retinaldehyde to form rhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]

Optic Disk: The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. [NIH]

Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the

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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] Optic nerve head: The circular area (disc) where the optic nerve connects to the retina. [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Oral Hygiene: The practice of personal hygiene of the mouth. It includes the maintenance of oral cleanliness, tissue tone, and general preservation of oral health. [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] Orlistat: A lipase inhibitor used for weight loss. Lipase is an enzyme found in the bowel that assists in lipid absorption by the body. Orlistat blocks this enzyme, reducing the amount of fat the body absorbs by about 30 percent. It is known colloquially as a "fat blocker." Because more oily fat is left in the bowel to be excreted, Orlistat can cause an oily anal leakage and fecal incontinence. Orlistat may not be suitable for people with bowel conditions such as irritable bowel syndrome or Crohn's disease. [NIH] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [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] Osmotic Fragility: Red blood cell sensitivity to change in osmotic pressure. When exposed to a hypotonic concentration of sodium in a solution, red cells take in more water, swell until the capacity of the cell membrane is exceeded, and burst. [NIH] Otitis: Inflammation of the ear, which may be marked by pain, fever, abnormalities of hearing, hearing loss, tinnitus, and vertigo. [EU] Otitis Media: Inflammation of the middle ear. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overall survival: The percentage of subjects in a study who have survived for a defined period of time. Usually reported as time since diagnosis or treatment. Often called the survival rate. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Ownership: The legal relation between an entity (individual, group, corporation, or-profit, secular, government) and an object. The object may be corporeal, such as equipment, or completely a creature of law, such as a patent; it may be movable, such as an animal, or

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immovable, such as a building. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidative metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, cell respiration, or aerobic metabolism. [NIH] Oxidative 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] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Oxygenator: An apparatus by which oxygen is introduced into the blood during circulation outside the body, as during open heart surgery. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pallor: A clinical manifestation consisting of an unnatural paleness of the skin. [NIH] Palsy: Disease of the peripheral nervous system occurring usually after many years of increased lead absorption. [NIH] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Papilla: A small nipple-shaped elevation. [NIH] Papillomavirus: A genus of Papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH] Paralysis: Loss of ability to move all or part of the body. [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]

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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] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Parietal Lobe: Upper central part of the cerebral hemisphere. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Particle: A tiny mass of material. [EU] Parturition: The act or process of given birth to a child. [EU] Parvovirus: A genus of the family Parvoviridae, subfamily Parvovirinae, infecting a variety of vertebrates including humans. Parvoviruses are responsible for a number of important diseases but also can be non-pathogenic in certain hosts. The type species is mice minute virus. [NIH] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] 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] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Care Team: Care of patients by a multidisciplinary team usually organized under the leadership of a physician; each member of the team has specific responsibilities and the whole team contributes to the care of the patient. [NIH] Patient Compliance: Voluntary cooperation of the patient in following a prescribed regimen. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Patient Participation: Patient involvement in the decision-making process in matters pertaining to health. [NIH] Pelvic: Pertaining to the pelvis. [EU] Penicillin: An antibiotic drug used to treat infection. [NIH] Penile Prosthesis: Rigid, semi-rigid, or inflatable cylindric hydraulic devices, with either combined or separate reservoir and pumping systems, implanted for the surgical treatment of organic impotence. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU]

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Peptic Ulcer: Ulcer that occurs in those portions of the alimentary tract which come into contact with gastric juice containing pepsin and acid. It occurs when the amount of acid and pepsin is sufficient to overcome the gastric mucosal barrier. [NIH] Peptic Ulcer Hemorrhage: Bleeding from a peptic ulcer. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periodicity: The tendency of a phenomenon to recur at regular intervals; in biological systems, the recurrence of certain activities (including hormonal, cellular, neural) may be annual, seasonal, monthly, daily, or more frequently (ultradian). [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontal Pocket: An abnormal extension of a gingival sulcus accompanied by the apical migration of the epithelial attachment and bone resorption. [NIH] Periodontitis: Inflammation of the periodontal membrane; also called periodontitis simplex. [NIH]

Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral Vascular Disease: Disease in the large blood vessels of the arms, legs, and feet. People who have had diabetes for a long time may get this because major blood vessels in their arms, legs, and feet are blocked and these limbs do not receive enough blood. The signs of PVD are aching pains in the arms, legs, and feet (especially when walking) and foot sores that heal slowly. Although people with diabetes cannot always avoid PVD, doctors say they have a better chance of avoiding it if they take good care of their feet, do not smoke, and keep both their blood pressure and diabetes under good control. [NIH] 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]

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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] Pernicious: Tending to a fatal issue. [EU] Pernicious anemia: A type of anemia (low red blood cell count) caused by the body's inability to absorb vitamin B12. [NIH] Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and peroxide to an oxidized donor and water. EC 1.11.1.7. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Petrolatum: A colloidal system of semisolid hydrocarbons obtained from petroleum. It is used as an ointment base, topical protectant, and lubricant. [NIH] Pharmacist: A person trained to prepare and distribute medicines and to give information about them. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] Phenolphthalein: An acid-base indicator which is colorless in acid solution, but turns pink to red as the solution becomes alkaline. It is used medicinally as a cathartic. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenylbutyrate: An anticancer drug that belongs to the family of drugs called differentiating agents. [NIH] Phenylthiohydantoin: Thiohydantoin benzene derivative. [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] Phosphates: Inorganic salts of phosphoric acid. [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

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stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylates: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Photodynamic therapy: Treatment with drugs that become active when exposed to light. These drugs kill cancer cells. [NIH] Phototherapy: Treatment of disease by exposure to light, especially by variously concentrated light rays or specific wavelengths. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physical Fitness: A state of well-being in which performance is optimal, often as a result of physical conditioning which may be prescribed for disease therapy. [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] 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] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma expander: Artificial plasma extender. [EU] 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,

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precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasma Volume: Volume of plasma in the circulation. It is usually measured by indicator dilution techniques. [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] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelet Count: A count of the number of platelets per unit volume in a sample of venous blood. [NIH] Plateletpheresis: The preparation of platelet concentrates with the return of red cells and platelet-poor plasma to the donor. [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]

Plethysmography: Recording of change in the size of a part as modified by the circulation in it. [NIH] Podiatrist: A doctor who treats and takes care of people's feet. [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] Polychlorinated Biphenyls: Industrial products consisting of a mixture of chlorinated biphenyl congeners and isomers. These compounds are highly lipophilic and tend to accumulate in fat stores of animals. Many of these compounds are considered toxic and potential environmental pollutants. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polydipsia: Chronic excessive thirst, as in diabetes mellitus or diabetes insipidus. [EU] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [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]

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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] Polyphagia: Great hunger; a sign of diabetes. People with this great hunger often lose weight. [NIH] 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] Polyuria: Urination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes. [NIH] Porphyria: A group of disorders characterized by the excessive production of porphyrins or their precursors that arises from abnormalities in the regulation of the porphyrin-heme pathway. The porphyrias are usually divided into three broad groups, erythropoietic, hepatic, and erythrohepatic, according to the major sites of abnormal porphyrin synthesis. [NIH]

Porphyria Cutanea Tarda: A form of hepatic porphyria (porphyria, hepatic) characterized by photosensitivity resulting in bullae that rupture easily to form shallow ulcers. This condition occurs in two forms: a sporadic, nonfamilial form that begins in middle age and has normal amounts of uroporphyrinogen decarboxylase with diminished activity in the liver; and a familial form in which there is an autosomal dominant inherited deficiency of uroporphyrinogen decarboxylase in the liver and red blood cells. [NIH] 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] Port: An implanted device through which blood may be withdrawn and drugs may be infused without repeated needle sticks. Also called a port-a-cath. [NIH] Port-a-cath: An implanted device through which blood may be withdrawn and drugs may be infused without repeated needle sticks. Also called a port. [NIH] Portal Vein: A short thick vein formed by union of the superior mesenteric vein and the splenic vein. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Postprandial: Occurring after dinner, or after a meal; postcibal. [EU] Postprandial Blood Glucose: Blood taken 1-2 hours after eating to see the amount of glucose (sugar) in the blood. [NIH] Post-traumatic: Occurring as a result of or after injury. [EU] 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]

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Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] Potassium Cyanide: Potassium cyanide (K(CN)). A highly poisonous compound that is an inhibitor of many metabolic processes, but has been shown to be an especially potent inhibitor of heme enzymes and hemeproteins. It is used in many industrial processes. [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] Precipitation: The act or process of precipitating. [EU] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Private Sector: That distinct portion of the institutional, industrial, or economic structure of a country that is controlled or owned by non-governmental, private interests. [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] Problem Solving: A learning situation involving more than one alternative from which a selection is made in order to attain a specific goal. [NIH] Proctosigmoidoscopy: An examination of the rectum and the lower part of the colon using a thin, lighted tube called a sigmoidoscope. [NIH] Progeny: The offspring produced in any generation. [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] Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Proinsulin: The substance made first in the pancreas that is then made into insulin. When insulin is purified from the pancreas of pork or beef, all the proinsulin is not fully removed. When some people use these insulins, the proinsulin can cause the body to react with a rash, to resist the insulin, or even to make dents or lumps in the skin at the place where the insulin is injected. The purified insulins have less proinsulin and other impurities than the

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other types of insulins. [NIH] 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 fertilization occur. [NIH] Proliferative Retinopathy: A disease of the small blood vessels of the retina of the eye. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes

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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 Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteoglycans: Glycoproteins which have a very high polysaccharide content. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]

Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] 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] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH]

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Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychogenic: Produced or caused by psychic or mental factors rather than organic factors. [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] Puberty: The period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Public Sector: The area of a nation's economy that is tax-supported and under government control. [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]

Punctures: Incision of tissues for injection of medication or for other diagnostic or therapeutic procedures. Punctures of the skin, for example may be used for diagnostic drainage; of blood vessels for diagnostic imaging procedures. [NIH] Pupil: The aperture in the iris through which light passes. [NIH] Purified Insulins: Insulins with much less of the impure proinsulin. It is thought that the use of purified insulins may help avoid or reduce some of the problems of people with diabetes such as allergic reactions. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] 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]

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Pyruvate Kinase: ATP:pyruvate 2-O-phosphotransferase. A phosphotransferase that catalyzes reversibly the phosphorylation of pyruvate to phosphoenolpyruvate in the presence of ATP. It has four isozymes (L, R, M1, and M2). Deficiency of the enzyme results in hemolytic anemia. EC 2.7.1.40. [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] Quiescent: Marked by a state of inactivity or repose. [EU] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation 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] 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] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiosensitization: The use of a drug that makes tumor cells more sensitive to radiation therapy. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an

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antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reabsorption: 1. The act or process of absorbing again, as the selective absorption by the kidneys of substances (glucose, proteins, sodium, etc.) already secreted into the renal tubules, and their return to the circulating blood. 2. Resorption. [EU] Reaction Time: The time from the onset of a stimulus until the organism responds. [NIH] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Reconstitution: 1. A type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. The restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recur: To occur again. Recurrence is the return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [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]

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Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regurgitation: A backward flowing, as the casting up of undigested food, or the backward flowing of blood into the heart, or between the chambers of the heart when a valve is incompetent. [EU] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a specific risk factor to the incidence rate among unexposed individuals; synonymous with risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [NIH] Relaxant: 1. Lessening or reducing tension. 2. An agent that lessens tension. [EU] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renal pelvis: The area at the center of the kidney. Urine collects here and is funneled into the ureter, the tube that connects the kidney to the bladder. [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respirator: A mechanical device that helps a patient breathe; a mechanical ventilator. [NIH]

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Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH] Respiratory Physiology: Functions and activities of the respiratory tract as a whole or of any of its parts. [NIH] Respiratory System: The tubular and cavernous organs and structures, by means of which pulmonary ventilation and gas exchange between ambient air and the blood are brought about. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Resuscitation: The restoration to life or consciousness of one apparently dead; it includes such measures as artificial respiration and cardiac massage. [EU] Reticulocytes: Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic "reticulum" (not the same as the endoplasmic reticulum), hence the name reticulocytes. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Artery: Central retinal artery and its branches. It arises from the ophthalmic artery, pierces the optic nerve and runs through its center, enters the eye through the porus opticus and branches to supply the retina. [NIH] Retinal Ganglion Cells: Cells of the innermost nuclear layer of the retina, the ganglion cell layer, which project axons through the optic nerve to the brain. They are quite variable in size and in the shapes of their dendritic arbors, which are generally confined to the inner plexiform layer. [NIH] Retinal Vessels: The vessels which supply and drain the retina. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] 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] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retrospective: Looking back at events that have already taken place. [NIH]

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Retrospective study: A study that looks backward in time, usually using medical records and interviews with patients who already have or had a disease. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rhythm Method: A contraceptive method whereby abstinence is practiced a few days before and after the estimated day of ovulation. [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] Ribonucleic acid: RNA. One of the two nucleic acids found in all cells. The other is deoxyribonucleic acid (DNA). Ribonucleic acid transfers genetic information from DNA to proteins produced by the cell. [NIH] Ribonucleoside Diphosphate Reductase: An enzyme of the oxidoreductase class that catalyzes the formation of 2'-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. (From Dorland, 27th ed) EC 1.17.4.1. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] 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] Rosiglitazone: A drug taken to help reduce the amount of sugar in the blood. Rosiglitazone helps make insulin more effective and improves regulation of blood sugar. It belongs to the family of drugs called thiazolidinediones. [NIH] Rubber: A high-molecular-weight polymeric elastomer derived from the milk juice (latex) of Hevea brasiliensis and other trees. It is a substance that can be stretched at room temperature to atleast twice its original length and after releasing the stress, retractrapidly, and recover its original dimensions fully. Synthetic rubber is made from many different chemicals, including styrene, acrylonitrile, ethylene, propylene, and isoprene. [NIH] Rural Population: The inhabitants of rural areas or of small towns classified as rural. [NIH] Saline: A solution of salt and water. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose.

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Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] 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] Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [NIH] Schistosoma: A genus of trematode flukes belonging to the family Schistosomatidae. There are over a dozen species. These parasites are found in man and other mammals. Snails are the intermediate hosts. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Sclerotherapy: Treatment of varicose veins, hemorrhoids, gastric and esophageal varices, and peptic ulcer hemorrhage by injection or infusion of chemical agents which cause localized thrombosis and eventual fibrosis and obliteration of the vessels. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Secretory Vesicles: Vesicles derived from the golgi apparatus containing material to be released at the cell surface. [NIH] Sediment: A precipitate, especially one that is formed spontaneously. [EU] 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] Self Care: Performance of activities or tasks traditionally performed by professional health care providers. The concept includes care of oneself or one's family and friends. [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] Sensor: A device designed to respond to physical stimuli such as temperature, light,

384 Hemoglobin

magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH] Sequence Analysis: A multistage process that includes the determination of a sequence (protein, carbohydrate, etc.), its fragmentation and analysis, and the interpretation of the resulting sequence information. [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] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Sharpness: The apparent blurring of the border between two adjacent areas of a radiograph having different optical densities. [NIH] Shedding: Release of infectious particles (e. g., bacteria, viruses) into the environment, for example by sneezing, by fecal excretion, or from an open lesion. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Shock, Septic: Shock due to circulatory insufficiency caused most commonly by gramnegative bacteremia. It is less often the result of the persistent presence of other microorganisms in the blood (fungemia, viremia); in rare instances, it is caused by gram-positive organisms, but with different symptomatology. [NIH] Sickle Cell Trait: The condition of being heterozygous for hemoglobin S. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU]

Dictionary 385

Sigmoid: 1. Shaped like the letter S or the letter C. 2. The sigmoid colon. [EU] Sigmoidoscope: A thin, lighted tube used to view the inside of the colon. [NIH] Sigmoidoscopy: Endoscopic examination, therapy or surgery of the sigmoid flexure. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Sister Chromatid Exchange: An exchange of segments between the sister chromatids of a chromosome, either between the sister chromatids of a meiotic tetrad or between the sister chromatids of a duplicated somatic chromosome. Its frequency is increased by ultraviolet and ionizing radiation and other mutagenic agents and is particularly high in Bloom syndrome. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin Pigmentation: Coloration of the skin. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small cell lung cancer: A type of lung cancer in which the cells appear small and round when viewed under the microscope. Also called oat cell lung cancer. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Support: Support systems that provide assistance and encouragement to individuals with physical or emotional disabilities in order that they may better cope. Informal social support is usually provided by friends, relatives, or peers, while formal assistance is provided by churches, groups, etc. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Sodium Channels: Cell membrane glycoproteins selective for sodium ions. Fast sodium current is associated with the action potential in neural membranes. [NIH] Sodium Nitrite: Nitrous acid sodium salt. Used in many industrial processes, in meat curing, coloring, and preserving, and as a reagent in analytical chemistry. It is used therapeutically as an antidote in cyanide poisoning. The compound is toxic and mutagenic and will react in vivo with secondary or tertiary amines thereby producing highly carcinogenic nitrosamines. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH]

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Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatosensory Cortex: Area of the parietal lobe concerned with receiving general sensations. It lies posterior to the central sulcus. [NIH] Sorbitol: A polyhydric alcohol with about half the sweetness of sucrose. Sorbitol occurs naturally and is also produced synthetically from glucose. It was formerly used as a diuretic and may still be used as a laxative and in irrigating solutions for some surgical procedures. It is also used in many manufacturing processes, as a pharmaceutical aid, and in several research applications. [NIH] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] Spasticity: A state of hypertonicity, or increase over the normal tone of a muscle, with heightened deep tendon reflexes. [EU] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrometer: An apparatus for determining spectra; measures quantities such as wavelengths and relative amplitudes of components. [NIH] Spectrophotometry: The art or process of comparing photometrically the relative intensities of the light in different parts of the spectrum. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] 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] Splenic Vein: Vein formed by the union (at the hilus of the spleen) of several small veins from the stomach, pancreas, spleen and mesentery. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Squamous: Scaly, or platelike. [EU]

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Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Stabilization: The creation of a stable state. [EU] Statistically significant: Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. [NIH] Steady state: Dynamic equilibrium. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cell Factor: Hematopoietic growth factor and the ligand of the c-kit receptor CD117 (proto-oncogene protein C-kit). It is expressed during embryogenesis and provides a key signal in multiple aspects of mast-cell differentiation and function. [NIH] Stem cell transplantation: A method of replacing immature blood-forming cells that were destroyed by cancer treatment. The stem cells are given to the person after treatment to help the bone marrow recover and continue producing healthy blood cells. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Sterile: Unable to produce children. [NIH] Sterilization: The destroying of all forms of life, especially microorganisms, by heat, chemical, or other means. [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] Steroid therapy: Treatment with corticosteroid drugs to reduce swelling, pain, and other symptoms of inflammation. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Streptococcal: Caused by infection due to any species of streptococcus. [NIH]

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Streptococcus: A genus of gram-positive, coccoid bacteria whose organisms occur in pairs or chains. No endospores are produced. Many species exist as commensals or parasites on man or animals with some being highly pathogenic. A few species are saprophytes and occur in the natural environment. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stress management: A set of techniques used to help an individual cope more effectively with difficult situations in order to feel better emotionally, improve behavioral skills, and often to enhance feelings of control. Stress management may include relaxation exercises, assertiveness training, cognitive restructuring, time management, and social support. It can be delivered either on a one-to-one basis or in a group format. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroke Volume: The amount of blood pumped out of the heart per beat not to be confused with cardiac output (volume/time). [NIH] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stupor: Partial or nearly complete unconsciousness, manifested by the subject's responding only to vigorous stimulation. Also, in psychiatry, a disorder marked by reduced responsiveness. [EU] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] Superantigens: Microbial antigens that have in common an extremely potent activating effect on T-cells that bear a specific variable region. Superantigens cross-link the variable region with class II MHC proteins regardless of the peptide binding in the T-cell receptor's pocket. The result is a transient expansion and subsequent death and anergy of the T-cells with the appropriate variable regions. [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]

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Supplementation: Adding nutrients to the diet. [NIH] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]

Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Suspensions: Colloids with liquid continuous phase and solid dispersed phase; the term is used loosely also for solid-in-gas (aerosol) and other colloidal systems; water-insoluble drugs may be given as suspensions. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatology: 1. That branch of medicine with treats of symptoms; the systematic discussion of symptoms. 2. The combined symptoms of a disease. [EU] 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] 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] Systolic pressure: The highest pressure to which blood pressure rises with the contraction of the ventricles. [NIH] T cell: One type of white blood cell that attacks virus-infected cells, foreign cells, and cancer cells. T cells also produce a number of substances that regulate the immune response. [NIH] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Teaching Materials: Instructional materials used in teaching. [NIH]

390 Hemoglobin

Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Tenesmus: Straining, especially ineffectual and painful straining at stool or in urination. [EU] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Thalassemia: A group of hereditary hemolytic anemias in which there is decreased synthesis of one or more hemoglobin polypeptide chains. There are several genetic types with clinical pictures ranging from barely detectable hematologic abnormality to severe and fatal anemia. [NIH] 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] Thinness: A state of insufficient flesh on the body usually defined as having a body weight less than skeletal and physical standards. [NIH] Thoracic: Having to do with the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH]

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Thromboembolism: Obstruction of a vessel by a blood clot that has been transported from a distant site by the blood stream. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Time Management: Planning and control of time to improve efficiency and effectiveness. [NIH]

Tinnitus: Sounds that are perceived in the absence of any external noise source which may take the form of buzzing, ringing, clicking, pulsations, and other noises. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Survival: The span of viability of a tissue or an organ. [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] Tonicity: The normal state of muscular tension. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Tourniquet: A device, band or elastic tube applied temporarily to press upon an artery to stop bleeding; a device to compress a blood vessel in order to stop bleeding. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU]

392 Hemoglobin

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] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transcutaneous: Transdermal. [EU] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] 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] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]

Transillumination: Passage of light through body tissues or cavities for examination of internal structures. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Transplantation Tolerance: An induced state of non-reactivity to grafted tissue from a donor organism that would ordinarily trigger a cell-mediated or humoral immune response. [NIH]

Transurethral: Performed through the urethra. [EU] Transurethral Resection of Prostate: Resection of the prostate using a cystoscope passed through the urethra. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat

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tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Troglitazone: A drug used in diabetes treatment that is being studied for its effect on reducing the risk of cancer cell growth in fat tissue. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor model: A type of animal model which can be 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] Tungsten: A metallic element with the atomic symbol W, atomic number 74, and atomic weight 183.85. It is used in many manufacturing applications, including increasing the hardness, toughness, and tensile strength of steel; manufacture of filaments for incandescent light bulbs; and in contact points for automotive and electrical apparatus. [NIH] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] 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] Umbilical Arteries: Either of a pair of arteries originating from the internal iliac artery and passing through the umbilical cord to carry blood from the fetus to the placenta. [NIH] Umbilical Cord: The flexible structure, giving passage to the umbilical arteries and vein, which connects the embryo or fetus to the placenta. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Unresectable: Unable to be surgically removed. [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

394 Hemoglobin

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] Ureters: Tubes that carry urine from the kidneys to the bladder. [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] Urinalysis: Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urine Testing: Checking urine to see if it contains glucose (sugar) and ketones. Special strips of paper or tablets (called reagents) are put into a small amount of urine or urine plus water. Changes in the color of the strip show the amount of glucose or ketones in the urine. Urine testing is the only way to check for the presence of ketones, a sign of serious illness. However, urine testing is less desirable then blood testing for monitoring the level of glucose in the body. [NIH] Urobilinogen: A colorless compound formed in the intestines by the reduction of bilirubin. Some is excreted in the feces where it is oxidized to urobilin. Some is reabsorbed and reexcreted in the bile as bilirubin. At times, it is re-excreted in the urine, where it may be later oxidized to urobilin. [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] Urticaria: A vascular reaction of the skin characterized by erythema and wheal formation due to localized increase of vascular permeability. The causative mechanism may be allergy, infection, or stress. [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] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagal: Pertaining to the vagus nerve. [EU] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vagus Nerve: The 10th cranial nerve. The vagus is a mixed nerve which contains somatic afferents (from skin in back of the ear and the external auditory meatus), visceral afferents

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(from the pharynx, larynx, thorax, and abdomen), parasympathetic efferents (to the thorax and abdomen), and efferents to striated muscle (of the larynx and pharynx). [NIH] Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]

Valproic Acid: A fatty acid with anticonvulsant properties used in the treatment of epilepsy. The mechanisms of its therapeutic actions are not well understood. It may act by increasing GABA levels in the brain or by altering the properties of voltage dependent sodium channels. [NIH] Valves: Flap-like structures that control the direction of blood flow through the heart. [NIH] Varicose: The common ulcer in the lower third of the leg or near the ankle. [NIH] Varicose vein: An abnormal swelling and tortuosity especially of the superficial veins of the legs. [EU] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasoactive Intestinal Peptide: A highly basic, single-chain polypeptide isolated from the intestinal mucosa. It has a wide range of biological actions affecting the cardiovascular, gastrointestinal, and respiratory systems. It is also found in several parts of the central and peripheral nervous systems and is a neurotransmitter. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vasomotor: 1. Affecting the calibre of a vessel, especially of a blood vessel. 2. Any element or agent that effects the calibre of a blood vessel. [EU] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventilator: A breathing machine that is used to treat respiratory failure by promoting ventilation; also called a respirator. [NIH]

396 Hemoglobin

Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Ventricular Pressure: The pressure within a cardiac ventricle. Ventricular pressure waveforms can be measured in the beating heart by catheterization or estimated using imaging techniques (e.g., Doppler echocardiography). The information is useful in evaluating the function of the myocardium, cardiac valves, and pericardium, particularly with simultaneous measurement of other (e.g., aortic or atrial) pressures. [NIH] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertigo: An illusion of movement; a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjective vertigo). The term is sometimes erroneously used to mean any form of dizziness. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Viremia: The presence of viruses in the blood. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Visual Acuity: Acuteness or clearness of vision, especially of form vision, which is dependent mainly on the sharpness of the retinal focus. [NIH] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitreous Hemorrhage: Hemorrhage into the vitreous body. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH]

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Warts: Benign epidermal proliferations or tumors; some are viral in origin. [NIH] Weight Gain: Increase in body weight over existing weight. [NIH] Wettability: The quality or state of being wettable or the degree to which something can be wet. This is also the ability of any solid surface to be wetted when in contact with a liquid whose surface tension is reduced so that the liquid spreads over the surface of the solid. [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] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment 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] Yohimbine: A plant alkaloid with alpha-2-adrenergic blocking activity. Yohimbine has been used as a mydriatic and in the treatment of impotence. It is also alleged to be an aphrodisiac. [NIH]

Zidovudine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. 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, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIVinduced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. [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]

399

INDEX 3 3-dimensional, 221, 303, 376 A Abdomen, 303, 315, 316, 335, 351, 355, 367, 369, 386, 387, 395, 396 Abdominal, 36, 37, 38, 139, 303, 304, 332, 351, 352, 353, 359, 367, 369, 370, 393 Abdominal Pain, 36, 37, 38, 303, 352, 393 Ablation, 93, 303 Abscess, 59, 303 Absolute risk, 38, 303 Acanthosis Nigricans, 42, 303 Acatalasia, 303, 319 Acceptor, 303, 355, 367, 392 Acetone, 224, 303, 353 Acetylcholine, 303, 364 Acidosis, 248, 303, 329 Acrylamide, 72, 146, 240, 303 Acrylonitrile, 146, 303, 382 Actin, 96, 304, 341 Activities of Daily Living, 304, 330 Acuity, 44, 304 Acute myelogenous leukemia, 304 Acute myeloid leukemia, 122, 304 Acute nonlymphocytic leukemia, 304 Acute renal, 304, 345 Adaptability, 80, 304, 319, 320 Adaptation, 80, 105, 113, 123, 236, 241, 304, 372 Adduct, 61, 72, 142, 304 Adenine, 304, 377 Adenocarcinoma, 304, 345, 364 Adenosine, 70, 165, 304, 317, 371, 390 Adenosine Diphosphate, 165, 304 Adenosine Triphosphate, 70, 165, 304, 371 Adenovirus, 68, 304 Adhesives, 170, 303, 304 Adipocytes, 304, 325, 354 Adjustment, 29, 31, 33, 230, 234, 236, 255, 304 Adjuvant, 202, 304, 341 Adolescence, 24, 40, 57, 80, 252, 305 Adrenal Cortex, 305, 306, 326, 336, 374 Adrenal Medulla, 305, 319, 335, 364 Adrenergic, 305, 331, 335, 389, 397 Adsorption, 113, 305 Adsorptive, 305

Adverse Effect, 5, 17, 77, 83, 91, 233, 247, 305, 384 Aerobic, 237, 305, 326, 360, 367 Aerobic Exercise, 237, 305 Aerobic Metabolism, 305, 367 Aerobic Respiration, 305, 367 Aerosol, 305, 389 Afferent, 305, 354 Agar, 215, 305, 327, 348, 371 Age of Onset, 306, 393 Agonist, 306, 331 Airway, 96, 187, 306 Alanine, 15, 35, 165, 306 Albumin, 16, 37, 44, 52, 74, 88, 154, 171, 197, 198, 200, 202, 245, 249, 252, 256, 298, 306, 371 Aldosterone, 258, 306 Alertness, 306, 317 Algorithms, 193, 306, 315 Alimentary, 4, 10, 37, 306, 334, 368, 369 Alkaline, 202, 217, 303, 306, 307, 313, 317, 367, 370 Alkaloid, 306, 361, 390, 397 Alleles, 306, 341 Allogeneic, 50, 161, 306, 344 Allografts, 306, 346 Alopecia, 172, 306 Alpha Particles, 306, 378 Alpha-fetoprotein, 306, 338 Alpha-Thalassemia, 306, 345 Alternative medicine, 266, 307 Alveoli, 307, 395 Ameliorated, 83, 100, 101, 307 Ameliorating, 52, 179, 307 Amine, 307, 346 Amino Acid Sequence, 110, 201, 307, 309 Amino Acid Substitution, 307, 345 Amino Acids, 55, 66, 165, 220, 221, 307, 311, 323, 369, 373, 376, 384, 393 Aminolevulinic Acid, 247, 258, 307 Ammonia, 307, 342, 393 Amniocentesis, 236, 307 Amnion, 307 Amniotic Fluid, 248, 307 Amplification, 102, 307 Ampulla, 307, 334 Amputation, 235, 261, 308 Amylase, 258, 308

400 Hemoglobin

Anaerobic, 188, 308, 326 Anaesthesia, 308, 349 Anal, 142, 308, 356, 366 Analgesics, 308, 349 Analogous, 71, 185, 308, 331, 392 Analytes, 14, 188, 203, 224, 308 Anaphylactic, 187, 190, 195, 216, 223, 308 Anaphylatoxins, 308, 324 Anaphylaxis, 308 Anatomical, 308, 312, 325, 330, 348, 383 Anemia, Sickle Cell, 158, 245, 308 Anemic, 65, 76, 131, 134, 147, 178, 201, 308 Anergy, 308, 388 Anesthesia, 75, 116, 120, 136, 139, 148, 306, 308, 333 Anesthetics, 308, 335 Aneurysm, 308, 395 Angiogenesis, 82, 308, 357 Angiopathy, 69, 309 Angioplasty, 92, 192, 309, 362 Angiotensin converting enzyme inhibitor, 192, 309 Animal model, 5, 49, 64, 68, 99, 104, 192, 309, 393 Anionic, 79, 309 Anions, 306, 309, 352, 384, 388 Ankle, 87, 309, 395 Anode, 202, 309 Anorexia, 251, 309 Antagonism, 309, 317, 390 Anthropometric measurements, 60, 309 Antibacterial, 309, 386 Antibiotic, 37, 309, 340, 368, 386, 390 Antibodies, 8, 63, 84, 112, 171, 188, 214, 226, 231, 254, 259, 309, 312, 343, 345, 348, 356, 360, 371, 378 Anticoagulant, 187, 309, 376 Anticonvulsant, 309, 395 Antidiabetic, 13, 166, 167, 247, 310, 342 Antidiabetic Agent, 13, 166, 167, 247, 310 Antidote, 310, 385 Antigen, 30, 171, 226, 305, 308, 309, 310, 324, 346, 347, 348, 349, 358, 378 Antigen-Antibody Complex, 310, 324 Anti-infective, 310, 347 Anti-inflammatory, 310, 312, 326, 329, 342 Anti-Inflammatory Agents, 310, 312, 326 Antimetabolite, 310, 382 Antimicrobial, 69, 310, 331 Antineoplastic, 310, 326, 347, 349 Antineoplastic Agents, 310, 349

Antioxidant, 53, 74, 116, 171, 172, 310, 311, 367 Antiseptic, 303, 310 Antisickling Agents, 89, 91, 134, 310 Antiviral, 310, 350, 382 Anuria, 310, 353 Anus, 308, 310, 316, 338 Anxiety, 29, 41, 298, 310 Aorta, 310, 318, 396 Apathy, 39, 310 Aperture, 310, 377 Aplasia, 135, 310 Aplastic anemia, 245, 310 Apnea, 66, 84, 122, 310 Apolipoproteins, 7, 310, 355 Apoptosis, 102, 172, 311, 319 Applicability, 98, 311 Aptitude, 43, 311 Aqueous, 185, 205, 311, 313, 328, 333, 347, 354, 355 Arachidonic Acid, 170, 311, 354, 375 Arginine, 192, 271, 308, 311, 364 Argon, 174, 311 Aromatic, 89, 152, 311, 370 Arteries, 68, 85, 223, 227, 309, 310, 311, 315, 316, 320, 326, 356, 359, 361, 377, 391, 393 Arteriolar, 52, 311, 317 Arterioles, 75, 159, 311, 316, 318, 359, 361, 395 Arteriosus, 311, 377 Arteriovenous, 311, 359 Arthropathy, 36, 311 Arthroplasty, 132, 311 Ascites, 36, 311 Ascorbic Acid, 228, 270, 311, 347 Aspartic, 127, 311 Aspartic Acid, 311 Aspiration, 312, 338 Aspirin, 21, 40, 312 Assay, 28, 53, 73, 82, 95, 130, 168, 171, 188, 200, 203, 226, 231, 239, 312, 348, 378 Astrocytes, 63, 312 Asymptomatic, 6, 36, 48, 303, 312, 314 Asynchronous, 209, 312 Ataxia, 282, 312, 390 Atrial, 312, 396 Atrium, 312, 318, 396 Atrophy, 36, 282, 312, 335 Attenuated, 93, 312, 330 Attenuation, 193, 209, 210, 312 Aurothioglucose, 97, 312

Index 401

Autoantibodies, 14, 40, 312 Autoantigens, 312 Autoimmune disease, 46, 312 Autoimmunity, 8, 312 Autologous, 161, 202, 312, 344 Autologous bone marrow transplantation, 312, 344 Autonomic, 8, 29, 38, 238, 303, 313, 364, 369, 389 Autonomic Nervous System, 313, 369, 389 Autonomic Neuropathy, 8, 38, 313 Avian, 145, 313 Axons, 313, 363, 365, 366, 381 B Bacteremia, 313, 384 Bacterial Physiology, 304, 313 Bacteriophage, 313, 371, 392 Bacterium, 58, 313, 325, 345 Bacteriuria, 313, 394 Barium, 37, 313 Basal Ganglia, 312, 313, 340, 377 Basal Ganglia Diseases, 312, 313 Base, 7, 25, 69, 170, 208, 240, 243, 304, 313, 328, 329, 353, 370, 372, 390 Basement Membrane, 254, 314, 337, 354 Basophils, 314, 319, 343, 354 Belching, 38, 314 Benign, 314, 340, 343, 363, 378, 397 Benzene, 314, 370 Benzocaine, 136, 314 Benzodiazepines, 126, 314 Benzoic Acid, 84, 314 Beta-Thalassemia, 55, 83, 95, 123, 160, 314 Bilateral, 314, 335 Bile, 255, 314, 340, 346, 352, 355, 387, 394 Bile Acids, 314, 387 Bile Acids and Salts, 314 Bile Pigments, 314, 352 Bilirubin, 53, 68, 117, 118, 167, 168, 186, 209, 210, 224, 245, 257, 258, 306, 314, 347, 394 Binding Sites, 68, 90, 98, 204, 314 Bioassay, 97, 314 Bioavailability, 83, 314 Biological response modifier, 315, 350 Biological therapy, 315, 343 Biological Transport, 315, 330 Bioluminescence, 315, 356 Biomarkers, 119, 146, 315 Biopsy, 15, 35, 36, 37, 52, 315, 369 Biosynthesis, 49, 107, 243, 247, 311, 315, 325, 384, 394

Biotechnology, 104, 114, 201, 243, 266, 277, 280, 281, 282, 283, 315 Biotype, 114, 315 Bladder, 313, 315, 327, 340, 349, 363, 375, 380, 394 Blastocyst, 315, 324, 371 Bloating, 38, 251, 315, 340, 349, 352 Blood Banks, 168, 178, 199, 211, 315 Blood Cell Count, 315, 344, 370 Blood Coagulation, 147, 315, 316, 317, 391 Blood Coagulation Factors, 315, 316 Blood Proteins, 189, 227, 315 Blood Substitutes, 79, 153, 155, 168, 169, 170, 171, 175, 190, 199, 219, 228, 316 Blood transfusion, 12, 49, 95, 102, 120, 159, 228, 316, 344 Blood Viscosity, 52, 75, 316, 344 Blood Volume, 81, 137, 178, 189, 206, 226, 227, 316 Blood Volume Determination, 226, 316 Blood-Brain Barrier, 74, 316 Body Composition, 61, 316 Body Fluids, 203, 245, 315, 316, 317, 339, 365, 385, 393 Body Mass Index, 20, 22, 24, 33, 34, 38, 47, 60, 316, 366 Bolus, 6, 44, 82, 92, 316 Bolus infusion, 316 Bolus injection, 92, 316 Bone Marrow, 15, 35, 49, 76, 94, 158, 176, 201, 207, 304, 310, 312, 314, 316, 336, 344, 356, 361, 386, 387, 388, 397 Bone Marrow Transplantation, 49, 202, 316 Bowel, 4, 37, 251, 308, 316, 330, 349, 351, 354, 363, 366, 370, 387, 393 Bowel Movement, 316, 330, 387 Brachytherapy, 317, 351, 352, 378, 397 Bradycardia, 84, 317 Bradykinin, 170, 317, 353, 364, 372 Branch, 30, 214, 263, 295, 317, 333, 356, 368, 377, 386, 389, 390 Breakdown, 12, 63, 69, 74, 96, 224, 251, 254, 317, 320, 329, 330, 340 Breast Feeding, 23, 317 Breeding, 101, 317, 341 Bronchi, 317, 335, 390, 392 Bronchial, 317, 346, 390 Bronchospasm, 96, 317 Bulimia, 24, 317 Burns, 170, 172, 195, 222, 223, 299, 317 Burns, Electric, 317

402 Hemoglobin

Butyrates, 62, 317 Butyric Acid, 317 Bypass, 66, 102, 317, 362 C Caffeine, 236, 317, 377 Calcium, 7, 85, 192, 258, 317, 323, 341, 357, 362, 376 Capillary, 75, 80, 82, 129, 131, 165, 170, 178, 181, 183, 196, 254, 258, 317, 318, 396 Capillary Permeability, 170, 317, 318 Carbohydrate, 14, 19, 61, 88, 105, 167, 234, 235, 318, 326, 342, 373, 384 Carbon Dioxide, 174, 200, 219, 316, 318, 328, 340, 371, 380, 395 Carboxy, 209, 210, 318 Carcinogen, 304, 318 Carcinogenic, 314, 318, 350, 364, 375, 385, 387 Carcinoma, 118, 318, 364, 387 Cardiac Output, 80, 154, 170, 189, 190, 192, 226, 227, 318, 388 Cardiomyopathy, 254, 318 Cardiopulmonary, 87, 92, 318, 344 Cardiopulmonary Bypass, 92, 318, 344 Cardiorespiratory, 153, 305, 318 Cardiovascular, 4, 5, 6, 21, 27, 28, 34, 45, 46, 86, 87, 123, 129, 160, 189, 192, 206, 216, 238, 239, 262, 313, 318, 354, 384, 395 Cardiovascular disease, 4, 21, 27, 28, 45, 123, 216, 238, 239, 262, 318 Cardiovascular System, 206, 313, 318 Carnitine, 148, 318 Carotene, 318, 381 Carrier Proteins, 319, 371, 378 Case report, 9, 43, 119, 134, 136, 246, 319, 322 Case series, 319, 322 Caspase, 63, 319 Catabolism, 68, 97, 319, 393 Catalase, 154, 303, 319 Cataracts, 254, 319 Catecholamine, 319, 331, 370 Catheterization, 309, 319, 351, 362, 396 Catheters, 84, 319, 340, 348, 351 Cathode, 202, 309, 319, 332 Cations, 319, 352 Causal, 319, 324, 345 Cause of Death, 60, 77, 84, 319 Cell Adhesion, 225, 319 Cell Cycle, 159, 319, 322 Cell Death, 63, 311, 319, 362 Cell Degranulation, 91, 319

Cell Differentiation, 153, 221, 319, 387 Cell Division, 282, 313, 319, 320, 343, 360, 371, 375 Cell Lineage, 76, 320 Cell membrane, 77, 96, 102, 172, 192, 196, 315, 319, 320, 336, 351, 352, 366, 370, 374, 385 Cell proliferation, 73, 78, 320 Cell Respiration, 305, 320, 360, 367, 380 Cell Size, 222, 320, 339 Cell Survival, 123, 159, 320, 343 Cell Transplantation, 50, 158, 236, 253, 320 Cellular metabolism, 165, 181, 220, 320 Cellulose, 320, 371 Central Nervous System Infections, 320, 343 Centrifugation, 168, 178, 223, 320, 344 Cerebellar, 312, 320, 379 Cerebral Arteries, 68, 85, 320 Cerebral Palsy, 320, 386 Cerebrovascular, 52, 85, 117, 313, 318, 320, 390 Cerebrum, 320, 393 Cervix, 65, 321 Chancroid, 103, 321 Character, 185, 207, 225, 321, 328 Chelating Agents, 202, 321 Chelation, 160, 321 Chelation Therapy, 160, 321 Chemotactic Factors, 321, 324 Chemotherapy, 81, 131, 134, 157, 158, 201, 321 Chlorophyll, 321 Cholecystokinin, 4, 321 Cholesterol, 4, 16, 17, 19, 21, 27, 30, 34, 46, 60, 87, 314, 321, 322, 326, 332, 347, 355, 356, 383, 387 Cholesterol Esters, 321, 355 Choroid, 321, 325, 381 Chromatin, 62, 73, 101, 311, 321, 335, 356 Chromosomal, 307, 321, 382 Chromosome, 50, 73, 113, 208, 280, 321, 325, 343, 353, 355, 385 Chronic Disease, 4, 19, 69, 87, 321 Chronic renal, 201, 233, 321, 372 Chylomicrons, 322, 355 Circulatory system, 190, 205, 206, 322, 333 CIS, 53, 57, 322, 381 Cisplatin, 65, 136, 322 Citrus, 311, 322 C-kit receptor, 322, 387 Clamp, 81, 85, 322

Index 403

Clinical Medicine, 178, 211, 322, 374 Clinical study, 139, 322, 325 Clinical trial, 48, 62, 79, 80, 83, 94, 136, 157, 162, 201, 277, 322, 325, 331, 376, 379 Clone, 53, 322 Cloning, 50, 64, 106, 107, 112, 315, 322 Clot Retraction, 74, 322 Coagulation, 57, 139, 223, 315, 322, 371, 391 Cod Liver Oil, 322, 333 Codon, 159, 323 Coenzyme, 311, 323 Cofactor, 58, 103, 323, 376, 391 Cognitive restructuring, 323, 388 Colitis, 37, 251, 323, 352 Collagen, 169, 170, 304, 314, 323, 337, 341, 357, 372, 375 Collapse, 187, 308, 317, 323 Colloidal, 142, 190, 306, 323, 333, 337, 370, 384, 389 Colorectal, 246, 323 Colorectal Cancer, 246, 323 Combination Therapy, 11, 12, 167, 247, 253, 323 Combinatorial, 98, 323 Community Health Centers, 26, 323 Comorbidity, 16, 323 Complement, 75, 308, 323, 324, 341, 353, 357, 371 Complementary and alternative medicine, 145, 150, 324 Complementary medicine, 145, 324 Complementation, 49, 50, 53, 64, 324 Complete remission, 324, 380 Compress, 324, 391 Computational Biology, 277, 280, 324 Computer Simulation, 81, 89, 324 Conception, 23, 257, 324, 325, 338 Concomitant, 47, 213, 324 Cones, 324, 381 Confounder, 85, 324 Confounding, 25, 324 Confusion, 324, 394 Congestion, 324, 335 Conjugated, 135, 171, 245, 314, 325, 327, 362 Conjugation, 205, 325 Connective Tissue, 40, 311, 316, 323, 325, 338, 340, 341, 382 Connective Tissue Cells, 325 Consciousness, 308, 325, 331, 345, 381 Constipation, 38, 325, 352

Constriction, 206, 223, 325, 352, 395 Constriction, Pathologic, 325, 395 Consumption, 60, 99, 325, 329, 365, 367 Contamination, 168, 190, 191, 325 Contraceptive, 236, 325, 382 Contractility, 192, 325 Contraindications, ii, 15, 35, 248, 325 Control group, 22, 25, 32, 33, 84, 325 Controlled clinical trial, 37, 325 Conus, 325, 377 Conventional therapy, 325 Conventional treatment, 38, 325 Coordination, 58, 321, 325 Coproporphyrinogen Oxidase, 247, 325 Cornea, 326, 388 Coronary, 7, 26, 60, 87, 92, 113, 161, 192, 318, 326, 359, 361 Coronary Arteriosclerosis, 326, 361 Coronary heart disease, 7, 26, 60, 87, 318, 326 Coronary Thrombosis, 326, 359, 361 Corpuscle, 169, 326, 335 Cortex, 71, 81, 177, 312, 320, 326, 336, 379 Cortical, 81, 326, 383, 390 Corticosteroid, 326, 387 Cortisol, 306, 326 Cortisone, 326, 329 Cost Savings, 59, 326 Cranial, 326, 343, 365, 369, 394 Craniocerebral Trauma, 313, 326, 343, 390, 391 Creatinine, 26, 30, 39, 44, 224, 236, 258, 326, 327, 353 Creatinine clearance, 258, 327 Criterion, 14, 28, 209, 327 Culture Media, 220, 305, 327 Curative, 50, 327, 390 Cutaneous, 255, 327 Cyanide, 152, 184, 198, 200, 327, 359, 374, 385 Cyanosis, 119, 255, 298, 327, 345 Cyclic, 68, 190, 317, 327, 343, 364, 373, 375, 390 Cysteine, 78, 97, 107, 110, 111, 142, 185, 327 Cystine, 327 Cystoscope, 327, 392 Cytochrome, 52, 63, 81, 175, 176, 193, 194, 281, 300, 327 Cytochrome A, 194, 327 Cytochrome b, 63, 175, 300, 327 Cytochrome b5, 63, 300, 327

404 Hemoglobin

Cytokine, 65, 76, 92, 102, 327, 350 Cytomegalovirus, 30, 327 Cytoplasm, 172, 311, 314, 320, 328, 335, 343 Cytoplasmic Structures, 173, 328 Cytotoxic, 74, 328, 350, 378 Cytotoxicity, 74, 322, 328 D Dairy Products, 328, 383 Data Collection, 328, 339 Databases, Bibliographic, 277, 328 Deamination, 328, 393 Decarboxylation, 326, 328, 346, 394 Decidua, 328, 371 Decision Making, 13, 328 Decitabine, 62, 328 Deferoxamine, 74, 328 Degenerative, 222, 223, 325, 328, 345, 381 Dehydration, 54, 91, 328 Deletion, 64, 105, 108, 110, 120, 311, 328 Delivery of Health Care, 323, 328 Denaturation, 244, 328 Dendrites, 328, 363 Deoxycytidine, 62, 329 Deoxyribonucleic, 255, 329, 382 Deoxyribonucleic acid, 255, 329, 382 Deoxyribonucleotides, 329, 382 Deprivation, 177, 181, 329 Dermal, 164, 174, 329 Dermatologist, 256, 329 Detoxification, 245, 329 Deuterium, 130, 329, 347 Developing Countries, 103, 178, 329 Dexamethasone, 97, 329 Diabetes Insipidus, 329, 372 Diabetic Foot, 254, 329 Diabetic Ketoacidosis, 235, 238, 254, 329, 353 Diabetic Retinopathy, 9, 44, 69, 235, 238, 239, 257, 261, 329, 371 Diagnostic Imaging, 329, 377 Diagnostic procedure, 163, 266, 329, 370 Dialysate, 329, 330, 332 Dialyzer, 330, 344 Diarrhea, 37, 38, 158, 195, 251, 330, 352, 354 Diastole, 330 Diastolic, 45, 330, 347, 357 Diastolic blood pressure, 45, 330 Diastolic pressure, 330, 347, 357 Diathesis, 79, 330 Dietary Fats, 24, 330, 355

Dietitian, 24, 256, 330 Diffusion, 75, 98, 110, 174, 315, 318, 330, 348, 351 Digestion, 72, 79, 306, 314, 316, 330, 332, 340, 349, 351, 355, 368, 387, 394 Digestive system, 162, 330 Digestive tract, 313, 330, 385, 387 Dihydrotestosterone, 330, 379 Dilatation, 308, 309, 330, 374, 395 Dilatation, Pathologic, 330, 395 Dilation, 53, 317, 330, 395 Dilator, 161, 330 Dilution, 169, 189, 209, 330, 335, 372 Diploid, 324, 330, 371 Disabled Persons, 208, 330 Discrimination, 66, 330 Disposition, 245, 331 Dissection, 57, 106, 331 Dissociation, 55, 75, 170, 215, 305, 331, 352 Dissociative Disorders, 331 Distal, 66, 105, 110, 331, 332, 376 Diuresis, 317, 331, 390 Dopamine, 258, 331, 370 Dose-dependent, 331, 397 Double-blinded, 120, 137, 148, 331 Doxycycline, 69, 331 Drive, ii, vi, 24, 42, 141, 249, 253, 261, 331, 351, 354 Drug Delivery Systems, 98, 331 Drug Design, 89, 271, 331 Drug Evaluation, 92, 331 Drug Interactions, 270, 331 Drug Tolerance, 332, 391 Duodenum, 314, 332, 334, 340, 387 Dwell time, 173, 332 Dyes, 173, 203, 314, 332, 339 Dyslipidemia, 4, 42, 46, 262, 332 Dyspepsia, 10, 332, 349 Dysplasia, 282, 332 Dystrophy, 282, 332 E Echocardiography, 135, 332, 396 Edema, 74, 170, 329, 332, 362 Effector, 51, 303, 323, 332, 363 Efficacy, 12, 13, 22, 35, 39, 51, 69, 75, 80, 83, 98, 160, 161, 166, 167, 201, 248, 331, 332 Elastin, 323, 332, 337 Elective, 132, 332 Electrochemistry, 199, 201, 332 Electrocoagulation, 322, 332

Index 405

Electrode, 116, 164, 189, 199, 202, 309, 319, 332 Electrolysis, 164, 309, 319, 332 Electrolyte, 25, 189, 202, 227, 306, 326, 332, 339, 353, 365, 373, 385 Electrons, 310, 313, 319, 332, 352, 360, 367, 378 Electrophoresis, 215, 263, 297, 299, 303, 333, 348, 352 Electrophysiological, 51, 81, 333 Elementary Particles, 332, 333, 363, 376 Embolus, 333, 349 Embryo, 64, 307, 315, 320, 333, 338, 349, 393 Embryogenesis, 333, 387 Empirical, 89, 333 Emulsion, 192, 333 Encapsulated, 171, 172, 198, 223, 333 Endarterectomy, 309, 333 Endemic, 333, 357, 386 Endocrine System, 333 Endocrinologist, 23, 333 Endocrinology, 29, 43, 128, 253, 258, 333 Endocytosis, 63, 102, 333 Endometrium, 328, 333, 358 Endoscope, 334 Endoscopic, 37, 334, 385 Endothelial cell, 70, 91, 100, 316, 334, 391 Endothelium, 57, 93, 96, 161, 334, 364 Endothelium, Lymphatic, 334 Endothelium, Vascular, 334 Endothelium-derived, 334, 364 Endotoxic, 334, 355 Endotoxin, 107, 142, 154, 194, 196, 219, 334 End-stage renal, 321, 334, 372 Energetic, 63, 334 Energy balance, 334, 354 Energy Intake, 88, 334 Enhancer, 73, 334, 356 Enteral Nutrition, 252, 334 Environmental Exposure, 334, 365 Environmental Health, 117, 138, 276, 278, 334 Environmental Medicine, 146, 334 Environmental Pollutants, 334, 372 Enzymatic, 68, 130, 165, 200, 318, 324, 334, 346, 381 Enzyme Inhibitors, 335, 371 Eosinophils, 319, 335, 343, 354 Epidemiological, 31, 72, 335 Epidermal, 164, 174, 335, 358, 397 Epidermis, 335, 377

Epigastric, 335, 367 Epinephrine, 255, 258, 305, 331, 335, 364, 393 Epithelial, 91, 97, 110, 147, 304, 315, 328, 335, 354, 369 Epithelial Cells, 97, 110, 147, 335, 354 Epithelium, 314, 334, 335, 352, 367 Epoetin alfa, 134, 201, 335 Erectile, 29, 47, 235, 261, 335 Erection, 30, 335 Erythema, 37, 335, 394 Erythema Nodosum, 37, 335 Erythroblasts, 176, 207, 335, 336 Erythrocyte Membrane, 100, 245, 335 Erythrocyte Volume, 54, 316, 335 Erythroid Progenitor Cells, 127, 179, 335, 336 Erythroleukemia, 94, 336 Erythropoiesis, 5, 53, 55, 73, 78, 93, 95, 103, 179, 266, 335, 336 Erythropoietin, 5, 53, 65, 129, 142, 201, 233, 299, 336 Esophageal, 336, 383 Esophageal Varices, 336, 383 Esophagus, 330, 336, 344, 387 Essential Tremor, 282, 336 Estradiol, 336 Estriol, 258, 336 Estrogen, 161, 336, 375 Ethnic Groups, 18, 126, 336 Eukaryotic Cells, 336, 366, 393 Evacuation, 325, 336, 340, 354 Evaluable patients, 4, 336 Evoke, 336, 387 Excitation, 172, 336, 338 Excrete, 310, 336, 353 Exercise Therapy, 255, 336 Exhaustion, 309, 336, 357 Exocrine, 321, 336, 367 Exocytosis, 319, 336 Exogenous, 168, 204, 305, 336, 393 Expander, 195, 337 Expiration, 337, 380 Extender, 337, 371 Extensor, 337, 376 External-beam radiation, 337, 352, 378, 397 Extracellular, 6, 63, 82, 92, 100, 168, 312, 325, 333, 337, 357, 385 Extracellular Matrix, 325, 337, 357 Extracellular Matrix Proteins, 337, 357 Extracorporeal, 189, 337

406 Hemoglobin

Extraction, 72, 227, 337 Extrapyramidal, 331, 337 Extravasation, 170, 337, 344 Extravascular, 63, 170, 177, 337 Extremity, 34, 337 Eye Infections, 304, 337 F Family Planning, 277, 337 Fatigue, 36, 37, 137, 159, 255, 337, 344 Fatty acids, 53, 251, 306, 329, 337, 355, 375, 391 Febrile, 40, 337, 357 Fecal occult blood test, 246, 337 Feces, 325, 337, 387, 394 Femoral, 318, 338 Femoral Artery, 318, 338 Ferritin, 5, 7, 18, 40, 63, 148, 338 Ferrochelatase, 247, 338 Fetal Development, 62, 179, 338, 363 Fetal Monitoring, 236, 338 Fetoprotein, 236, 338 Fetus, 160, 179, 306, 336, 338, 371, 374, 393, 394 Fibrin, 315, 322, 338, 390, 391 Fibrinogen, 4, 338, 371, 390 Fibronectin, 108, 112, 338 Fibrosis, 12, 36, 282, 338, 383 Filtration, 219, 223, 338, 353 Flank Pain, 159, 338 Flatulence, 38, 251, 338 Flatus, 338, 340 Flow Cytometry, 176, 207, 338 Fluid Therapy, 339, 365 Fluorescence, 65, 74, 126, 172, 176, 193, 207, 221, 338, 339 Fluorescent Dyes, 338, 339 Flushing, 255, 339 Focus Groups, 18, 339 Folate, 245, 255, 299, 339 Fold, 55, 66, 215, 229, 339, 359, 367 Folic Acid, 36, 245, 339 Follicles, 339 Food Exchange, 237, 339 Foot Care, 238, 339 Foot Ulcer, 329, 339 Foramen, 339, 369 Forearm, 161, 315, 339 Fractionation, 101, 339 Fructosamine, 19, 69, 201, 238, 239, 246, 339 Fructose, 165, 339, 346

Functional magnetic resonance imaging, 51, 340 Fundus, 69, 186, 340, 365 Fungemia, 340, 384 Fungi, 315, 325, 337, 340, 343, 359, 397 Fungistatic, 314, 340 G Galago, 57, 340 Gallbladder, 303, 321, 330, 340 Gamma Rays, 340, 378 Ganglia, 303, 313, 340, 363, 369, 389 Ganglion, 340, 365, 381 Gas exchange, 187, 340, 381, 395 Gastric, 3, 8, 10, 38, 217, 318, 340, 344, 346, 368, 369, 383 Gastric Emptying, 8, 10, 38, 340 Gastrin, 340, 346 Gastrointestinal tract, 338, 340, 354, 384, 393 Gastroparesis, 8, 10, 29, 38, 235, 340 Gastrostomy, 334, 340 Gelatin, 327, 341, 342, 390 Gels, 64, 153, 341 Gelsolin, 96, 341 Gene Expression, 49, 50, 53, 55, 57, 62, 73, 93, 94, 95, 97, 101, 103, 108, 109, 240, 283, 341 Gene Frequency, 18, 341 Gene Silencing, 62, 64, 341 Genetic Engineering, 152, 315, 322, 341 Genetic Screening, 208, 341 Genetic testing, 14, 236, 341 Genetics, 49, 53, 64, 76, 240, 242, 254, 262, 325, 341 Genital, 103, 313, 341 Genotype, 45, 85, 152, 306, 315, 341, 370 Germ Cells, 208, 341, 365, 366, 390 Gestation, 179, 236, 341, 369, 371 Gestational, 13, 22, 235, 236, 238, 248, 250, 254, 257, 341 Gland, 305, 326, 341, 367, 375, 383, 387, 391 Globins, 49, 108, 200, 204, 341 Globus Pallidus, 313, 341, 377 Glomerular, 341, 353, 380 Glucocorticoid, 92, 329, 342 Glucokinase, 342, 346 Glucose Intolerance, 329, 342 Glucose tolerance, 4, 21, 28, 30, 235, 239, 248, 254, 342 Glucose Tolerance Test, 4, 21, 28, 30, 239, 248, 254, 342

Index 407

Glucosidases, 3, 342 Glutamic Acid, 339, 342, 345, 375 Glutamine, 82, 342 Glyburide, 39, 45, 166, 167, 342 Glycine, 204, 228, 307, 314, 342, 384 Glycoprotein, 201, 336, 338, 342, 354, 391 Glycosuria, 246, 342 Glycosylation, 100, 201, 342 Gonad, 342 Gonadal, 255, 342, 387 Governing Board, 342, 374 Graft, 12, 117, 189, 306, 343, 346, 362 Gram-negative, 334, 343, 384 Gram-positive, 343, 384, 388 Granulocytes, 343, 397 Grasses, 339, 343 Growth factors, 62, 179, 343 Guanylate Cyclase, 101, 185, 225, 343, 364 H Habitat, 343, 364 Habitual, 321, 343 Hair follicles, 164, 343 Half-Life, 188, 219, 343 Halitosis, 38, 343 Haploid, 343, 371 Haplotypes, 117, 343 Haptens, 305, 343, 378 Headache, 251, 298, 317, 343 Headache Disorders, 343 Health Planning, 344 Health Priorities, 278, 344 Health Status, 16, 17, 86, 209, 344 Heart attack, 27, 172, 261, 318, 344 Heart failure, 36, 344 Heartbeat, 344, 357 Heartburn, 38, 344, 349 Hematologic Diseases, 255, 344 Hematology, 119, 120, 126, 127, 128, 130, 133, 134, 146, 168, 184, 221, 242, 263, 344, 370 Hematoma, 75, 344 Hematopoiesis, 76, 344 Hematopoietic Stem Cell Transplantation, 130, 344 Hematopoietic Stem Cells, 76, 344 Hemin, 63, 114, 123, 204, 344 Hemochromatosis, 18, 36, 49, 344 Hemodialysis, 121, 189, 233, 329, 330, 344, 353 Hemodilution, 75, 139, 190, 344

Hemoglobin E, 52, 95, 105, 111, 115, 131, 132, 139, 151, 179, 187, 191, 215, 262, 263, 345 Hemoglobin H, 63, 83, 116, 142, 178, 196, 212, 218, 219, 281, 338, 345 Hemoglobinopathies, 73, 79, 99, 102, 117, 126, 137, 138, 157, 158, 179, 242, 243, 345 Hemoglobinuria, 126, 159, 282, 297, 299, 345 Hemolysis, 12, 91, 200, 209, 213, 300, 335, 345 Hemolytic, 15, 35, 76, 116, 120, 245, 308, 345, 378, 390 Hemorrhage, 37, 63, 68, 74, 85, 187, 195, 216, 223, 316, 326, 332, 343, 345, 362, 377, 388, 396 Hemorrhoids, 345, 383 Hepatic, 30, 36, 86, 126, 167, 306, 342, 345, 373 Hepatic Encephalopathy, 126, 345 Hepatitis, 11, 12, 15, 35, 40, 168, 175, 188, 191, 216, 345 Hepatitis Viruses, 168, 345 Hepatocellular, 36, 345 Hepatocellular carcinoma, 36, 345 Hepatocyte, 204, 345 Hereditary, 18, 36, 50, 53, 77, 82, 101, 105, 108, 180, 207, 208, 281, 345, 370, 381, 390 Heredity, 341, 345 Heritability, 9, 94, 345 Heterogeneity, 123, 305, 346 Heterogenic, 346 Heterogenous, 254, 346 Hexokinase, 83, 346 Histamine, 170, 308, 346 Histidine, 346 Histocompatibility, 190, 346 Histology, 8, 74, 346 Histone Deacetylase, 62, 73, 94, 346 Holidays, 235, 346 Homeostasis, 85, 217, 346 Homologous, 103, 104, 114, 306, 344, 346 Homozygotes, 18, 346 Hormonal, 254, 312, 326, 346, 369 Hormone, 3, 4, 5, 8, 201, 236, 257, 306, 314, 326, 333, 335, 336, 340, 346, 350, 354, 374, 375, 382, 390, 391 Hormone Replacement Therapy, 4, 236, 346 Host, 59, 69, 84, 111, 114, 127, 306, 313, 346, 354, 382, 394, 396 Human papillomavirus, 147, 346

408 Hemoglobin

Humoral, 59, 346, 392 Humour, 346 Hybrid, 55, 71, 98, 123, 322, 346 Hybridization, 208, 346 Hydration, 91, 111, 303, 347 Hydrogen, 99, 105, 107, 110, 188, 191, 198, 202, 251, 263, 303, 307, 313, 318, 319, 328, 329, 337, 347, 355, 360, 363, 364, 367, 376, 388 Hydrogen Bonding, 191, 347, 364 Hydrogen Peroxide, 99, 319, 347, 355, 388 Hydrolysis, 311, 322, 347, 351, 373, 376 Hydrophilic, 124, 347 Hydrophobic, 347, 355 Hydroxylysine, 323, 347 Hydroxyproline, 323, 347 Hydroxyurea, 49, 53, 62, 77, 82, 90, 94, 101, 104, 108, 119, 127, 134, 159, 160, 271, 347 Hyperbilirubinemia, 245, 347, 352 Hypercholesterolemia, 161, 332, 347 Hyperlipidemia, 332, 347 Hypersensitivity, 191, 202, 308, 347, 354, 382 Hypertension, 17, 21, 30, 39, 42, 93, 161, 257, 262, 318, 343, 347, 391 Hypertriglyceridemia, 332, 347 Hypoglycemic, 3, 6, 22, 29, 180, 236, 253, 258, 259, 347 Hypoglycemic Agents, 236, 253, 347 Hypotension, 190, 347 Hypothermia, 344, 347 Hypovolemia, 148, 347 Hypoxemia, 84, 230, 348 I Id, 143, 149, 288, 294, 296, 348 Immune response, 59, 95, 97, 304, 308, 310, 312, 326, 343, 348, 357, 388, 389, 392, 394, 396 Immune system, 188, 312, 315, 348, 354, 356, 357, 362, 394, 397 Immunity, 109, 224, 306, 348, 350 Immunoassay, 171, 226, 231, 348 Immunodeficiency, 127, 201, 282, 348 Immunodiffusion, 305, 348 Immunoelectrophoresis, 305, 348 Immunofluorescence, 91, 348 Immunogenic, 348, 355, 378 Immunoglobulin, 171, 220, 309, 348, 360 Immunohistochemistry, 65, 68, 348 Immunologic, 321, 348, 379, 397 Immunology, 304, 305, 339, 348

Immunosuppressive, 31, 50, 342, 348 Impairment, 56, 74, 87, 118, 177, 312, 337, 348, 358 Implant radiation, 348, 351, 352, 378, 397 Implantation, 324, 348 Impotence, 235, 236, 261, 335, 348, 368, 397 In situ, 65, 91, 348 In vivo, 54, 58, 62, 63, 64, 68, 72, 75, 78, 91, 93, 95, 96, 101, 115, 160, 171, 172, 179, 180, 182, 183, 186, 188, 190, 201, 204, 217, 218, 219, 225, 229, 348, 355, 385, 391 Incision, 349, 351, 377 Incontinence, 349, 366 Incubation, 96, 349 Indicative, 69, 183, 209, 224, 239, 349, 368, 395 Indigestion, 349, 354 Induction, 47, 53, 81, 83, 91, 94, 95, 101, 104, 107, 109, 112, 127, 128, 132, 349, 350, 375 Infancy, 8, 84, 179, 349 Infarction, 192, 349, 380 Infection, 12, 15, 30, 40, 59, 76, 85, 92, 103, 109, 112, 116, 178, 201, 228, 235, 303, 313, 315, 321, 328, 329, 335, 337, 348, 349, 356, 363, 368, 382, 387, 388, 394, 397 Inflammatory bowel disease, 4, 37, 251, 349 Information Systems, 19, 349 Infuse, 23, 349 Infusion, 7, 44, 53, 75, 196, 247, 316, 349, 350, 362, 383, 392 Infusion Pumps, 247, 349 Infusion Pumps, Implantable, 247, 349 Ingestion, 95, 142, 342, 343, 349, 350, 359, 372 Inhalation, 305, 349, 372 Initiation, 12, 46, 59, 93, 350, 392 Inlay, 350, 381 Inorganic, 322, 350, 356, 361, 364, 370 Inotropic, 331, 350 Inpatients, 228, 350 Insight, 63, 68, 106, 350 Insulin Infusion Systems, 349, 350 Insulin-dependent diabetes mellitus, 38, 350 Insulin-like, 247, 350 Intensive Care, 77, 136, 138, 187, 189, 209, 227, 350 Intensive Care Units, 187, 350 Interferon, 11, 12, 15, 35, 117, 350 Interferon-alpha, 350

Index 409

Interleukin-1, 102, 350 Interleukin-18, 102, 350 Interleukin-2, 350 Intermittent, 43, 96, 129, 339, 351, 356, 369 Internal Medicine, 10, 11, 18, 100, 137, 148, 333, 344, 351 Internal radiation, 351, 352, 378, 397 Interstitial, 317, 351, 352, 380, 397 Intestinal, 3, 91, 251, 318, 321, 342, 351, 357, 395 Intestine, 10, 26, 91, 314, 316, 323, 351, 354 Intoxication, 351, 397 Intracellular, 62, 85, 172, 185, 192, 317, 349, 351, 364, 373, 375 Intramuscular, 351, 368 Intraocular, 70, 351 Intraocular pressure, 70, 351 Intraperitoneal, 247, 351 Intravascular, 75, 79, 80, 91, 93, 351 Intravenous, 30, 83, 227, 248, 254, 316, 340, 349, 351, 368 Intrinsic, 51, 81, 305, 314, 351 Intubation, 136, 319, 351 Invasive, 65, 67, 69, 76, 177, 181, 182, 183, 185, 186, 192, 208, 235, 348, 351, 357, 367 Invertebrates, 342, 351, 356 Involuntary, 313, 336, 351, 362, 385 Ion Channels, 312, 351, 363 Ion Exchange, 215, 320, 351 Ion Transport, 54, 351 Ionization, 72, 116, 130, 153, 352 Ionizing, 172, 306, 334, 352, 378, 385 Ions, 188, 313, 321, 331, 332, 338, 341, 347, 351, 352, 360, 374, 376, 385 Iris, 311, 326, 352, 377 Irradiation, 164, 182, 352, 397 Irritable Bowel Syndrome, 352, 366 Ischemia, 30, 37, 52, 68, 74, 85, 102, 170, 171, 172, 188, 189, 192, 213, 312, 352, 362, 380 Islet, 30, 43, 236, 238, 253, 254, 352 Isoelectric, 98, 131, 352 Isoelectric Focusing, 98, 131, 352 Isoelectric Point, 352 Isoenzyme, 346, 352 Isotonic, 184, 221, 223, 352, 360 Isozymes, 67, 352, 378 J Jaundice, 36, 186, 255, 347, 352 Jejunostomy, 334, 353 Joint, 311, 353, 389

K Kallidin, 317, 353 Karyotype, 307, 353 Kb, 57, 113, 276, 353 Keto, 165, 353 Ketone Bodies, 303, 329, 353 Ketonuria, 246, 353 Ketosis, 329, 353 Keyhole, 171, 226, 353 Kidney Disease, 6, 13, 31, 38, 42, 48, 87, 159, 160, 162, 178, 235, 253, 261, 276, 282, 353 Kidney Failure, 26, 334, 353 Kidney Failure, Acute, 353 Kidney Failure, Chronic, 353 Kidney stone, 258, 353, 394 Kinetic, 64, 66, 82, 98, 133, 153, 165, 185, 225, 352, 353 L Labile, 30, 182, 323, 354 Lactation, 354, 375 Lactose Intolerance, 252, 354 Laminin, 314, 337, 354 Large Intestine, 323, 330, 351, 354, 379, 385 Laxative, 305, 354, 386 Lens, 319, 354, 396 Leptin, 4, 354 Lesion, 174, 213, 339, 354, 355, 361, 384, 393 Lethal, 327, 354 Leukemia, 176, 198, 207, 217, 282, 338, 354 Leukocytes, 184, 224, 314, 315, 316, 321, 335, 343, 350, 354, 370 Leukocytosis, 37, 354 Leukopenia, 354, 397 Leukotrienes, 170, 311, 354 Libido, 36, 354 Library Services, 294, 354 Life Expectancy, 248, 354 Ligament, 354, 376 Ligands, 68, 179, 185, 194, 212, 225, 241, 354 Ligation, 73, 97, 355 Linkage, 50, 64, 191, 355 Lipase, 34, 355, 366 Lipid A, 4, 355, 366 Lipid Peroxidation, 91, 355, 367 Lipid Peroxides, 123, 355 Lipophilic, 355, 372 Lipopolysaccharide, 92, 148, 343, 355 Lipoprotein, 4, 60, 170, 171, 220, 226, 332, 343, 355, 356

410 Hemoglobin

Liposome, 223, 355 Lipoxygenase, 354, 355 Liver cancer, 36, 306, 355 Liver Transplantation, 12, 117, 355 Localization, 52, 66, 68, 111, 348, 355 Localized, 52, 129, 174, 188, 193, 206, 321, 333, 344, 349, 354, 355, 361, 371, 383, 393, 394 Locomotion, 355, 371 Locus Control Region, 57, 73, 76, 355 Longitudinal study, 57, 84, 356 Long-Term Care, 16, 356 Loop, 98, 230, 350, 356 Low-density lipoprotein, 123, 129, 332, 355, 356 Lumen, 91, 334, 356 Luminescence, 73, 356 Lutein Cells, 356, 375 Lymph, 322, 326, 334, 346, 356 Lymphatic, 334, 349, 356, 386 Lymphatic system, 356, 386 Lymphocyte, 95, 138, 310, 356, 357, 358 Lymphocyte Count, 138, 356 Lymphoid, 309, 356 Lymphoma, 282, 356 Lymphoproliferative, 30, 356 Lysine, 107, 345, 347, 356 Lytic, 175, 184, 206, 207, 356, 384 M Macronutrients, 36, 38, 356 Macrophage, 350, 356 Magnetic Resonance Imaging, 66, 357, 364 Major Histocompatibility Complex, 343, 357 Malabsorption, 282, 357 Malaria, 84, 89, 95, 120, 153, 357 Malaria, Falciparum, 357 Malaria, Vivax, 357 Malignancy, 40, 303, 357, 367 Malignant, 146, 147, 282, 304, 310, 355, 357, 363, 378 Malnutrition, 16, 251, 306, 312, 357, 361 Mammography, 52, 357 Matrix metalloproteinase, 69, 147, 357 Mean blood pressure, 17, 357 Meat, 330, 357, 383, 385 Meat Products, 330, 357 Mediate, 76, 103, 123, 331, 357 Mediator, 70, 96, 199, 321, 350, 358, 384 Medical Records, 16, 17, 34, 358, 382 Medical Staff, 331, 358 MEDLINE, 277, 280, 283, 358

Medullary, 358, 377 Megacolon, 37, 358 Megaloblastic, 255, 339, 358 Melanin, 164, 173, 352, 358, 370, 393 Melanocytes, 358 Melanoma, 142, 282, 358 Melanosis, 303, 358 Membrane Glycoproteins, 358 Memory, 131, 217, 309, 358 Menopause, 236, 358, 373 Menorrhagia, 9, 358 Menstrual Cycle, 236, 358, 374 Menstruation, 9, 328, 358 Mental Disorders, 162, 358, 376 Mental Health, iv, 48, 162, 239, 276, 279, 358, 377 Mental Processes, 331, 358, 377 Mentors, 81, 358 Mercury, 338, 358 Mesenteric, 359, 373 Mesentery, 91, 359, 370, 386 Metabolic disorder, 247, 329, 359 Metabolite, 61, 183, 336, 359 Metastasis, 357, 359 Methanol, 202, 359 Methemoglobin Reductase, 119, 281, 359 Methylene Blue, 359 MI, 20, 22, 24, 33, 34, 38, 47, 61, 182, 235, 300, 359 Mice Minute Virus, 359, 368 Microbe, 359, 391 Microbiology, 59, 304, 313, 359 Microcirculation, 75, 80, 148, 344, 359 Micronutrients, 14, 36, 359 Microorganism, 323, 359, 368, 396 Micro-organism, 359, 384 Microscopy, 56, 68, 74, 91, 148, 303, 314, 359 Migration, 75, 360, 369 Mitochondria, 193, 360, 362, 366 Mitochondrial Swelling, 360, 362 Mitosis, 311, 360 Mixed Function Oxidases, 327, 360 Mobility, 215, 360 Mobilization, 131, 189, 360 Modeling, 6, 9, 89, 185, 225, 331, 360 Modulator, 95, 360 Molecular Structure, 136, 204, 360 Monoclonal, 46, 92, 231, 352, 360, 378, 397 Monoclonal antibodies, 92, 231, 360 Monocyte, 92, 142, 360 Monogenic, 208, 360

Index 411

Monophosphate, 190, 360 Monotherapy, 5, 35, 167, 361 Monounsaturated fat, 88, 361 Morphine, 361, 362 Morphological, 222, 333, 358, 361 Morphology, 8, 222, 344, 361 Motility, 8, 235, 341, 361, 384 Motion Sickness, 361, 362 Mouth Ulcer, 37, 361 Mucosa, 37, 91, 252, 321, 361, 375, 395 Mucus, 361, 393 Muscle Fibers, 361 Muscle Relaxation, 97, 361 Muscular Atrophy, 282, 361 Muscular Dystrophies, 332, 361 Mutagenesis, 49, 56, 64, 66, 78, 98, 361 Mutagenic, 61, 361, 364, 385 Mutagenicity, 61, 361 Mutagens, 361 Mydriatic, 330, 361, 397 Myelofibrosis, 202, 361 Myelosuppression, 160, 361 Myocardial infarction, 48, 192, 326, 359, 361, 362 Myocardial Ischemia, 192, 361 Myocardial Reperfusion, 362, 380 Myocardial Reperfusion Injury, 362, 380 Myocardium, 155, 191, 359, 361, 362, 396 Myoglobin, 63, 66, 88, 114, 153, 185, 188, 193, 204, 220, 222, 241, 257, 258, 341, 362, 373 Myotonic Dystrophy, 282, 362 N Naive, 166, 362 Narcosis, 362 Narcotic, 83, 361, 362 Nasogastric, 334, 362 Nausea, 38, 251, 340, 349, 353, 362, 394 NCI, 1, 162, 275, 322, 362 Necrosis, 181, 192, 311, 349, 359, 361, 362, 380, 384 Neonatal, 76, 133, 230, 237, 363 Neonatal period, 76, 363 Neoplasia, 246, 282, 363 Neoplasm, 363 Neoplastic, 9, 356, 363 Neoplastic Processes, 9, 363 Neostriatum, 363, 377 Nephropathy, 6, 31, 38, 42, 69, 92, 100, 235, 238, 239, 249, 253, 254, 261, 353, 363 Nerve Endings, 314, 363 Nerve Fibers, 314, 363

Nervous System, 216, 282, 303, 305, 306, 313, 314, 317, 320, 321, 340, 342, 354, 358, 361, 363, 366, 369, 384, 389, 390 Neural, 58, 74, 186, 305, 338, 346, 363, 369, 385 Neural tube defects, 338, 363 Neurologist, 81, 363 Neuronal, 51, 63, 74, 75, 81, 362, 363 Neurons, 63, 217, 328, 340, 363, 389 Neuropathy, 10, 29, 31, 38, 69, 235, 238, 239, 250, 253, 254, 261, 313, 363 Neurotransmitters, 360, 363 Neutrons, 306, 352, 363, 378 Neutrophil, 59, 75, 102, 364 Niche, 67, 364 Nitric Oxide, 5, 52, 67, 68, 69, 70, 78, 85, 90, 91, 93, 96, 104, 108, 110, 111, 113, 114, 124, 125, 127, 153, 161, 170, 185, 203, 204, 220, 221, 225, 265, 364 Nitrogen, 67, 93, 96, 99, 107, 128, 220, 306, 307, 311, 337, 342, 353, 364, 393 Nitrogen Oxides, 93, 96, 364 Nitrosamines, 364, 385 Nitrosation, 111, 364 Non-small cell lung cancer, 146, 364 Norepinephrine, 258, 305, 331, 364 Nuclear, 106, 131, 172, 176, 207, 227, 313, 325, 333, 336, 340, 362, 364, 381 Nuclear magnetic resonance imaging, 227, 364 Nuclei, 172, 173, 231, 306, 325, 332, 341, 357, 360, 363, 364, 366, 376 Nucleic acid, 346, 361, 364, 377, 382, 397 Nucleic Acid Hybridization, 346, 364 Nurse Practitioners, 42, 364 Nutritional Status, 16, 96, 365 Nutritional Support, 251, 340, 365 O Observational study, 18, 365 Occult, 245, 337, 365 Occult Blood, 246, 365 Ocular, 70, 365 Odour, 311, 365 Oliguria, 353, 365 Oncogene, 282, 365, 387 Oocytes, 220, 365 Opacity, 184, 319, 328, 365 Operating Rooms, 211, 365 Operon, 365, 380 Ophthalmic, 365, 381 Ophthalmic Artery, 365, 381 Ophthalmoscope, 365

412 Hemoglobin

Opsin, 365, 381 Optic Chiasm, 365, 366 Optic Disk, 186, 325, 329, 365 Optic Nerve, 70, 365, 366, 381 Optic nerve head, 70, 366 Oral Health, 245, 366 Oral Hygiene, 343, 366 Organelles, 320, 328, 358, 366, 381 Orlistat, 34, 366 Osmosis, 366 Osmotic, 79, 145, 188, 306, 360, 366, 384 Osmotic Fragility, 145, 366 Otitis, 67, 366 Otitis Media, 67, 366 Outpatient, 21, 22, 31, 33, 46, 250, 366 Ovary, 201, 336, 342, 366 Overall survival, 65, 366 Overexpress, 63, 68, 366 Overweight, 34, 35, 143, 237, 278, 366 Ovulation, 366, 382 Ovum, 328, 341, 366, 374, 375, 397 Ownership, 32, 366 Oxidation, 58, 66, 79, 81, 129, 132, 139, 175, 187, 202, 229, 303, 310, 327, 329, 345, 355, 367 Oxidative metabolism, 177, 305, 354, 367 Oxidative Stress, 69, 123, 172, 197, 198, 367 Oxides, 93, 364, 367 Oximetry, 70, 84, 89, 115, 126, 183, 230, 367 Oxygen Consumption, 367, 380 Oxygenase, 52, 63, 75, 113, 147, 367 Oxygenator, 318, 367 P Palliative, 367, 390 Pallor, 37, 255, 367 Palsy, 39, 367 Pancreas, 23, 180, 236, 237, 238, 254, 303, 315, 330, 344, 350, 352, 355, 367, 374, 386, 393 Pancreatic, 3, 118, 253, 282, 318, 321, 367 Pancreatic cancer, 282, 367 Papilla, 164, 367 Papillomavirus, 367 Paralysis, 367, 386 Parasite, 37, 84, 120, 153, 367, 368 Parasitic, 96, 109, 368 Parenteral, 170, 334, 368 Parietal, 8, 368, 370, 386 Parietal Lobe, 368, 386 Paroxysmal, 159, 282, 344, 368 Partial remission, 368, 380

Particle, 174, 231, 355, 368, 392 Parturition, 368, 375 Parvovirus, 135, 359, 368 Patch, 81, 85, 325, 368 Pathogen, 110, 349, 368 Pathogenesis, 54, 59, 63, 68, 79, 84, 95, 103, 254, 368 Pathologic, 50, 172, 252, 303, 308, 311, 315, 326, 347, 368, 376, 380 Pathologic Processes, 311, 368 Pathologies, 197, 368 Pathophysiology, 51, 56, 93, 97, 240, 246, 254, 259, 368 Patient Care Team, 239, 256, 368 Patient Compliance, 48, 368 Patient Education, 26, 253, 262, 267, 286, 292, 294, 301, 368 Patient Participation, 239, 368 Pelvic, 22, 368, 376 Penicillin, 309, 368, 395 Penile Prosthesis, 30, 368 Peptic, 368, 369, 383 Peptic Ulcer, 369, 383 Peptic Ulcer Hemorrhage, 369, 383 Peptide, 4, 14, 30, 45, 54, 130, 133, 205, 248, 259, 321, 354, 369, 373, 376, 388 Percutaneous, 192, 307, 369 Perforation, 37, 310, 339, 369 Perfusion, 51, 75, 131, 181, 192, 348, 369 Pericardium, 369, 396 Perinatal, 237, 369 Periodicity, 173, 369 Periodontal disease, 59, 369 Periodontal Pocket, 59, 369 Periodontitis, 59, 69, 369 Peripheral blood, 76, 111, 160, 176, 179, 207, 344, 350, 369 Peripheral Nervous System, 367, 369, 388, 395 Peripheral Vascular Disease, 129, 254, 369 Peritoneal, 142, 196, 233, 311, 330, 332, 351, 369 Peritoneal Cavity, 196, 311, 351, 369 Peritoneal Dialysis, 142, 233, 330, 332, 369 Peritoneum, 359, 369, 370 Perivascular, 85, 370 Pernicious, 187, 216, 223, 245, 255, 358, 370 Pernicious anemia, 187, 216, 223, 255, 370 Peroxidase, 63, 99, 355, 370 Peroxide, 370 Petrolatum, 333, 370 Pharmacist, 132, 256, 370

Index 413

Pharmacokinetic, 81, 370 Pharmacologic, 42, 53, 62, 83, 103, 132, 181, 247, 253, 262, 308, 343, 370, 392 Pharmacotherapy, 46, 370 Phenolphthalein, 333, 370 Phenotype, 56, 64, 84, 92, 104, 324, 370 Phenylalanine, 165, 370, 393 Phenylbutyrate, 271, 370 Phenylthiohydantoin, 72, 370 Phlebotomy, 134, 370 Phosphates, 258, 370 Phospholipids, 337, 355, 370 Phosphorus, 317, 371 Phosphorylates, 93, 371 Phosphorylation, 73, 93, 185, 225, 371, 378 Photocoagulation, 257, 322, 371 Photodynamic therapy, 81, 371 Phototherapy, 186, 371 Physical Examination, 29, 37, 41, 236, 251, 256, 257, 371 Physical Fitness, 336, 371 Physiology, 58, 71, 90, 92, 98, 115, 117, 127, 129, 130, 142, 172, 243, 333, 344, 371 Pigment, 160, 174, 193, 255, 314, 358, 362, 365, 371 Pigmentation, 36, 228, 358, 371 Pilot study, 32, 82, 119, 371 Placenta, 22, 336, 371, 374, 393 Plants, 77, 104, 132, 306, 311, 317, 318, 321, 322, 342, 361, 364, 371, 382, 392 Plaque, 59, 188, 309, 371 Plasma cells, 309, 371 Plasma expander, 75, 190, 194, 195, 196, 371 Plasma protein, 168, 223, 244, 306, 334, 371, 376, 384 Plasma Volume, 129, 153, 190, 316, 372 Plasticity, 123, 345, 372 Platelet Aggregation, 185, 308, 364, 372, 391 Platelet Count, 125, 160, 372 Plateletpheresis, 125, 372 Platelets, 57, 169, 211, 219, 319, 361, 364, 372, 384, 390, 391 Platinum, 322, 356, 372 Plethysmography, 177, 372 Podiatrist, 256, 372 Point Mutation, 64, 100, 110, 372 Poisoning, 202, 300, 321, 351, 359, 362, 372, 385 Polychlorinated Biphenyls, 117, 372 Polycystic, 42, 282, 372

Polydipsia, 42, 372 Polyethylene, 75, 80, 135, 219, 372 Polymerase, 372, 380 Polymers, 72, 172, 198, 200, 205, 372, 376 Polypeptide, 99, 204, 307, 323, 338, 346, 362, 373, 375, 376, 390, 395, 397 Polyphagia, 42, 373 Polyposis, 323, 373 Polysaccharide, 199, 205, 310, 320, 373, 376 Polyuria, 42, 373 Porphyria, 247, 370, 373 Porphyria Cutanea Tarda, 370, 373 Porphyrins, 105, 247, 258, 373 Port, 228, 373 Port-a-cath, 373 Portal Vein, 30, 373 Posterior, 308, 311, 312, 321, 352, 367, 373, 386 Postmenopausal, 4, 7, 60, 373 Postnatal, 373, 387 Postoperative, 9, 209, 340, 373 Postprandial, 3, 6, 10, 11, 19, 20, 28, 29, 38, 39, 43, 44, 167, 373 Postprandial Blood Glucose, 28, 29, 43, 373 Post-traumatic, 102, 343, 373 Potassium, 52, 85, 200, 217, 258, 306, 373, 374 Potassium Channels, 52, 374 Potassium Cyanide, 200, 217, 374 Potentiates, 350, 374 Practice Guidelines, 233, 279, 374 Precipitation, 55, 374 Preclinical, 50, 83, 374 Precursor, 61, 130, 179, 311, 331, 332, 334, 364, 370, 374, 376, 393, 395 Prenatal, 84, 133, 180, 208, 333, 341, 374 Prevalence, 18, 20, 29, 33, 41, 83, 175, 216, 254, 278, 374 Private Sector, 42, 374 Probe, 91, 92, 188, 189, 207, 374 Problem Solving, 32, 235, 374 Proctosigmoidoscopy, 37, 374 Progeny, 64, 179, 208, 325, 374 Progesterone, 374, 375, 387 Prognostic factor, 125, 374 Progression, 15, 35, 36, 38, 44, 48, 59, 65, 69, 87, 249, 257, 309, 374, 393 Progressive, 9, 167, 319, 321, 332, 343, 353, 361, 362, 374, 380 Proinsulin, 14, 374, 377 Projection, 150, 364, 366, 375, 379

414 Hemoglobin

Prolactin, 30, 375 Proliferative Retinopathy, 257, 375 Proline, 58, 323, 347, 375 Promoter, 50, 78, 95, 101, 102, 375 Prone, 159, 375 Prophase, 365, 375 Prophylaxis, 375, 381, 394 Proportional, 38, 87, 213, 215, 375 Prospective study, 40, 356, 375 Prostaglandin, 98, 375, 391 Prostaglandins A, 375 Prostate, 282, 315, 375, 392, 393 Protease, 107, 127, 218, 323, 376 Protein Conformation, 58, 307, 376 Protein S, 15, 58, 63, 66, 93, 112, 116, 136, 243, 283, 315, 376, 390 Proteinuria, 47, 69, 376 Proteoglycans, 314, 337, 376 Proteolytic, 323, 338, 376 Prothrombin, 376, 390 Protocol, 30, 50, 52, 86, 88, 91, 376 Protons, 202, 306, 347, 352, 376, 378 Protozoa, 315, 325, 359, 376 Proximal, 66, 99, 101, 102, 192, 300, 331, 376 Psoriasis, 172, 376, 381 Psychiatric, 8, 358, 376 Psychiatry, 376, 388, 395 Psychic, 354, 377, 383 Psychogenic, 29, 377 Psychology, 243, 252, 331, 377 Psychomotor, 42, 377 Puberty, 249, 252, 377 Public Health, 47, 85, 86, 103, 118, 126, 135, 137, 242, 243, 263, 279, 377 Public Policy, 277, 377 Public Sector, 10, 377 Publishing, 9, 15, 17, 22, 35, 36, 37, 38, 48, 104, 185, 191, 258, 377 Pulmonary, 70, 93, 102, 172, 213, 315, 325, 353, 354, 377, 381, 389, 395, 396 Pulmonary Artery, 70, 315, 377, 396 Pulmonary Edema, 353, 377 Pulmonary hypertension, 93, 377 Pulse, 84, 89, 126, 139, 164, 173, 174, 183, 208, 209, 230, 251, 360, 367, 377 Punctures, 186, 377 Pupil, 186, 326, 330, 361, 377 Purified Insulins, 374, 377 Purines, 70, 377, 384 Purpura, 255, 377 Purulent, 303, 377

Putamen, 63, 313, 363, 377 Pyruvate Kinase, 165, 378 Q Quality of Life, 13, 36, 56, 69, 80, 86, 121, 131, 134, 378 Quaternary, 73, 111, 133, 175, 207, 376, 378 Quiescent, 76, 378 R Race, 13, 229, 353, 360, 378 Radiation therapy, 65, 131, 137, 303, 337, 339, 351, 352, 378, 397 Radioactive, 82, 343, 347, 348, 351, 352, 360, 364, 378, 397 Radiography, 37, 378 Radioimmunoassay, 68, 378 Radioimmunotherapy, 378, 379 Radioisotope, 335, 378 Radiolabeled, 352, 378, 397 Radiological, 369, 378 Radiosensitization, 229, 378 Radiotherapy, 125, 146, 317, 352, 378, 397 Randomized, 7, 13, 22, 31, 34, 35, 37, 44, 60, 61, 80, 86, 120, 121, 137, 147, 148, 332, 379 Randomized clinical trial, 31, 80, 137, 148, 379 Reabsorption, 258, 379 Reaction Time, 231, 379 Reactivation, 62, 94, 101, 103, 379 Reactive Oxygen Species, 5, 63, 91, 107, 379 Reagent, 103, 166, 170, 175, 178, 184, 197, 198, 206, 207, 217, 221, 379, 385 Recombination, 325, 379 Reconstitution, 76, 379 Rectum, 310, 316, 323, 330, 338, 340, 349, 354, 374, 376, 379 Recur, 369, 379 Recurrence, 12, 369, 379 Red Nucleus, 312, 379 Reductase, 99, 106, 300, 379 Refer, 1, 237, 323, 340, 344, 355, 362, 363, 378, 379 Refraction, 379, 386 Refractory, 62, 332, 380 Regeneration, 222, 379, 380 Regimen, 10, 11, 17, 31, 41, 43, 62, 201, 216, 262, 332, 368, 370, 380 Regurgitation, 38, 344, 380 Relapse, 11, 380 Relative risk, 303, 380 Relaxant, 220, 221, 380

Index 415

Remission, 252, 379, 380 Renal failure, 23, 148, 380 Renal pelvis, 353, 380 Reperfusion, 74, 154, 171, 172, 189, 191, 192, 362, 380 Reperfusion Injury, 171, 172, 189, 191, 192, 380 Repressor, 67, 103, 365, 380 Reproductive cells, 341, 380 Resorption, 369, 379, 380 Respiration, 186, 310, 318, 360, 380, 381 Respirator, 380, 395 Respiratory failure, 381, 395 Respiratory Physiology, 381, 395 Respiratory System, 381, 395 Restoration, 68, 111, 362, 379, 380, 381, 397 Resuscitation, 170, 190, 195, 237, 381 Reticulocytes, 93, 335, 381 Retina, 9, 70, 186, 257, 321, 324, 325, 329, 354, 365, 366, 375, 381, 382, 396 Retinal, 9, 19, 70, 185, 186, 329, 365, 366, 381, 396 Retinal Artery, 70, 381 Retinal Ganglion Cells, 366, 381 Retinal Vessels, 186, 381 Retinoblastoma, 282, 381 Retinoids, 381, 396 Retinol, 381 Retinopathy, 9, 10, 26, 28, 31, 38, 44, 47, 69, 100, 230, 235, 238, 253, 254, 256, 257, 329, 381 Retrospective, 25, 46, 381, 382 Retrospective study, 25, 382 Retrovirus, 191, 382 Rheumatism, 382 Rheumatoid, 40, 202, 382 Rheumatoid arthritis, 202, 382 Rhythm Method, 236, 382 Ribavirin, 11, 12, 15, 35, 126, 382 Ribonucleic acid, 85, 382 Ribonucleoside Diphosphate Reductase, 347, 382 Ribose, 304, 382 Rigidity, 72, 371, 382 Risk factor, 6, 7, 8, 9, 12, 21, 34, 42, 45, 60, 77, 87, 235, 257, 261, 262, 375, 380, 382 Risk patient, 132, 382 Rod, 313, 322, 382 Rosiglitazone, 167, 382 Rubber, 303, 382 Rural Population, 24, 382

S Saline, 223, 382 Salivary, 327, 330, 367, 382 Salivary glands, 327, 330, 382 Saponins, 382, 387 Saturated fat, 60, 88, 383 Scatter, 183, 184, 211, 221, 383 Schistosoma, 111, 121, 383 Schizoid, 383, 397 Schizophrenia, 383, 397 Schizotypal Personality Disorder, 383, 397 Sclerosis, 282, 383 Sclerotherapy, 173, 383 Secretion, 3, 8, 30, 146, 167, 326, 346, 350, 354, 361, 383, 394 Secretory, 96, 319, 383 Secretory Vesicles, 319, 383 Sediment, 257, 383, 394 Seizures, 368, 383 Self Care, 40, 236, 239, 304, 383 Semen, 376, 383 Sensor, 6, 58, 182, 183, 189, 209, 226, 227, 350, 383 Sepsis, 91, 172, 340, 384 Sequence Analysis, 87, 384 Sequencing, 62, 109, 384 Sequester, 321, 384 Serine, 96, 384 Serologic, 86, 348, 384 Serotonin, 370, 384, 393 Serous, 334, 384 Serum Albumin, 16, 20, 91, 202, 315, 378, 384 Sex Characteristics, 305, 377, 384, 390 Sex Determination, 282, 384 Sharpness, 384, 396 Shedding, 92, 142, 384 Shock, 75, 102, 136, 170, 172, 187, 188, 190, 195, 196, 216, 223, 255, 308, 347, 384, 392 Shock, Septic, 187, 216, 223, 384 Sickle Cell Trait, 56, 128, 384 Sigmoid, 385 Sigmoidoscope, 374, 385 Sigmoidoscopy, 37, 385 Signs and Symptoms, 16, 36, 234, 235, 255, 380, 385 Sister Chromatid Exchange, 119, 385 Skeletal, 193, 322, 361, 385, 390 Skeleton, 304, 353, 375, 385 Skin Pigmentation, 36, 385 Skull, 183, 326, 363, 385, 390 Small cell lung cancer, 385

416 Hemoglobin

Small intestine, 322, 332, 346, 351, 362, 385 Smooth muscle, 85, 97, 161, 212, 220, 221, 308, 317, 325, 346, 361, 385, 388 Sneezing, 384, 385 Social Environment, 378, 385 Social Support, 10, 239, 385, 388 Sodium, 83, 136, 142, 217, 236, 258, 271, 306, 366, 379, 385, 395 Sodium Channels, 385, 395 Sodium Nitrite, 142, 385 Soft tissue, 316, 385 Solid tumor, 308, 386 Solvent, 88, 303, 314, 359, 366, 386 Somatic, 305, 333, 346, 360, 369, 385, 386, 394 Somatosensory Cortex, 51, 81, 386 Sorbitol, 346, 386 Spastic, 68, 352, 386 Spasticity, 386 Specialist, 17, 288, 330, 386 Specificity, 81, 99, 105, 305, 386 Spectrometer, 72, 386 Spectrophotometry, 91, 129, 167, 178, 193, 198, 386 Spectrum, 18, 28, 88, 173, 176, 194, 221, 250, 386 Sperm, 321, 380, 386 Spinal cord, 312, 320, 321, 340, 363, 369, 386, 389 Spleen, 36, 142, 327, 356, 386 Splenic Vein, 373, 386 Sporadic, 373, 381, 386 Squamous, 364, 386, 387 Squamous cell carcinoma, 364, 387 Stabilization, 89, 93, 113, 205, 387 Statistically significant, 35, 387 Steady state, 77, 387 Steel, 322, 387, 393 Stem Cell Factor, 159, 160, 322, 387 Stem cell transplantation, 50, 158, 344, 387 Stem Cells, 76, 94, 103, 179, 336, 344, 387 Sterile, 194, 387 Sterilization, 236, 387 Steroid, 252, 314, 326, 382, 387 Steroid therapy, 252, 387 Stimulant, 317, 346, 353, 387, 395 Stimulus, 53, 70, 325, 331, 332, 336, 351, 379, 387, 390 Stomach, 8, 10, 235, 303, 314, 330, 336, 340, 342, 346, 353, 362, 369, 385, 386, 387 Stool, 37, 245, 337, 349, 352, 354, 387, 390 Strand, 56, 372, 387

Streptococcal, 116, 387 Streptococcus, 387, 388 Stress management, 239, 388 Stroke, 47, 53, 74, 75, 96, 162, 171, 172, 217, 261, 276, 318, 388 Stroke Volume, 318, 388 Stroma, 74, 178, 195, 196, 211, 212, 228, 352, 388 Stromal, 178, 194, 196, 211, 388 Stupor, 298, 362, 388 Subacute, 349, 388 Subarachnoid, 68, 85, 343, 388 Subclinical, 349, 383, 388 Subcutaneous, 6, 7, 44, 201, 227, 247, 304, 332, 368, 388 Subspecies, 386, 388 Substance P, 359, 379, 383, 388 Substrate, 171, 226, 327, 335, 360, 388 Suction, 338, 388 Superantigens, 254, 388 Superoxide, 152, 154, 192, 212, 388 Superoxide Dismutase, 152, 192, 388 Supplementation, 5, 137, 147, 148, 236, 389 Support group, 239, 389 Suppression, 15, 35, 78, 88, 170, 259, 326, 341, 389, 397 Suppressive, 95, 389 Surfactant, 175, 198, 207, 221, 389 Survival Rate, 366, 389 Suspensions, 193, 389 Sympathetic Nervous System, 216, 313, 389 Sympathomimetic, 331, 335, 364, 389 Symphysis, 376, 389 Symptomatic, 12, 49, 127, 389 Symptomatology, 384, 389 Synergistic, 375, 389 Systemic disease, 245, 389 Systolic, 34, 45, 192, 347, 357, 389 Systolic blood pressure, 34, 45, 389 Systolic pressure, 357, 389 T T cell, 47, 351, 389 Tachycardia, 37, 313, 389 Teaching Materials, 32, 389 Telangiectasia, 282, 390 Temporal, 51, 81, 343, 390 Tenesmus, 37, 390 Terminator, 323, 390, 397 Testicular, 36, 390 Testis, 336, 390 Testosterone, 30, 379, 390

Index 417

Tetracycline, 69, 331, 390 Thalamic, 312, 390 Thalamic Diseases, 312, 390 Thalassemia, 49, 55, 83, 157, 158, 160, 182, 202, 208, 240, 262, 314, 390 Theophylline, 377, 390 Therapeutics, 4, 10, 37, 122, 128, 135, 146, 165, 174, 175, 270, 390 Thermal, 164, 169, 173, 174, 202, 223, 228, 331, 363, 390 Thinness, 24, 390 Thoracic, 137, 390, 397 Threonine, 384, 390 Threshold, 21, 48, 87, 146, 152, 181, 347, 390 Thrombin, 74, 338, 372, 376, 390, 391 Thrombocytes, 184, 372, 390 Thromboembolism, 349, 391 Thrombomodulin, 376, 391 Thrombosis, 30, 142, 147, 376, 383, 388, 391 Thromboxanes, 311, 391 Thrombus, 326, 349, 361, 362, 372, 391 Thyroid, 8, 22, 30, 250, 255, 391, 393 Thyroxine, 306, 370, 391 Time Management, 388, 391 Tinnitus, 366, 391 Tissue Survival, 75, 391 Tolerance, 21, 28, 30, 50, 87, 248, 254, 304, 342, 391 Tomography, 51, 71, 391 Tonicity, 345, 352, 391 Tooth Preparation, 304, 391 Topical, 136, 164, 172, 347, 370, 391 Torsion, 349, 391 Tourniquet, 227, 391 Toxicology, 117, 146, 147, 278, 392 Toxins, 197, 198, 310, 349, 360, 378, 392 Trachea, 317, 391, 392 Traction, 322, 392 Transcriptase, 382, 392 Transcription Factors, 99, 101, 392 Transcutaneous, 349, 392 Transduction, 76, 109, 392 Transfection, 103, 113, 315, 392 Transferases, 342, 392 Transfusion, 52, 62, 102, 120, 131, 132, 159, 161, 190, 191, 196, 213, 228, 266, 286, 337, 392 Transgenes, 64, 191, 392 Transillumination, 189, 193, 392 Translational, 51, 57, 93, 94, 341, 392

Transmitter, 303, 312, 331, 351, 358, 364, 392 Transplantation, 12, 23, 30, 51, 117, 158, 179, 238, 253, 254, 322, 353, 357, 392 Transplantation Tolerance, 51, 392 Transurethral, 131, 392 Transurethral Resection of Prostate, 131, 392 Trauma, 92, 102, 168, 170, 172, 178, 211, 228, 362, 392 Triglyceride, 46, 347, 392 Troglitazone, 45, 167, 393 Tryptophan, 323, 384, 393 Tuberculosis, 98, 104, 105, 110, 325, 393 Tuberous Sclerosis, 282, 393 Tumor marker, 315, 393 Tumor model, 81, 393 Tungsten, 319, 393 Tyrosine, 67, 331, 393 U Ubiquitin, 93, 393 Ulcer, 103, 369, 393, 395 Ulcerative colitis, 4, 37, 251, 349, 393 Ultrasonography, 236, 393 Umbilical Arteries, 393 Umbilical Cord, 23, 393 Unconscious, 308, 348, 393 Unresectable, 118, 393 Urea, 166, 167, 224, 258, 353, 393, 394 Uremia, 353, 380, 394 Ureters, 353, 394 Urethra, 375, 392, 394 Uric, 7, 258, 377, 394 Urinalysis, 224, 257, 394 Urinary, 44, 61, 88, 201, 246, 257, 313, 349, 365, 373, 394 Urine Testing, 235, 251, 394 Urobilinogen, 224, 258, 394 Uroporphyrinogen Decarboxylase, 247, 373, 394 Urticaria, 202, 308, 394 Uterus, 307, 321, 328, 333, 340, 358, 374, 394 V Vaccination, 109, 112, 394 Vaccine, 59, 103, 117, 304, 376, 394 Vacuoles, 333, 366, 394 Vagal, 84, 394 Vagina, 300, 321, 358, 394 Vagus Nerve, 394 Valine, 72, 107, 138, 395 Valproic Acid, 128, 395

418 Hemoglobin

Valves, 169, 395, 396 Varicose, 383, 395 Varicose vein, 383, 395 Vascular endothelial growth factor, 146, 395 Vascular Resistance, 170, 206, 395 Vasculitis, 40, 395 Vasoactive, 54, 97, 170, 395 Vasoactive Intestinal Peptide, 97, 395 Vasoconstriction, 53, 70, 75, 185, 196, 335, 395 Vasodilation, 53, 212, 220, 255, 395 Vasodilator, 68, 161, 212, 317, 331, 346, 362, 395 Vasomotor, 68, 102, 395 Vector, 392, 395 Vein, 39, 70, 77, 178, 189, 228, 308, 311, 351, 364, 370, 373, 386, 393, 395 Venous, 69, 84, 177, 183, 206, 227, 311, 315, 345, 372, 376, 395 Venous blood, 177, 315, 372, 395 Ventilation, 187, 381, 395 Ventilator, 84, 187, 230, 380, 395 Ventricle, 377, 389, 396 Ventricular, 134, 192, 362, 396 Ventricular Pressure, 192, 396 Venules, 316, 318, 334, 359, 396 Vertigo, 366, 396 Veterinary Medicine, 263, 277, 396 Viral, 11, 15, 35, 76, 382, 392, 396, 397 Viral vector, 76, 396 Viremia, 384, 396 Virulence, 104, 312, 391, 396 Virus, 11, 12, 68, 127, 191, 201, 313, 320, 334, 341, 346, 350, 371, 389, 392, 396

Viscera, 359, 386, 396 Visceral, 313, 370, 394, 396 Viscosity, 52, 75, 79, 88, 117, 316, 396 Visual Acuity, 44, 396 Vitamin A, 236, 381, 396 Vitreous Body, 381, 396 Vitreous Hemorrhage, 30, 329, 396 Vitro, 54, 55, 62, 65, 68, 72, 73, 78, 80, 82, 91, 93, 95, 96, 100, 101, 104, 127, 136, 147, 160, 179, 180, 186, 196, 220, 316, 348, 396 W Warts, 346, 397 Weight Gain, 35, 44, 236, 247, 397 Wettability, 202, 397 White blood cell, 40, 176, 184, 187, 207, 219, 221, 309, 354, 356, 360, 361, 364, 371, 389, 397 Windpipe, 391, 397 Withdrawal, 12, 397 Womb, 160, 394, 397 Wound Healing, 67, 69, 357, 397 X Xenograft, 309, 393, 397 X-ray, 37, 66, 119, 139, 154, 319, 339, 340, 352, 364, 378, 397 X-ray therapy, 352, 397 Y Yeasts, 340, 370, 397 Yohimbine, 30, 397 Z Zidovudine, 201, 397 Zygote, 324, 325, 397 Zymogen, 376, 397

Index 419

420 Hemoglobin

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