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

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

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

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2003 by ICON Group International, Inc. Copyright 2003 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., 1960Blood Tests: 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: 0-597-83795-3 1. Blood Tests-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 blood tests. 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 BLOOD TESTS ............................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Blood Tests .................................................................................. 15 E-Journals: PubMed Central ....................................................................................................... 28 The National Library of Medicine: PubMed ................................................................................ 29 CHAPTER 2. NUTRITION AND BLOOD TESTS .................................................................................. 57 Overview...................................................................................................................................... 57 Finding Nutrition Studies on Blood Tests................................................................................... 57 Federal Resources on Nutrition ................................................................................................... 58 Additional Web Resources ........................................................................................................... 58 CHAPTER 3. DISSERTATIONS ON BLOOD TESTS .............................................................................. 61 Overview...................................................................................................................................... 61 Dissertations on Blood Tests........................................................................................................ 61 Keeping Current .......................................................................................................................... 61 CHAPTER 4. PATENTS ON BLOOD TESTS ......................................................................................... 63 Overview...................................................................................................................................... 63 Patents on Blood Tests ................................................................................................................. 63 Patent Applications on Blood Tests ............................................................................................. 78 Keeping Current .......................................................................................................................... 85 CHAPTER 5. BOOKS ON BLOOD TESTS ............................................................................................ 87 Overview...................................................................................................................................... 87 Book Summaries: Federal Agencies.............................................................................................. 87 Book Summaries: Online Booksellers........................................................................................... 91 Chapters on Blood Tests............................................................................................................... 93 CHAPTER 6. MULTIMEDIA ON BLOOD TESTS .................................................................................. 95 Overview...................................................................................................................................... 95 Video Recordings ......................................................................................................................... 95 Audio Recordings......................................................................................................................... 97 Bibliography: Multimedia on Blood Tests.................................................................................... 98 CHAPTER 7. PERIODICALS AND NEWS ON BLOOD TESTS ............................................................... 99 Overview...................................................................................................................................... 99 News Services and Press Releases................................................................................................ 99 Newsletter Articles .................................................................................................................... 101 Academic Periodicals covering Blood Tests ............................................................................... 103 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 105 Overview.................................................................................................................................... 105 U.S. Pharmacopeia..................................................................................................................... 105 Commercial Databases ............................................................................................................... 107 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 111 Overview.................................................................................................................................... 111 NIH Guidelines.......................................................................................................................... 111 NIH Databases........................................................................................................................... 113 Other Commercial Databases..................................................................................................... 119 APPENDIX B. PATIENT RESOURCES ............................................................................................... 121 Overview.................................................................................................................................... 121 Patient Guideline Sources.......................................................................................................... 121 Finding Associations.................................................................................................................. 128 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 131 Overview.................................................................................................................................... 131

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Preparation................................................................................................................................. 131 Finding a Local Medical Library................................................................................................ 131 Medical Libraries in the U.S. and Canada ................................................................................. 131 ONLINE GLOSSARIES................................................................................................................ 137 Online Dictionary Directories ................................................................................................... 137 BLOOD TESTS DICTIONARY................................................................................................... 139 INDEX .............................................................................................................................................. 203

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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 blood tests 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 blood tests, 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 blood tests, 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 blood tests. 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 blood tests, 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 blood tests. 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 BLOOD TESTS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on blood tests.

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

Understanding Pancreatitis and Pancreatic Cancer Source: Digestive Health and Nutrition. 3(3): 17-20. May-June 2001. Contact: Available from American Gastroenterological Association. 7910 Woodmont Avenue, 7th Floor, Bethesda, MD 20814. (877) DHN-4YOU or (301) 654-2055, ext. 650. Email: [email protected]. Summary: Acute pancreatitis (inflammation of the pancreas) can happen to anyone, anytime. However, repeated episodes put the patient at risk for chronic pancreatitis and pancreatic cancer, so it is important to learn about the risk factors and symptoms of these diseases. This article reviews the presenting symptoms of pancreatitis, the anatomy and physiology of the healthy pancreas, treatment options, and the risk factors for pancreatic cancer. The most common cause of acute pancreatitis is gallstones that get

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caught at the opening into the small intestine. Excessive alcohol use is another common cause of the disease. Diagnosis can include blood tests, an abdominal CT (computed tomography) scan, and endoscopic ultrasound. Treatment for acute pancreatitis is usually relatively low tech, featuring hydration (adequate fluids), pain management, and nutrition support (intravenous). During an episode of acute pancreatitis, which can last days or even a week, patients usually do not eat any food at all initially. Clear liquids and then low fat foods are added gradually as symptoms improve. When gallstones cause pancreatitis, surgery to remove them is usually necessary. For those who already have chronic pancreatitis or are at risk for developing it, a healthy lifestyle and positive attitude are essential. Many people with pancreatitis find that a low fat diet helps reduce the severity of acute episodes and also slows the progression of the chronic disease. One sidebar offers a description of hereditary pancreatitis, which is a rare condition. The final section of the article discusses pancreatic cancer, noting that both chronic and hereditary pancreatitis put people at higher risk for developing pancreatic cancer. Appended to the article is a list of websites for readers who want to locate additional information about pancreatitis. 2 figures. •

Gastrointestinal Safety and Tolerance of Ibuprofen at Maximum Over-the-Counter Dose Source: Alimentary Pharmacology and Therapeutics. 13(7): 897-906. July 1999. 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: Determining nonsteroidal antiinflammatory drug (NSAID) gastrointestinal toxicity has largely depended on retrospective epidemiologic studies that demonstrate that lower doses of NSAIDs pose a lower risk of gastrointestinal toxicity. Ibuprofen, a proprionic acid NSAID has, in most such studies, exhibited a favorable profile in terms of gastrointestinal bleeding. This article reports on a study that prospectively evaluated the gastrointestinal tolerability, as compared to placebo, of the maximum nonprescription dose and duration of ibuprofen use in healthy subjects representative of a nonprescription analgesic user population. Gastrointestinal adverse experiences were similar in the placebo and ibuprofen groups (67 out of 413 patients, 16 percent with placebo versus 161 out of 833 patients, 19 percent with ibuprofen). There was no difference between the two groups in the proportion discontinuing due to a gastrointestinal event. Gastrointestinal adverse experiences reported by more than 1 percent of subjects were dyspepsia (heartburn), abdominal pain, nausea, diarrhea, flatulence (gas), and constipation. Seventeen (1.4 percent) subjects had positive occult blood tests; their frequency was comparable between treatments. The authors conclude that, when used as directed to treat episodic pain, nonprescription ibuprofen at the maximum dose (1200 mg per day for 10 days) is well tolerated. 4 tables. 22 references.

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Post-Treatment Diagnostic Accuracy of a New Enzyme Immunoassay to Detect Helicobacter Pylori in Stools Source: Alimentary Pharmacology and Therapeutics. 15(3): 395-401. March 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: Helicobacter pylori has attracted increasing attention among gastroenterologists because of its pathogenic (disease causing) potential, stimulating the

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search for non invasive diagnostic tests. This article reports on a study undertaken to evaluate the efficacy of a new enzyme immunoassay designed to detect H. pylori antigens in stools (HpSA), before and after eradication therapy. HpSA was performed on stool samples collected from 268 patients whose H. pylori status was defined on the basis of concordant results for the 13C urea breath test, rapid urease test, and histology. The H. pylori positive patients were treated with a 1 week triple therapy to eradicate the infection. One (T30) and 3 months (T90) after the end of therapy. 13C urea breath tests and HpSA were repeated in the treated patients. The overall diagnostic accuracy of HpSA at T30 (83 percent) was significantly lower in comparison to the values obtained at baseline (94 percent) and at T90 (97 percent). No significant difference was found between the diagnostic accuracy of HpSA at baseline and at T90. The authors conclude that these data suggest HpSA provides a low diagnostic accuracy when used shortly after treatment. It needs a longer period of followup (8 to 12 weeks) to reach a reliability comparable to the 13C urea breath test. In regards to the issue of cost effectiveness, the kit and technical support for the HpSA is approximately $27 per test; this cost is higher than serology (blood tests), which cannot be reliably used in the post treatment phase, but lower than the 13C urea breath test, at approximately $50. The authors believe that HpSA can be reasonably included among non invasive tests as an accurate and cost effective alternative to the 13C urea breath test for the pretreatment diagnosis of H. pylori infection; for the assessment of eradication, it can be highly reliable, provided that it is performed 3 months after the end of treatment. 5 figures. 25 references. •

Noninvasive Monitoring of Patients with Chronic Hepatitis C Source: Hepatology. 36(5 Supplemental 1): S57-S64. November 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Hepatic (liver) fibrosis is the main determinant of clinical outcomes of chronic hepatitis C. Liver biopsy is frequently considered the gold standard for assessing hepatic fibrosis. However, liver biopsy is associated with sampling error, interobserver variability, and potential complications. This article considers the options for noninvasive monitoring of and assessing disease severity in patients with chronic hepatitis C. Clinical examination is unreliable in differentiating different stages of compensated liver disease. Among the routine laboratory tests, decreased platelet count, increase in the ratio of aspartate to alanine aminotransferase (AST ALT), and prolonged prothrombin time are the earliest indicators of cirrhosis and portal hypertension. Individual serum fibrosis markers (blood tests) have limited accuracy in predicting hepatic fibrosis. Indices composed of a panel of markers correlate better with histological fibrosis, but their reliability requires further validation. Currently, noninvasive monitoring of patients with chronic hepatitis C relies on clinical evaluation, routine laboratory tests, and ultrasound and endoscopic surveillance in patients with cirrhosis. Initial evaluation should focus on assessment of activity and stage of liver disease for prognosis and decisions regarding treatment, and to rule out coinfections and other causes of liver disease. Subsequent follow up should focus on detection of liver disease progression and the need for treatment. The frequency of monitoring and the tests used will depend on the patient's age, stage of liver disease, and comorbid conditions. The authors conclude that there is an urgent need to develop and validate noninvasive tests that can accurately reflect the full spectrum of hepatic inflammation and fibrosis in chronic hepatitis C. 5 tables. 37 references.

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Hemorrhoids and More: Common Causes of Blood in the Stool Source: Digestive Health and Nutrition. 3(4): 24-26. July-August 2001. Contact: Available from American Gastroenterological Association. 7910 Woodmont Avenue, 7th Floor, Bethesda, MD 20814. (877) DHN-4YOU or (301) 654-2055, ext. 650. Email: [email protected]. Summary: Most rectal bleeding is caused by hemorrhoids, which usually can be simply and effectively treated. This article reviews the many other conditions, including some serious disorders, that can cause blood in the stool. The author reminds readers that bleeding from any part of the nearly 40 foot long digestive tract can cause blood in the stool. Accurate and timely diagnostic tests are important to determine the cause of any bleeding. Bleeding higher up in the gut, from the esophagus or stomach, can result in stools with a black, tarry appearance. Bleeding from the lower end, such as the colon, or in large amounts, can appear as pure blood, blood clots, or as blood mixed with or streaking the stool. Another kind of blood, occult or hidden blood, may not be visible at all. A number of prescription and over the counter (OTC) medications can cause bleeding in the stomach and small intestine. The blood thinning drug warfarin also can induce bleeding in the intestine, as can some antibiotics. Other causes of bleeding can include ulcers, gastritis (inflammation of the stomach lining), ulcerative colitis, Crohn's disease, polyps (small growths inside the intestine), diverticular disease, abnormalities in the blood vessels (vascular anomalies), anal fissures (tears) and fistulas (abnormal openings between the anal canal and other organs, such as the bladder), and abscesses (pockets of infection. The author reiterates the importance of timely diagnosis, including a thorough patient history and evaluation of symptoms. Diagnostic tests can include blood tests, digital rectal examination, endoscopy, colonoscopy, sigmoidoscopy, fecal occult blood test, barium x rays, angiography (x rays of blood vessels), and nuclear scanning. Treatment depends on the source and extent of the bleeding.

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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

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determining which screening practices are most practical and effective for identifying HH. 1 figure. 6 tables. 33 references. •

Progressive Sensorineural Hearing Loss, Subjective Tinnitus and Vertigo Caused By Elevated Blood Lipids Source: ENT. Ear, Nose, and Throat Journal. 76(10): 716-730. October 1997. Summary: The otologist frequently sees patients with progressive sensorineural hearing loss, subjective aural tinnitus, and vertigo with no apparent cause. Elevated blood lipids may be a cause of inner ear malfunction on a biochemical basis. This article reports on a study undertaken to establish the true incidence of this condition. All new patients (n = 4,251) seen during an eight-year period were evaluated; of these, 2,332 patients had complaints of inner ear disease. All the patients had a complete neurotologic examination, appropriate audiometric and vestibular studies and imaging, and blood tests including lipid phenotype studies. Hyperlipoproteinemia was found in 120 patients (5.1 percent). Most patients were found to be overweight and had additional coexisting conditions such as diabetes mellitus. Treatment with vasodilators and a 500 calorie, high-protein, low-carbohydrate diet yielded improvement of symptoms in 83 percent of patients within five months of initiation of treatment. The authors include three detailed case studies. The authors conclude that the cause-and-effect relationship between hyperlipoproteinemia and dysfunction of the inner ear is indisputable. 6 figures. 14 references. (AA-M).

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Review Article: Invasive and Non-Invasive Tests for Helicobacter Pylori Infection Source: Alimentary Pharmacology and Therapeutics. 14(Supplement 3): 13-22. October 2000. 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: There are two general ways in which a diagnosis of infection by Helicobacter pylori can be made: by using either an invasive or a noninvasive procedure. This article reviews the current thinking on the use of these tests. The invasive procedures involve an endoscopy and biopsy. A biopsy is essential because often the mucosa may appear macroscopically normal but nevertheless be inflamed. A biopsy is obtained by histological examination, culture, polymerase chain reaction (PCR), or detection of the presence of urease activity in biopsy material. The noninvasive tests that can be used to diagnose the infection are serology (blood tests); detection of labeled metabolic products of urea hydrolysis in the breath, the urine, or the blood; and detection of H. pylori antigen in a stool specimen. The authors conclude that at present, no single test can be relied upon to detect definitely colonization by H. pylori, and a combination of two is recommended if this is feasible. The choice of the test to be used is not straightforward and may vary according to the clinical condition and local expertise. 8 tables. 95 references.

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Inside the Billion - Dollar Business of Blood Source: Money; March 1986. Contact: Time, Incorporated, Time and Life Bldg, Rockefeller Ctr, New York, NY, 10020, (212) 522-3082.

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Summary: This article examines the blood bank industry's initial response to the AIDS crisis in the early 1980's. Following a trail of events, meetings, and documentations of transfusion-associated AIDS cases, the author concludes that the blood bankers acted too slowly in alerting the public about contamination of the blood supply with the AIDS virus and in responding to protect the safety of that supply. She charges that the not-forprofit blood centers mishandled the AIDS crisis in the beginning by: 1) refusing initially to accept evidence that the AIDS virus could be transmitted by transfusion; 2) delaying the implementation of active screening procedures designed to discourage blood donations from people at high risk for AIDS; 3) resisting the use of surrogate blood tests that could be used as stopgap measures to reduce risk until a more specific AIDS screening test became available; and 4) making exaggerated claims about the antibody test's ability to identify AIDS-contaminated blood. The author traces the history and growth of the blood business, particularly the American Red Cross, focusing on the profit margins and competitive nature of the industry. •

Protect Your Liver from Potentially Harmful Medications, Vitamins and Supplements Source: Digestive Health and Nutrition. 3(5): 27-29. September-October 2001. Contact: Available from American Gastroenterological Association. 7910 Woodmont Avenue, 7th Floor, Bethesda, MD 20814. (877) DHN-4YOU or (301) 654-2055, ext. 650. Email: [email protected]. Summary: This article helps readers protect their livers from potentially harmful medications, vitamins and supplements. Written particularly for people with chronic liver diseases, such as viral hepatitis, cirrhosis (liver scarring), or other liver diseases, the article reviews how the liver works and why it is vulnerable to drug complications. Many seemingly innocuous products can cause significant injury if the liver is not able to properly process them. For example, liver patients and people with alcohol abuse can only tolerate the common medication, acetaminophen (Tylenol) at lower doses. And while acetaminophen can be tolerated in small doses in liver patients, ibuprofen products (Advil, Motrin) as well as other nonsteroidal antiinflammatory drugs (NSAIDs) should be avoided by those with hepatitis and cirrhosis. Some herbal supplements and vitamins also can damage the liver if taken in higher than recommended amounts or if there is an existing liver disease. When potentially hepatotoxic (liver damaging) medications are required to treat a patient's disease, the patient should consult with their physician about performing regular blood tests to monitor liver enzyme levels. One sidebar lists products containing acetaminophen and NSAIDs. The article concludes with a list of five websites for readers who wish to obtain more information. 1 table.

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Bacterial Osteomyelitis in Adults: Evolving Considerations in Diagnosis and Treatment Source: American Journal of Medicine. 101:550-561. November 1996. Summary: This article presents pathophysiologic and clinical aspects of an adult patient with bacterial osteomyelitis and considerations for its diagnosis and treatment. Diagnostic methods to be considered include radiologic evaluation, nonspecific blood tests, and establishing a microbiologic diagnosis. Also explored are the selection of the optimal antimicrobial regimen, monitoring the adequacy of therapy, and the use of hyperbaric oxygen therapy. The authors indicate that the approach to osteomyelitis depends upon the route by which bacteria gained access to bone, bacterial virulence, local and systemic host immune factors, and patient age. While imaging studies and

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nonspecific blood tests may suggest the diagnosis, an invasive technique is generally required to identify the causative pathogens. Given the paucity of comparative clinical trials, antibacterial regimen selection has been largely guided by knowledge of the relative activities and pharmacokinetics of individual drugs which are supported by data from animal models. Definitive therapy often requires a combined medical and surgical approach. Currently, there are newer microvascular and distraction osteogenesis techniques, including use of laser doppler, that allow more complete surgical resection of infected material while maintaining function. Despite recent advances, many patients with osteomyelitis fail aggressive medical and surgical therapy. More accurate diagnostic methods, better was to assess and monitor the effectiveness of therapy, and novel approaches to eradicate sequestered bacteria are still needed. 4 tables, and 117 references. (AA-M). •

Helicobacter Pylori Testing in the Primary Care Setting: Which Diagnostic Test Should be Used? Source: Alimentary Pharmacology and Therapeutics. 15(8): 1205-1210. August 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: This article reports on a study undertaken to identify the most accurate and efficient test for diagnosing Helicobacter pylori infection in primary care patients. A whole blood test, an ELISA, and carbon 13 urea breath test (CUBT) were evaluated in a primary care setting and validated against two different gold standards that used gastric (stomach) biopsies. The study included primary care patients who had complaints of dyspepsia lasting at least 2 weeks (n = 136) and who were referred for endoscopy. Data from these patients were compared with data from the gold standards. The positive predictive value of the whole blood test was in the range 71 to 75 percent, the ELISA 83 to 86 percent, and the CUBT 88 to 92 percent, while the negative predictive values were in the ranges 72 to 77 percent, 96 to 100 percent, and 95 to 98 percent, respectively. The sensitivity of the whole blood test was in the range 36 to 42 percent, the ELISA 93 to 100 percent, and the CUBT 92 to 97 percent, while the specificities were in the ranges 92 to 93 percent, 90 to 91 percent, and 93 to 95 percent, respectively. The positive predictive value of the ELISA dropped significantly at lower H. pylori infection rates. The authors conclude that both the ELISA and CUBT are effective in the primary care setting, while the whole blood tests produces inferior results. ELISA might, however, be less suitable for detecting H. pylori infection in a population with a low rate of infection. 1 figure. 3 tables. 24 references.

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Stepwise Approach to the Diagnosis and Treatment of Hereditary Hearing Loss Source: Pediatric Clinics of North America. 46(1): 35-48. February 1999. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Summary: This article, from a monograph on hearing loss in children, suggests a stepwise approach to the diagnosis and treatment of hereditary hearing loss. The authors stress that the pediatrician can play a major role in the diagnosis, workup, and treatment of hereditary hearing impairment. Armed with the proper degree of suspicion, careful elicitation of family history, meticulous physical examination, evaluation of the audiogram, and adequate fund of knowledge of common types of genetic deafness, the pediatrician can make a timely diagnosis and appropriate referrals.

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This avoids delay in detection of significant hearing impairment and the associated lack of essential skills in speech, language, and social interaction. Early detection and intervention are best done with a multidisciplinary team approach. In the future, blood tests using genetic probes may be available to screen for many types of hereditary hearing impairment. The article also describes the work of the Hereditary Hearing Impairment Resource Registry (HHIRR), a registry that collects information about individuals with hearing impairment or deafness, matches families with appropriate research projects, and disseminates information to professionals and families about hereditary hearing impairment. An appendix lists helpful sources for additional information. 1 table. 25 references. •

New Safety Recommendations for Use of Cisapride (Propulsid) Source: Harvard Heart Letter. 10(8): 7. April 2000. Contact: Available from Harvard Medical School Health Publications Group. Harvard Heart Letter, P.O. Box 420300, Palm Coast, FL 32142-0300. (800) 829-9045. E-mail: [email protected]. Website: www.health.harvard.edu. Summary: This brief newsletter article, from the Harvard Heart Letter, reminds readers of the new safety recommendations for the use of cisapride (Propulsid). Cisapride is used to treat severe nighttime heartburn, usually caused by gastroesophageal reflux disease (GERD), a condition where the band of muscle that prevents stomach acid from leaking back into the esophagus relaxes spontaneously, creating a painful heartburn like sensation. Cisapride works by moving gastric acids through the digestive tract, thereby preventing their painful reflux into the esophagus. Because this drug has some risks, it is generally reserved for patients who have not responded well to lifestyle changes or other medications used to manage GERD. Serious adverse reactions occurring in patients on cisapride have included heart rhythm disorders and death (most often occurring in people with certain health problems or who were taking other medications). Although it could not find a direct link between the reported problems and cisapride, the U.S. Food and Drug Administration (FDA) did strengthen the precautions on using this drug. In January 2000, the FDA bolstered its efforts to reduce the likelihood of complications from cisapride by recommending that physicians consider performing an electrocardiogram and certain blood tests before prescribing it. The article lists the drugs that should not be combined with cisapride, as well as the complicating medical conditions that contraindicate its use.

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Liver Disease: Fat Inflames the Liver Source: Harvard Health Letter. 26(4): 4. February 2001. Contact: Harvard Health Letter. P.O. Box 420300, Palm Coast, FL 32142-0300. (800) 8299045. Website: www.health.harvard.edu/newsletters/subinfo.html. Summary: This health education newsletter article describes nonalcoholic steatohepatitis (NASH), a common form of chronic liver disease in which the liver has excess fat cells and those cells cause inflammation. The author contends that NASH is another result of the epidemics of obesity and diabetes sweeping the United States. NASH is found most often in people who are 10 to 40 percent of their ideal body weight, or have diabetes, or both. At the cellular level, the changes produced by NASH resemble the liver tissue inflammation caused by alcohol. For up to 20 percent of people with NASH, the condition is the beginning of a dangerous cycle that leads to fibrosis (a buildup of fibrous tissue in the liver) and that can lead to life threatening cirrhosis (scarring of the liver). Most people with NASH have no symptoms, or vague symptoms, such as fatigue,

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an achy feeling on the right side of the abdomen, and malaise (generally feeling bad). Liver function tests (blood tests) can show the first signs of trouble, but a liver biopsy must be used to confirm the diagnosis of NASH. Treatment involves weight loss, close monitoring of blood glucose levels in patients with diabetes, and cessation of alcohol consumption. Present research studies are investigating the role of vitamin E and ursodeoxycholic acid as possible drug therapies for NASH. •

15-Year Longitudinal Study of Blood Pressure and Dementia Source: Lancet. 347: 1141-1145. April 27, 1996. Summary: This journal article describes a 15-year study of the association between blood pressure and the development of dementia in older people. Residents of Goteborg, Sweden, who were 70 years in 1970-1972 participated in this study. A random subsample of 382 residents who did not have dementia on psychiatric evaluation at age 70 years were followed for 15 years with repeated neuropsychiatric examination and physical examination, electrocardiogram, chest radiograph, and blood tests. The results suggest that participants who developed dementia at age 79-85 years had significantly higher systolic blood pressure at age 70 years and significantly higher diastolic blood pressure at ages 70 and 75 years than did those who did not develop dementia. A significant association was found between higher diastolic blood pressure at age 70 years and subsequent development of Alzheimer's disease, and between higher diastolic blood pressure at age 75 years and subsequent development of vascular dementia. Participants with white matter lesions on computed tomography at age 85 years had higher blood pressure at age 70 than those without such lesions. In participants who developed dementia, blood pressure declined just before dementia onset and was then similar to or lower than that in participants without dementia. The authors conclude that increased blood pressure at age 70 years may increase the risk of developing dementia 10 to 15 years later. 4 figures, 1 table, 30 references.

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Music Therapy Increases Serum Melatonin Levels in Patients With Alzheimer's Disease Source: Alternative Therapies. 5(6): 49-57. November 1999. Summary: This journal article describes a study of the effects of music therapy on neurotransmitters and neurohormones in patients with Alzheimer's disease (AD). Participants were 20 male patients at the Miami Veterans Administration Medical Center. The researchers took blood tests to determine the concentrations of melatonin, norepinephrine, epinephrine, serotonin, and prolactin in the patients before initiating the therapy, immediately at the end of four weeks of therapy, and at a six week followup after cessation of the therapy sessions. Melatonin concentration increased significantly after therapy and had increased further at the six week follow-up. Norepinephrine and epinephrine levels increased after four weeks of music therapy, but returned to pre-therapy levels at the follow-up. Prolactin and platelet serotonin levels were unchanged. The authors conclude that increased levels of melatonin following the therapy may have contributed to patients' relaxed and calm mood. 2 tables, 86 references.

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Symptomatic Treatment of Elderly Patients With Early Alzheimer's Disease at a Memory Clinic Source: Journal of Geriatric Psychiatry and Neurology. 10: 33-38. 1997.

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Summary: This journal article discusses the treatment of excess disability in patients with early Alzheimer's disease (AD). Researchers conducted a prospective study of 117 patients referred to a Dutch memory clinic in the Netherlands. Ninety-nine patients had minimal or mild dementia, and 18 had moderate dementia. Excess disability, defined as treatable coexisting physical and psychiatric disorders, was assessed by neurologists with the Dutch version of the Cambridge Examination for Mental Disorders of the Elderly, a standardized medical history and physical examination, and measures of cognitive function, impairment in activities of daily living, behavioral changes, and caregiver burden. Seventy-seven forms of excess disability were already diagnosed and treated before referral in 61 of the 117 patients. Further clinical examinations and ancillary tests revealed 48 new diagnoses in 38 AD patients. Overall, 78 patients (66.6 percent of the sample) had a total of 125 conditions comprising excess disability. Of the ancillary tests performed, only the blood tests produced unexpected results with consequences for diagnosis, treatment, or outcome. The authors conclude that patients with AD should receive a careful examination with attention to secondary pathology and noncognitive symptoms; and they recommend doing blood tests in all AD patients. The question of which tests to routinely administer merits further study. 4 tables, 30 references. •

Dementia of the Alzheimer Type: Identification and Management of Neuropsychiatric Features Source: Older Patient. 4(3): 4-8. Fall 1990. Summary: This journal article examines the diagnosis, management, and clinical features of dementia of the Alzheimer type (DAT). In 1989, it was estimated that 4 million cases of DAT existed in the United States. The diagnosis of DAT involves documentation of intellectual decline, physical and laboratory examinations, blood tests, and neuroimaging. DAT has an insidious onset and is progressive, leading to eventual death in 6 to 12 years after onset. Patients with DAT experience memory loss, language and comprehension disturbances, spatial difficulties, mood disturbances, and psychoses. Management of psychoses is primarily pharmacologic, using neuroleptics (haloperidol, thiothixene, and thioridazine) with only a modest amount of benefit and numerous side effects. Nonpharmacologic interventions include gentle reassurance and distraction in an attempt to prevent a confrontation with the patient. The pharmacologic management of depression in DAT is similar to that employed in the nondemented depressed elderly. If a patient is physically violent, the caregiver should remove any potentially dangerous objects and assure his or her own safety. Restlessness, anxiety, and irritability are not always responsive to direct pharmacologic treatment. While the disorder is presently incurable, some of the pathologic behaviors commonly encountered can be manageable if appropriately identified and treated.

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Acute Monoarthritis: A Practical Approach to Assessment and Treatment Source: American Family Physician. 54(7):2239-2243. November 15, 1996. Contact: American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237 or (913) 906-6000. E-mail: [email protected]. Website: www.aafp.org. Summary: This journal article for health professionals presents a practical approach to the assessment and treatment of acute monoarthritis. A basic approach to the patient presenting with acute monoarthritis includes a careful history, a physical examination, and a selected battery of laboratory tests and radiographs. Rapid assessment and

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treatment are required because of the possibility of septic joint. The most common causes of acute monoarthritis are trauma, crystals, and infection. The most important cause of acute monoarthritis is infection, which must be excluded through the use of diagnostic joint aspiration and culture of synovial fluid. Other investigations include blood tests and radiographs of the involved joint. General principles of patient care management include joint rest, application of ice, and physiotherapy to help maintain joint range of motion and minimize muscle atrophy. Specific therapy includes antibiotics for bacterial monoarthritis, nonsteroidal anti-inflammatory drugs or intraarticular steroid injections for noninfectious inflammatory monoarthritis, and arthroscopy for internal derangement. Patients suspected of having septic arthritis should be started on empiric antibiotic therapy, pending synovial fluid Gram stain and culture results. 9 references, 1 figure, and 3 tables. (AA-M). •

Arthritis: Types and Diagnosis Source: Women's Health Digest. 2(2):122-125; 1996. Summary: This journal article for the general public and individuals with arthritis describes common rheumatic diseases. Connective tissue diseases include juvenile arthritis, lupus erythematosus, scleroderma, and Sjogren's syndrome. Examples of arthritis associated with spondylitis are ankylosing spondylitis and psoriatic arthritis. Types of infectious arthritis include Lyme disease and Reiter's syndrome. Metabolic diseases associated with rheumatic states are gout and pseudogout. Extra-articular disorders include bursitis and tendinitis. A common condition that may or may not be a specific disease is fibromyalgia. The major warning signs of arthritis are outlined. Techniques commonly used in the diagnosis of arthritis are discussed, focusing on the physical examination; laboratory tests, such as blood tests and joint aspiration; and radiologic studies, such as conventional x-rays, an arthrogram, radionuclide bone scans, computerized axial tomography, magnetic resonance imaging, and arthroscopy. 4 references and 2 figures.

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Osteoarthritis: Current Concepts in Diagnosis and Management Source: American Family Physician. 61(6): 1795-1804. March 15, 2000. Contact: American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237 or (913) 906-6000. E-mail: [email protected]. Website: www.aafp.org. Summary: This journal article provides health professionals with information on the pathophysiology, clinical features, diagnosis, and management of osteoarthritis (OA). Cartilage destruction is the main feature of OA. Biomechanical and biochemical forces are involved in cartilage destruction. The typical patient who has OA is middle aged or elderly and complains of pain in the knee, hip, hand, or spine. Pain typically worsens with use of the affected joint and is alleviated with rest. The physical examination should include a careful assessment of the affected joints, surrounding soft tissue, and bursal areas. Although radiographs can usually confirm the diagnosis of OA, the findings are nonspecific. The cardinal radiographic features of OA are a loss of joint space and the presence of new bone formation or osteophytes. Most routine blood tests are normal in patients who have uncomplicated OA. Treatment of OA should be individualized. The safest initial approach is to use a simple oral analgesic such as acetaminophen. If pain relief is inadequate, oral nonsteroidal antiinflammatory drugs or intraarticular injections of hyaluronic acid like products should be considered. Intraarticular corticosteroid injections may provide short term pain relief in disease

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flares. Alleviation of pain does not alter the underlying disease. Attention must also be given to nonpharmacologic measures such as patient education, weight loss, and exercise. Relief of pain and restoration of function can be achieved in some patients with early OA, particularly if an integrated approach is used. Patients with advanced disease may eventually require surgery, which generally provides excellent results. 2 figures, 5 tables, and 39 references. (AA-M). •

Arthritis 101: Sjogren's SyndroMen Source: Arthritis Today. 14(4): 32-33. July-August 2000. Summary: This journal article uses a question and answer format to provide people who have Sjogren's syndrome with information on the etiology, epidemiology, diagnosis, and treatment of this arthritis related disease affecting several organs. Sjogren's syndrome is an autoimmune disease in which lymphocytes attacks moisture producing glands, and, in some cases, the lungs, kidneys, liver, skin, nerves, or joints. Risk factors include being a postmenopausal woman, having an autoimmune disease, and having a family member with Sjogren's. Diagnosis is based on a complete physical examination; medical history evaluation; and various diagnostic tests, including the slit lamp test, the Schirmer test, a lip biopsy, and blood tests to detect antibodies. Although there is no cure for Sjogren's syndrome, it can be treated with medications and other measures to relieve the common symptoms of the condition. The article presents some general treatment modalities as well as treatments for some of the specific symptoms of Sjogren's. 1 figure.

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What Is Alkaline Phosphatase and What Does an Elevated Level Mean to Paget 's Patients? Source: Update. (18)1:4. Spring 1996. Contact: Paget Foundation for Paget 's Disease of 200 Varick Street, Suite 1004. New York, NY 10014-4810. (212) 229-1582 or Fax (212) 229-1502. Price: Free. Summary: This question-and-answer session explains what alkaline phosphatase (AP) is, and its use in diagnosing Paget 's disease ( PD ) and monitoring therapy. It reveals that this naturally produced enzyme in bone cells, once elevated, can point to a diagnosis of PD if blood tests show it is coming from the bone. Once diagnosed, successful treatment should show a drop in AP levels. In some cases, PD can be present (inactive or in small amounts) even when AP levels are normal.

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Role of Liver Biopsy in Management of Chronic Hepatitis C: A Systematic Review Source: Hepatology. 36(5 Supplemental 1): S161-S172. November 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: This review article considers two topics pertinent to the need for pretreatment liver biopsy in patients with chronic hepatitis C: how liver biopsy results predict treatment outcomes; and how well biochemical blood tests and serological measures of fibrosis predict biopsy findings in chronic hepatitis C. The authors searched MEDLINE and other electronic databases from January 1985 to March 2002. Additional articles were sought in references of pertinent articles and recent journals and by querying experts. Articles were eligible for review if they reported original human data from a study that used virological, histological, pathologic, or clinical outcome measures. Studies suggested that advanced fibrosis or cirrhosis (scarring) on initial liver

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biopsy is associated with a modestly decreased likelihood of a sustained virological response (SVR) to treatment. Also, studies relatively consistently showed that serum aminotransferases have modest value in predicting fibrosis on biopsy; that extracellular matrix tests hyaluronic acid and laminin may have value in predicting fibrosis; and that panels of tests may have the greatest value in predicting fibrosis or cirrhosis. Biochemical and serologic tests were best at predicting no or minimal fibrosis, or at predicting advanced fibrosis or cirrhosis, and were poor at predicting intermediate levels of fibrosis. Thus, evidence suggests that liver biopsy may have some usefulness in predicting efficacy of treatment in patients with chronic hepatitis C, and biochemical blood tests and serologic tests currently have only modest value in predicting fibrosis on liver biopsy. 2 tables. 81 references. •

AGA Technical Review on Constipation Source: Gastroenterology. 119(6): 1766-1778. December 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: This technical review identifies a rational, effective, and cost effective approach to the patient presenting with constipation. The authors review the epidemiology of constipation, risk factors, the economic impact of constipation, the clinical features and pathophysiology, clinical evaluation, secondary encounters and referral consultations, diagnostic tests (balloon expulsion test, defecography, colonic transit, and anorectal manometry), medical management, and the role of surgery in treating constipation. Constipation is associated with inactivity, low caloric intake, the number of medications being taken, low income, and a low education level. Constipation is also associated with depression as well as with physical and sexual abuse. These are noted as risk factors, not necessarily as causative agents. The review summarizes three patient care algorithms. After the initial history and physical examination, patients can be classified into one of several subgroups. Standard blood tests and a colonic structural evaluation should be performed to rule out organic causes of the constipation. If the initial evaluation is normal or negative, an empiric trial of fiber (and or dietary changes) can be followed by simple osmotic laxatives. Most patients will obtain symptom relief with these measures. Patients who fail to respond to this initial approach are appropriate candidates for more specialized testing. 5 tables. 95 references.

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

Project Title: A NEW MARKER FOR COLON CANCER SCREENING Principal Investigator & Institution: Kinders, Robert J.; Bion Diagnostic Sciences 12277 134Th Crt Ne Redmond, Wa 98052 Timing: Fiscal Year 2001; Project Start 20-SEP-2001; Project End 31-AUG-2002 Summary: (provided by applicant): Replace the current FOBT (fecal occult-blood tests) used in CRC screening for colorectal cancer in individuals over age 50. We have shown upregulation of TAA mRNA expression in colon tumors. We have produced monoclonal antibodies and affinity purified antisera to the TAA and have used these to formulate a prototype sandwich enzyme immunoassay in a microplate format. We have used this assay to test 70 stool specimens and a number of colonic washes from patients in which a tumor was subsequently found. In a head-to-head comparison with two different fecal occult blood tests (FOBT), the prototype sandwich assay has demonstrated superior clinical diagnostic performance to both. Work has begun on assembling two, 500 specimen panels to demonstrate utility of the marker in relevant populations. Additional Phase I objectives are to 1) generate additional monoclonal antibodies to the TAA; 2) complete cloning and sequencing of the TAA from human tumor specimens. The product we visualize is a low cost, one-step immunoassay device suitable for use in a screening mode in which patients with a positive test result would be worked up by sigmoidoscopy or colonoscopy. PROPOSED COMMERCIAL APPLICATIONS: Replace the current FOBT ( fecal occult-blood tests) used in CRC screening with an immunoassay for a TAA found in stool. A successful product will more than double the number of cancers detected, detect pre-cancerous lesions not currently detected, and cut the number of false-positives by 3 to 5 fold or more. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AV SHUNT IMPLANTATION IN HEMODIALYSIS PATIENTS Principal Investigator & Institution: Harker, Laurence A.; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2001 Summary: This is a placebo-controlled, safety and efficacy dose-finding study assessing the effects of dosing FFR-rFVIIa vs placebo in 4 cohorts of patients each (4:1 randomization favoring active therapy) on AVG 111In-platelet deposition at the time of AVG surgical placement or replacement (primary outcome). Imaging of 111In-platelets accumulating at the sites of AVG anastomoses, and an escalating bolus FFR-rFVIIa in subsequent cohorts will establish safety, tolerance and an effective antithrombotic dose regimen for FFR-rFVIIa administration in dialysis patients undergoing surgical AVG placement or replacement. This dose will subsequently be used in a controlled clinical trial of AVG failure. We also propose to compare the dose-response effects of FFRrFVIIa vs placebo on post-operative changes in blood tests of thrombosis, tests of hemostasis and measured surgical blood loss. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COLORECTAL CANCER SCREENING--FECAL BLOOD VS DNA Principal Investigator & Institution: Ahlquist, David A.; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 15-JUN-2001; Project End 31-MAY-2004 Summary: APPLICANT?S Colorectal cancer remains the second leading cause of malignant death, and better preventive strategies are needed. Stool testing, unlike other conventional screening approaches, is noninvasive and requires no cathartic preparation. However, widely-used fecal blood tests yield frequent false-negative and false-positive results that lower the screening effectiveness and raise program costs. There is a compelling biological rationale to target altered DNA exfoliated from neoplasms into stool, and multiple DNA markers would need to be targeted due to the genetic heterogeneity of colorectal neoplasia. Preliminary data suggest that a prototype multi-target DNA-based assay system has potential to detect screen-relevant colorectal neoplasia (early-stage cancer and advanced adenomas) with substantially higher sensitivity and specificity than that of fecal blood tests. The overall objective of this application is to prospectively assess the fecal DNA-based test as a promising new approach to the general screen-detection of colorectal neoplasia. A 3-year cross-sectional multicenter study is planned to compare the validity of the DNA-based test and the most commonly used fecal blood test (Hemoccult) for identification of screen-relevant colorectal neoplasia in 2900 demographically representative average-risk persons using colonoscopy as a gold standard. The performance of the DNA-based test will also be compared to a surrogate for flexible sigmoidoscopy (distal 60 cm of colonoscopy) and to the combination of sigmoidoscopy + Hemoccult. The design will further allow an assessment of the impact of dietary, medication, demographic, and other covariates on test outcomes. Assays will be performed blindly at central laboratories. A specimen bank will be maintained as an important resource for the economical evaluation of additional markers. A state-of-the-art web-based data management system will be employed to efficiently enter and transfer data across the six participating centers with the highest quality control. If the DNA-based test proves to have greater screening accuracy than fecal blood testing, this could translate into more effective cancer control and more efficient use of our limited health care resources. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC VARIABILITY IN COLORECTAL NEOPLASIA Principal Investigator & Institution: Gerner, Eugene W.; Professor; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 05-SEP-2002; Project End 31-MAR-2007 Summary: (provided by applicant): The translational goal of this project is to develop simple blood tests to predict colon cancer risk and to tailor therapy for colorectal intraepithelial neoplasia (IEN). Diagnosis of colon cancer at an early stage continues to be problematic, and response to treatment is limited in late stage colon cancer. Better measures of risk will contribute to colon IEN prevention or earlier detection. Earlier detection combined with methodologies to predict response to therapy will decrease colon cancer incidence and mortality. The hypothesis to be tested in this proposal is that the risk of colorectal cancer is influenced by genetic variability affecting the expression/function of the adenomatous polyposis coli (APC) tumor suppressor gene and/or APC modifier genes, such as ornithine decarboxylase (ODC). Measures of this genetic variability may be prognostic and/or predictive factors for colorectal IEN. To test this hypothesis, four specific aims are proposed. First, we will measure specific

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mutations in the APC tumor suppressor gene in colorectal adenomas from participants in colon cancer prevention trials. Second, we will measure germline polymorphism frequencies in codon 1822 of APC. We will determine associations between genetic variability in APC with dietary factors and adenoma recurrence in this patient group. Third, we will measure the genetic variability in the c-myc-dependent region of the ODC promoter in groups at risk for colorectal IEN, and determine whether polymorphisms are associated with adenoma recurrence. Finally, we will ascertain the functional significance of these polymorphisms in intestinal carcinogenesis. Future studies will measure variability in other downstream mediators of APC. These other mediators include networks regulating polyamine and arachidonic acid metabolism. Since these pathways are targets for IEN therapy (e.g., DFMO, NSAIDs), genetic variability in these pathways may be predictive factors for therapeutic response to treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOE901 VERSUS NPH HUMAN INSULIN WITH TYPE I DIABETES MELLITUS Principal Investigator & Institution: Feinglos, Mark N.; Duke University Durham, Nc 27706 Timing: Fiscal Year 2001 Summary: PURPOSE: The purpose of this study is to compare the effects of HOE 901 and NPH on glycated hemoglobin and to compare the safety of HOE 901 with NPH in subjects with type I diabetes mellitus. A comparison between the two treatments will also be made in terms of blood glucose variability, hypoglycemia, other indicators of metabolic control, quality-of-life, and pharmacoeconomics. METHODS: This is a phase III, randomized, multicenter, open, NPH human insulin controlled, randomized (1:1), 28-week parallel-group study with two treatment groups (HOE901 and NPH human insulin). A total of 520 patients ( a total for all sites) will be evaluated in this study. The study consists of a 1 to 4-week screening phase and a 28-week treatment phase which includes an initial active dose titration phase. Subjects randomized to the NPH insulin group will continue their previous regimen of injections per day. Subjects randomized to HOE901 will receive a single injection of HOE 901 at bedtime. Both treatment groups will also receive regular insulin in addition to either HOE901 or NPH human insulin. The subjects will be stratified by whether they were being treated with a basal insulin once versus twice daily. This study will involve 5 outpatient visits and 3 inpatient visits. During the screen visit, subjects will undergo a history and physical examination, blood tests, pregnancy screen, dilated eye exam, and fundus photography. Subjects will be instructed in home blood glucose monitoring, issued a glucose meter and supplies, and will be asked to monitor their blood glucose 4x/day. At the following visit, patients who qualify will be admitted to the GCRC for approximately 36 hours, during which 24 hr blood glucose samples will be taken. Patients will also have an EKG and blood tests. Patients are randomized at this visit. Outpatient follow-up visits including blood tests will occur at Weeks 1 & 4. Patients will be readmitted for an inpatient stay, including 24 hr sampling, at Week 8. Outpatient follow-up visits including blood tests will occur at Weeks 12 & 20, with optional eye exam and fundus photos at Week 12. The final admission will occur at Week 28. In addition to 24 hr sampling, an EKG, eye exam, fundus photos, and blood tests will be performed. Patients will restart their prestudy insulin regimen at this visit. RESULTS AND CONCLUSIONS: The study was completed in June 1998. This is a pharmaceutical-sponsored, multicenter study, and results have not been provided to date. SIGNIFICANCE: Type I diabetes mellitus is characterized by

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general insulin deficiency due islet beta-cell loss and requires insulin replacement therapy. Normal pancreatic beta-cells secrete approximately 50% of insulin as boluses in response to food and the rest as a continuous basal secretion. Longer-acting insulins such as NPH or Ultralente are often used to simulate endogenous basal insulin in the treatment of type I diabetes. However, neither NPH nor Ultralente provides a stable 24 hr basal insulin supply because either the duration of action is too short (NPH) or absorption from the site is erratic (Ultralente). NPH also often results in nocturnal hypoglycemia due to plasma insulin peaks during the night. Consequently, the bedtime NPH dose cannot be safely increased as appropriate, resulting in elevated blood glucose in the morning, a major obstacle to overall euglycemia. The Diabetes Control and Complications Trial has shown that tight blood glucose control greatly reduces the risk of diabetic complications such as retinopathy, neuropathy, and nephropathy. Human insulin analogue HOE901 is a long-acting insulin that, if proven safe and effective, can be given as a single daily injection to provide near normal blood glucose control and a smoother 24 hr basal insulin profile than previously possible with available medications. FUTURE PLANS:The results of this study will provide the basis for future investigation of HOE901. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SCREENING

INTERVENTIONS

TO

INCREASE

COLORECTAL

CANCER

Principal Investigator & Institution: Menon, Usha; None; University of Utah 200 S University St Salt Lake City, Ut 84112 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2003 Summary: Colorectal cancer (CRC) is the third leading cause of cancer death in the United States with the majority of CRC diagnosed in those aged 50 or older. Prospective data indicate that annual fecal occult blood tests (FOBT) can decease mortality from CRC. The American Cancer Society recommends an annual FOBT and a flexible sigmoidoscopy every 5 years. Utilization of these tests is very low, ranging from 19% to 39%, especially among those who are 50 or older and most at risk for developing the disease. Tailored interventions have demonstrated significant increases in mammography use, and may be effective in the area of CRC screening as well. The purpose of this study is to compare the effectiveness of a tailored versus a non-tailored intervention designed to increase the use of FOBT and sigmoidoscopy, and to determine its effect on cognitive stage of behavior. The theoretical framework for this study was derived from the Health Belief and Transtheoretical Models. Institutional review board approval will be obtained before data collection. All instruments proposed in this study were previously tested for reliability and validity. Trained research assistants will contact members of a Midwest-based health maintenance organization (HMO), aged 56 or older and who have not had an FOBT in the last 15 months. Once eligibility criteria is verified, those who agree to participate with be randomized to one of three groups; 1) control, 2) tailored print communication, and 3) non- tailored print communication. Baseline data will be collected by telephone from a sample of 600 HMO members. Interventions will be mailed 2 weeks from the baseline interview, and post intervention interviews conducted 2 months from the intervention. Logistic regression will be conducted modeling the odds of having an FORT or sigmoidoscopy by intervention group. Those independent variables significant in bivariate analyses at p equal to or