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

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

J AM ES N. P ARK ER , 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., 1960Helicobacter Pylori: 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: 0-597-84447-X 1. Helicobacter Pylori-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 Helicobacter pylori. 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 HELICOBACTER PYLORI ............................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Helicobacter Pylori...................................................................... 62 E-Journals: PubMed Central ..................................................................................................... 123 The National Library of Medicine: PubMed .............................................................................. 167 CHAPTER 2. NUTRITION AND HELICOBACTER PYLORI ................................................................ 215 Overview.................................................................................................................................... 215 Finding Nutrition Studies on Helicobacter Pylori .................................................................... 215 Federal Resources on Nutrition ................................................................................................. 223 Additional Web Resources ......................................................................................................... 224 CHAPTER 3. DISSERTATIONS ON HELICOBACTER PYLORI ............................................................ 225 Overview.................................................................................................................................... 225 Dissertations on Helicobacter Pylori ......................................................................................... 225 Keeping Current ........................................................................................................................ 226 CHAPTER 4. PATENTS ON HELICOBACTER PYLORI....................................................................... 227 Overview.................................................................................................................................... 227 Patents on Helicobacter Pylori................................................................................................... 227 Patent Applications on Helicobacter Pylori............................................................................... 247 Keeping Current ........................................................................................................................ 280 CHAPTER 5. BOOKS ON HELICOBACTER PYLORI .......................................................................... 281 Overview.................................................................................................................................... 281 Book Summaries: Federal Agencies............................................................................................ 281 Book Summaries: Online Booksellers......................................................................................... 282 Chapters on Helicobacter Pylori ................................................................................................ 285 CHAPTER 6. MULTIMEDIA ON HELICOBACTER PYLORI ............................................................... 289 Overview.................................................................................................................................... 289 Video Recordings ....................................................................................................................... 289 CHAPTER 7. PERIODICALS AND NEWS ON HELICOBACTER PYLORI ............................................ 291 Overview.................................................................................................................................... 291 News Services and Press Releases.............................................................................................. 291 Newsletter Articles .................................................................................................................... 296 Academic Periodicals covering Helicobacter Pylori ................................................................... 297 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 299 Overview.................................................................................................................................... 299 U.S. Pharmacopeia..................................................................................................................... 299 Commercial Databases ............................................................................................................... 300 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 305 Overview.................................................................................................................................... 305 NIH Guidelines.......................................................................................................................... 305 NIH Databases........................................................................................................................... 307 Other Commercial Databases..................................................................................................... 309 The Genome Project and Helicobacter Pylori............................................................................. 309 APPENDIX B. PATIENT RESOURCES ............................................................................................... 313 Overview.................................................................................................................................... 313 Patient Guideline Sources.......................................................................................................... 313 Finding Associations.................................................................................................................. 322 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 325 Overview.................................................................................................................................... 325 Preparation................................................................................................................................. 325

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Finding a Local Medical Library................................................................................................ 325 Medical Libraries in the U.S. and Canada ................................................................................. 325 ONLINE GLOSSARIES................................................................................................................ 331 Online Dictionary Directories ................................................................................................... 331 HELICOBACTER PYLORI DICTIONARY............................................................................... 333 INDEX .............................................................................................................................................. 417

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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 Helicobacter pylori 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 Helicobacter pylori, 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 Helicobacter pylori, 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 Helicobacter pylori. 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 Helicobacter pylori, 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 Helicobacter pylori. 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 HELICOBACTER PYLORI Overview In this chapter, we will show you how to locate peer-reviewed references and studies on Helicobacter pylori.

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

Review Article: Helicobacter Pylori and Gastro-Oesophageal Reflux Disease. Clinical Implications and Management Source: Alimentary Pharmacology and Therapeutics. 13(2): 117-127. February 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: A significant proportion of patients with gastroesophageal reflux disease (GERD) have Helicobacter pylori infection, but it is unclear whether H. pylori should be treated in this clinical setting. This review article critically assesses the relationship between H. pylori and GERD and its potential implications for the management of

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GERD. Data for the review were gathered from the biomedical database MEDLINE, a detailed review of medical journals, and a review of abstracts submitted to relevant international meetings, up to April 1998. On average, 40 percent of GERD patients carry H. pylori infection, with a reported infection prevalence ranging from 16 to 88 percent. To date, there has been no reported controlled trial of effective H. pylori therapy in GERD. GERD has been reported to develop de novo following the cure of H. pylorirelated peptic ulcer disease. In the presence of H. pylori, proton pump inhibitor therapy appears to accelerate the development of atrophic corpus gastritis, a potentially precancerous condition. Conversely, proton pump inhibitor therapy seems to become less effective after cure of H. pylori. The mechanisms underlying these important contrasting phenomena are poorly understood. The author concludes that the relationship between H. pylori and GERD is complex, and it is difficult to give definitive guidelines on the management of H. pylori infection in GERD. Controlled trials of H. pylori therapy in CERD are urgently needed, as well as further long term data on both the natural history of gastric histopathological changes in the H. pylori positive GERD patient treated with proton pump inhibitors, and the impact of H. pylori status on the clinical efficacy of antisecretory therapy. Pending these data, it is perhaps advisable to advocate cure of H. pylori in young patients with proton pump inhibitor dependent GERD who, in the absence of antireflux surgery, are faced with the likelihood of long term medical therapy. 2 tables. 108 references. (AA-M). •

Eradication of Helicobacter Pylori May Reduce Disease Severity in Rheumatoid Arthritis Source: Alimentary Pharmacology and Therapeutics. 16(7):1291-1299. 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: A triggering infectious agent has long been postulated in rheumatoid arthritis. Data on the possible role of Helicobacter pylori are lacking. This article reports on a study undertaken to assess the effect of H. pylori eradication in patients with rheumatoid arthritis (RA). The study included 58 adults patients with established RA and dyspeptic symptoms; 28 were H. pylori positive and 30 were H. pylori negative on the basis of invasive tests. All infected patients were treated successfully. The authors found that H. pylori-eradicated RA patients showed progressive improvement over time of all clinical indices, compared with baseline, whereas H. pylori-negative RA patients remained substantially unchanged. After 2 years, H. pylori-eradicated RA patients differed significantly from patients without H. pylori infection in terms of improvement of all clinical parameters. The authors conclude that their data suggest that H. pylori infection is implicated in the pathogenesis (development) of RA, in that its eradication may induce a significant improvement of disease activity over 24 months. H. pylori eradication seems to be advantageous in infected RA patients, but controlled studies are needed. 3 figures. 3 tables. 26 references.

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Helicobacter Pylori Infection, Gastritis and Gastric Cancer: A Short-Term Eradication Therapy for Helicobacter Pylori Acute Gastritis Source: Journal of Gastroenterology and Hepatology. 15(12): 1377-1381. December 2000. Contact: Available from Blackwell Science. 54 University Street, Carlton South 3053, Victoria, Australia. +61393470300. Fax +61393475001. E-mail: [email protected]. Website: www.blackwell-science.com.

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Summary: Acute gastritis (stomach inflammation), caused by an initial infection of Helicobacter pylori, may resolve spontaneously, but the infection sometimes becomes chronic. The authors of this article examined the efficacy of a short term H. pylori eradication therapy on acute gastritis. Among the 15 patients with hemorrhage acute gastritis who were randomly allocated to group A (eradication therapy) or group B (lansoprazole), 10 of the patients started to receive treatment within 1 day after the disease onset. The other five patients began the eradication therapy 4 to 6 days after disease onset (group C). Eradication therapy consisted of a daily oral administration of each of 30 milligrams lansoprazole (LPZ) once a day; 400 milligrams clarithromycin, twice a day; 1000 milligrams amoxicillin, twice a day; and 300 milligrams rebamipide, three times a day, for one week. If the endoscopy was normal, medication was stopped for the following 4 weeks before gastric endoscopy was performed again in order to assess H. pylori eradication. All group A patients were cured after the 1 week treatment and, therefore, they became H. pylori negative. Group B and C patients had erosions or ulcers after the 1 week treatment and so received an additional 3 week administration of LPZ. Four weeks later, their gastritis was cured and except for one group B patient, they became H. pylori negative. The authors conclude that in patients with acute gastritis, caused by an initial H. pylori infection, eradication therapy was efficacious in achieving early healing. This therapy should therefore be started as soon as possible after disease onset. 1 table. 25 references. •

Cure of Helicobacter Pylori Infection in Elderly Patients: Comparison of Low Versus High Doses of Clarithromycin in Combination with Amoxicillin and Pantoprazole Source: Alimentary Pharmacology and Therapeutics. 15(7): 1031-1036. July 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: Advancing age may influence the pharmacokinetics of the antibiotic clarithromycin. No studies have yet compared the effects of different dosages of clarithromycin in combination with a proton pump inhibitor (PPI) and amoxicillin in elderly patients. This article reports on a study undertaken to compare the efficacy and tolerability of clarithromycin 250 milligrams versus clarithromycin 500 milligrams twice daily (b.d.) in combination with pantoprazole (a PPI) and amoxicillin in elderly patients. Subjects were 154 elderly patients with Helicobacter pylori associated ulcer disease or chronic gastritis (inflamed stomach). They were randomized to receive pantoprazole 40 milligrams daily plus amoxicillin 1 gram and either clarithromycin 250 milligrams b.d. (PAC 250) or clarithromycin 500 milligrams b.d. (PAC 500). Two months after therapy, endoscopy and gastric (stomach) biopsies were repeated. The cure rates of H. pylori infection in the PAC 250 and PAC 500 groups were, respectively 83 percent and 79 percent (using the intention to treat, or ITT, analysis) and 94 percent and 88 percent respectively (using the per protocol, or PP, analysis). Significant decreases in chronic gastritis activity both in the body and the antrum of the stomach were found in H. pylori cured patients, independently of clarithromycin dosage. Four patients in PAC 250 (5 percent) and seven in PAC 500 (9 percent) reported adverse events. Of these, one patient in PAC 250 (25 percent) and three in PAC 500 (43 percent) discontinued the study because of these drug related side effects. The authors conclude that in elderly patients, 1 week triple therapy with a PPI, amoxicillin, and clarithromycin is a highly effective and well tolerated anti H. pylori treatment. With this combination, clarithryomycin at the lower dose of 250 milligrams b.d. achieved excellent cure rates and minimized adverse events and costs. 2 tables. 22 references.

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H. Pylori Eradication for Individuals on Chronic NSAID Therapy: Should We Kill the Bug If You Need the Drug? Source: Practical Gastroenterology. 25(5): 12, 16, 19, 23-24. May 2001. Contact: Available from Shugar Publishing. 12 Moniebogue Lane, Westhampton Beach, NY 11978. (516) 288-4404. Fax (516) 288-4435. Summary: Although it is widely agreed that Helicobacter pylori (a bacterium) causes peptic ulcer disease, controversy persists regarding the impact of H. pylori infection on the incidence of NSAID associated complications. This article considers the role of H. pylori eradication for individuals on chronic NSAID therapy. H. pylori gastritis can increase protective prostaglandin levels in the upper GI tract mucosa, but there is little evidence that eradication of infection leads to an increased risk for clinically significant events in those taking NSAIDs. Since both H. pylori and NSAIDs increase ulcer risk, elimination of either risk factor does not provide protection against the other. Given the prevalence of NSAID associated toxicity, preventive strategies to reduce NSAID side effects remain important. In addition, a compelling argument can be made for H. pylori testing of chronic NSAID users at increased risk for ulcer disease, from the cost effectiveness standpoint. Testing for H. pylori does not appear to be indicated for all patients starting on NSAID therapy. Patients with a pre existing history of peptic ulcer disease should be tested for H. pylori and treated with antibiotics if the test is positive, in order to reduce recurrence of H. pylori associated ulcers. 1 figure. 14 references.

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Helicobacter Pylori Screening for Individuals Requiring Chronic NSAID Therapy: A Decision Analysis Source: Alimentary Pharmacology and Therapeutics. 15(1): 63-71. January 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: Although it is without question that Helicobacter pylori causes peptic ulcer disease, controversy persists regarding the impact of H. pylori infection on the incidence of NSAID (nonsteroidal antiinflammatory drugs) related complications and whether H. pylori eradication reduces the rate of adverse events. This article reports on a symptom driven decision analytic model that was developed to compare the clinical and economic impact of H. pylori screening compared to a strategy of no H. pylori testing for individuals requiring chronic NSAID therapy. In the principal analysis, it was assumed that untreated H. pylori infection increased the ulcer risk by 50 percent and that successful eradication reduced the risk of adverse events to that of uninfected patients. Patients' ulcer risk and the protective effect of H. pylori eradication were evaluated using sensitivity analysis. When compared to no H. pylori testing, H. pylori screening led to fewer symptomatic ulcers and ulcer complications and a higher cost per patient. The incremental cost attributable to the H. pylori screening strategy to prevent a symptomatic and complicated ulcer was $16,805 and $31,842 respectively. The clinical and cost effectiveness advantage of H. pylori screening improved as patients' ulcer risk increased or the protective effect of H. pylori eradication was enhanced. The authors conclude that based upon the available evidence, H. pylori screening has the potential to reduce NSAID related adverse events for average risk patients at an incremental cost. Until controlled investigations definitively quantify the effect of H. pylori eradication on clinically significant NSAID related adverse events, a compelling argument can be made for H. pylori testing for chronic NSAID users at increased risk of ulcer disease. 3 figures. 2 tables. 32 references.

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Ranitidine Bismuth Citrate, Tetracycline, Clarithromycin Twice-A-Day Triple Therapy for Clarithromycin Susceptible Helicobacter Pylori Infection Source: Alimentary Pharmacology and Therapeutics. 13(2): 169-172. February 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: Although many combination therapies have been proposed, there is still interest in identifying simple, inexpensive, effective protocols that have high rates of success. This article reports on a study undertaken to investigate the role of the new soluble form of bismuth (ranitidine bismuth citrate) in twice a day therapy for Helicobacter pylori infection. Patients with histologically and culture proven H. pylori infection received ranitidine bismuth citrate 400 mg, tetracycline HCl 500 mg, and clarithromycin 500 mg, each b.d. for 14 days, followed by 300 mg ranitidine once a day for 4 additional weeks. Outcome was assessed 4 or more weeks after the end of antimicrobial therapy by repeat endoscopy with histology and culture (49 patients) or urea breath testing (14 patients). Sixty three patients completed the therapy (59 men and 4 women; average age 56.7 years, range 31 to 75 years). All patients had clarithromycin susceptible strains prior to therapy. H. pylori infection was cured in 94 percent. There was a therapy failure in one patient who took the medicine for only 1 day and stopped because of side effects. Three of the isolates from treatment failures were available post failure; two were clarithromycin resistant and one was susceptible. Side effects, primarily diarrhea, were severe in two patients (3 percent) and moderate in three. The authors conclude that this therapeutic regimen was well tolerated and effective for the treatment of H. pylori infection in patients with clarithromycin susceptible H. pylori. 33 references. (AA-M).

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Eradication of Helicobacter Pylori Prevents Ulcer Development in Patients with Ulcer-Like Functional Dyspepsia Source: Alimentary Pharmacology and Therapeutics. 15(2): 195-201. February 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: Although the eradication of Helicobacter pylori infection benefits patients with gastric or duodenal ulcers, the value of eradicating the bacterial infection in the patients with functional dyspepsia (FD, includes heartburn as a primary symptom) remains controversial. This article reports on a study undertaken to determine whether eradicating H. pylori can prevent the subsequent development of ulcers or relieve the symptoms of FD patients. In the double blind, placebo controlled trial, 161 patients infected with H. pylori who had FD were randomly assigned to 7 days of treatment with a lansoprazole based triple therapy or placebo and then followed for 1 year. The main outcome measures were the development of peptic ulcers and the resolution of symptoms. H. pylori was eradicated in 63 out of 81 patients (78 percent) in the treatment group and none of the 80 patients (0 percent) in the placebo group. During the followup period, two patients in the treatment group and six patients in the placebo group developed peptic ulcers at repeat endoscopy (2.5 percent versus 7.5 percent). The reduction in ulcer rates was statistically significant in the 'ulcer like' subgroup but not in the 'dysmotility like' and 'unclassifiable' subgroups. Regarding symptom response, the resolution rates of symptoms were similar between the treatment and placebo groups (58 percent versus 55 percent, respectively). Additionally, no significant differences

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existed in the symptom responses between the treatment and control arms in each of the dyspepsia subgroups. The authors conclude that eradicating H. pylori can prevent the subsequent development of peptic ulcers in the patients with 'ulcer like' FD. However, this approach does not significantly reduce the symptoms of functional dyspepsia patients. 2 figures. 2 tables. 26 references. •

Trend Toward a Reduced Prevalence of Helicobacter Pylori Infection, Chronic Gastritis, and Gastric Cancer in Japan Source: Gastroenterology Clinics of North America. 29(3): 623-631. September 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32821-9816. (800) 654-2452. Summary: Although there has been a remarkable decline in the prevalence and mortality (death) rates of gastric (stomach) cancer in developed countries, gastric cancer is one of the common malignancies in the world and is still the main cause of death in Japan. This article investigates the trends in Helicobacter pylori infection and gastritis in Japan over the past few decades. The author notes that it is important to investigate the relationship between H. pylori infection and gastric cancer and gastritis to understand better the mechanisms for carcinogenesis (the development of cancer) in the stomach. The author speculates that declines in H. pylori infection and gastritis over the past few decades may lead to a decline in gastric cancer in Japan, supplemented by excellent procedures for the early detection of gastric cancer. H. pylori infection rarely is acquired in adult life, so once it is eradicated, reinfection is not expected in adult patients. The author concludes that adequate treatment of H. pylori provides long term protection against gastric cancer.

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Helicobacter Pylori Infection and Anorexia of Aging (commentary) Source: Archives of Internal Medicine. 157(3): 269-272. February 10, 1997. Summary: Anorexia and malnutrition are frequently encountered problems in the geriatric patient population. Anorexia of aging, i.e., anorexia caused by the aging process itself, has been proposed as the cause of clinically unexplained anorexia in patients of advanced age. In this article, the author reports three cases in which anorexia and geriatric failure-to-thrive (GFTT) syndrome were associated with Helicobacter pylori, then reversed after treatment with antibiotics and a hydrogen-ion proton inhibitor. The clinical presentation of the infection was characterized by the lack of symptoms typically associated with gastric diseases, such as nausea, vomiting, dyspepsia, and abdominal pain. Instead, patients exhibited signs of aversion to food, decline in mental functions, and the inability to perform activities of daily living. The possible causative relationship between H. pylori infection, anorexia of aging, and GFTT syndrome is suggested by the presented cases. The author calls for a major clinical study to explore this relationship. 12 references.

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Helicobacter Pylori Infection as a Risk Factor for Gastrointestinal Symptoms in Patients Using Aspirin to Prevent Ishaemic Heart Disease Source: Alimentary Pharmacology and Therapeutics. 15(7): 1055-1059. July 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.

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Summary: Aspirin use in the secondary prevention of ischemic heart disease may provoke gastrointestinal (GI) discomfort. This article reports on a study undertaken to register GI symptoms and complications in patients with cardiovascular disease using aspirin and to relate these symptoms to infection with H. pylori. Blood samples were obtained from 398 consecutive patients in the Coronary Care Unit at a hospital in the Netherlands; samples were analyzed for serum antibody levels to H. pylori infection. Questionnaires were sent 2 weeks after discharge to assess GI symptoms. Questionnaires were returned by 314 patients (79 percent). A total of 183 out of 314 patients (46 percent) reported GI symptoms. Of the 238 patients using 80 to 100 milligrams of aspirin daily, 145 (61 percent) recorded GI symptoms. Besides aspirin, the use of calcium antagonists was correlated with GI symptoms. Of the 128 patients using calcium antagonists, 84 (66 percent) reported GI symptoms. The prevalence of GI symptoms in H. pylori positive and negative patients using aspirin was 48 percent and 52 percent respectively. The authors conclude that 2 weeks after discharge, almost 50 percent of the patients with cardiovascular disease experienced GI symptoms, especially patients using aspirin or calcium antagonists. Patients seropositive for H. pylori and using aspirin or calcium antagonists did not have more GI discomfort compared to non infected patients. 2 tables. 16 references. •

Review Article: Have We Found the Source of Helicobacter Pylori? Source: Alimentary Pharmacology and Therapeutics. 14(Supplement 3): 7-12. 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: Besides the well established Helicobacter pylori reservoir (i.e., the human stomach), numerous other sources of the bacteria have been hypothesized. This article explores the research into the source of H. pylori. The authors note that none of the hypothesized sources have been proven. In some instances (e.g., pig, sheep), Helicobacter species closely related but different from H. pylori were detected, but the results were misleading because culture of sufficiently discriminating molecular techniques were not used. In other cases, the strain was really H. pylori (in cats), but the case was anecdotal or the animal species (monkey) has so little contact with humans that the possible source has no epidemiological consequence. This is also the case for houseflies, which theoretically can be a vehicle (for bacteria transmission) but practically speaking are not because of too few viable bacteria present in feces. Molecular epidemiology studies demonstrating the route of transmission (fecal-oral, oral-oral, or gastro-oral) are still lacking, but recent studies have confirmed the presence of viable H. pylori in vomitus and in feces in the event of diarrhea. 44 references.

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Evaluation of Five Commercial Serological Tests for the Detection of Helicobacter Pylori Infection in Chinese Source: Alimentary Pharmacology and Therapeutics. 15(5): 703-706. May 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: Commercial serological (blood) tests for the detection of Helicobacter pylori infection must be locally validated. This article reports on a study that evaluated the accuracy of five commercial tests in the Chinese population. Serum samples were

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collected from patients referred for upper endoscopy. Antral (stomach) biopsies were taken for histological examination and culture of H. pylori. The gold standard for diagnosing H. pylori infection was positive histological staining and or positive H. pylori culture. The serum samples were tested for H. pylori antibodies using the following tests: Cobas Core Anti H pylori EIA; GAP IgG; GAP IgM; H. pylori microwell EIA (Quidel); and Premier H. pylori. The sensitivity, specificity, and accuracy of each test was calculated according to the manufacturers' instructions or according to a new cut off value. A total of 158 patients were recruited among whom 114 (72 percent) were H. pylori positive. Indeterminate results varied from 7 to 19 percent. The accuracy of the tests varied from 57 to 85 percent. By using new cut off values, the accuracy was much improved, ranging from 73.4 percent to 86.7 percent. The authors conclude that by defining new cutoff values for the Chinese population, the researchers were able to improve the performance of some of the serology tests. This illustrates the importance of local validation. 3 tables. 13 references. •

Helicobacter Pylori Eradication Does Not Worsen Quality of Life Related to Reflux Symptoms: A Prospective Trial Source: Alimentary Pharmacology and Therapeutics. 16(6): 1143-1148. June 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: Concern has been raised that drug therapy to eradicate Helicobacter pylori infections may lead to the development of gastroesophageal reflux disease (GERD). This article reports on a prospective study that was designed to assess reflux-related quality of life and the symptoms of GERD in patients undergoing H. pylori therapy. Patients with a primary complaint of dyspepsia (upper abdominal pain or discomfort) and endoscopic biopsy positive for H. pylori received triple therapy for 2 weeks. In 48 of 61 patients, H. pylori was eradicated. The mean scores in cured patients for each of the five domains were comparable at baseline and 6 months after therapy. The proportion of cured patients with a large decrease in quality of life (10 to 17 percent) was similar to the proportion with a large increase (15 to 21 percent). Heartburn was present at baseline in 22 cured patients; at 6 months, it persisted in 13 and resolved in 9, while 9 patients developed new heartburn. The authors conclude that a population of patients presenting with dyspepsia should have no overall increase or decrease in quality of life due to symptomatic gastroesophageal reflux disease in the 6 months after H. pylori therapy. 2 tables. 25 references.

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Helicobacter Pylori Eradication: Comparison of Three Treatment Regimens in India Source: Journal of Clinical Gastroenterology. 28(4): 348-351. June 1999. Contact: Available from Lippincott-Raven Publishers. P.O. Box 1550, Hagerstown, MD 21741. (800) 638-3030 or (301) 714-2300. Summary: Conventional bismuth based triple therapy for Helicobacter pylori has multiple problems, such as inadequate drug compliance, side effects, and drug resistance. The combination of omeprazole and clarithromycin with or without antibiotics like amoxycillin has been shown to be effective in eradicating H. pylori. Reports from India on the efficacy of clarithromycin based drug combinations are few. This article reports on a study that evaluated the efficacy of omeprazole and clarithromycin with or without amoxycillin for treating H. pylori infection. The study comprised 64 consecutive patients with upper gastrointestinal symptoms and H. pylori

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infection. In every patient, complete upper gastrointestinal endoscopy was done. H. pylori infection was diagnosed by identification of organism on antral biopsies and by positive rapid urease test. Patients were treated with omeprazole 40 milligrams per day and clarithromycin 250 milligrams twice daily (group I, n = 22), or omeprazole 40 milligrams per day and clarithromycin 250 milligrams twice daily and amoxycillin 500 milligrams three times daily (group II, n = 20), or bismuth subcitrate 120 milligrams four times daily and amoxycillin 500 milligrams three times daily and metronidazole 400 milligrams three times daily (group III, n = 22) for 2 weeks. H. pylori status was reevaluated 1 month after completion of treatment. One patient in each group stopped taking the drugs because of side effects. The eradication rate was not significantly different in group I (68 percent), group II (70 percent), and group III (59 percent). Of those completing therapy, side effects were observed in three patients in group III (nausea, skin rash, metallic taste), whereas none of the patients in group I and group II had any side effects. Addition of amoxycillin did not appear to improve efficacy of dual omeprazole and clarithromycin therapy, and this combination appeared to be no different from bismuth, metronidazole, and amoxycillin triple therapy. The authors conclude that, overall, none of the regimens was particularly good. 1 table. 28 references. (AA). •

13 C-Urea Breath Test Without a Test Meal Is Highly Accurate for the Detection of Helicobacter Pylori Infection in Chinese Source: Alimentary Pharmacology and Therapeutics. 14(10): 1353-1358. 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: Conventional C-urea breath testing (13CUBT) includes a test meal to delay gastric emptying, which, theoretically, improves the accuracy of the test. Citric acid has been proposed as the best test meal. However, recent studies have suggested that a test meal may not be necessary. This article reports on a study undertaken to investigate a new 13CUBT protocol without a test meal, in a population of Chinese persons. Consecutive patients with dyspepsia referred for upper endoscopy were recruited for the study (n = 202). 13CUBT was performed on two separate days with or without a test meal (2.4 grams citric acid) and compared with the 'gold standard' (CLO test and histology). Using receiver operating characteristics (ROC) analysis, the optimal delta value and optimal measurement interval for UBT were 5 percent and 30 minutes, respectively, with or without a test meal. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 13CUBT were similar with and without the test meal. The authors conclude that this simplified 13CUBT protocol without a test meal produced highly accurate and reliable results in the Chinese population. 2 figures. 2 tables. 29 references.

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Modified Seven-Day, Quadruple Therapy as a First Line Helicobacter Pylori Treatment Source: Alimentary Pharmacology and Therapeutics. 15(7): 1061-1065. July 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: Cure rates of 7 day, triple drug therapy undertaken to treat Helicobacter pylori infections seem to be decreasing. Quadruple therapies may be an alternative,

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although their complex administration makes patient acceptance difficult. This article reports on a study undertaken to test the usefulness of a thrice a day, quadruple therapy to cure H. pylori infection. A total of 122 consecutive patients with peptic ulcer and H. pylori infection were treated with omeprazole 20 milligrams twice daily (b.d.), tetracycline chlorhydrate 500 milligrams thrice daily (t.d.s.), metronidazole 500 milligrams t.d.s., and bismuth subcitrate 120 milligrams t.d.s., administered with meals for 7 days. Cure was tested by either endoscopy or breath test after 2 months, and by urea breath test 6 months after therapy. Seven patients were lost to followup. Of the remaining 115, 110 were cured at the first control, giving an intention to treat cure rate of 90.2 percent and a per protocol cure rate of 95.7 percent. All but pne of 103 patients who returned for a 6 month breath test were cured. Side effects were minimal or minor in 47 patients (40.8 percent) and moderate in four (3.4 percent). Compliance was good; 95 percent of patients took more than 90 percent of the pills. Six (5 percent) patients stopped treatment after 1, 2, 4 (two patients), and 6 (two patients) days. The authors conclude that thrice a day quadruple therapy shows excellent cure rates, far above 90 percent, and is well tolerated and easy to comply. Head to head comparison with triple therapies as first line H. pylori treatment seems warranted. 1 table. 32 references. •

Evaluation of Invasive and Non-Invasive Tests for the Diagnosis of Helicobacter Pylori Infection in Chinese Source: Alimentary Pharmacology and Therapeutics. 15(4): 505-511. 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: Different tests are available for diagnosing Helicobacter pylori (a bacterium) infection. This article reports on a study undertaken to compare the most commonly used tests either alone or in combination in Chinese patients with respect to routine clinical use or research purpose. A total of 294 consecutive patients with dyspepsia without previous H. pylori treatment were recruited. During upper endoscopy, biopsies were taken from the antrum and corpus of the stomach, for a commercially available CLO test, an in house rapid urease test, culture, polymerase chain reaction (PCR), and histological examination. Patients then received a 13C urea breath test. The H. pylori status of each patient was determined by a concordance of test results. For routine clinical use, histology (examination of the cells from antral plus corpus biopsies) had an accuracy of 100 percent, while the rapid urease test had an accuracy of 99.7 percent. The 13C urea test was equally reliable, with an accuracy of 94.5 percent. Combinations of two tests did not confer additional advantage over the most accurate single test. For research purposes, the accuracy of using the criteria of two positives out of three diagnostic tests was 100 percent and equivocal results were not found. 2 tables. 23 references.

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Treatment of Helicobacter Pylori in Patients with Upper Abdominal Pain Syndromes Source: Canadian Journal of Gastroenterology. 13(4): 299-300. May 1999. Contact: Available from Pulsus Group, Inc. 2902 South Sheridan Way, Oakville, Ontario, Canada L6J 7L6. Summary: Dyspepsia has been defined as a syndrome of upper abdominal pain that is endoscopy negative (i.e., no ulcer). The cause of this syndrome is not clear, but it is believed that it may be heterogeneous; to date, no cause has been elucidated, but some investigators believe that Helicobacter pylori might be important. This article

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summarizes three recent research studies that investigated the role of H. pylori eradication in the treatment of upper abdominal pain syndromes. Despite the differences in design among the three studies, similar conclusions were reached by the investigator. In once, a treatment regimen designed to eradicate H. pylori had only a marginal impact, at best, on symptoms, while the other two studies did not demonstrate a convincing benefit. The author hypothesizes that perhaps the minor differences in the results obtained between the first study and the other two studies related largely to the definition of dyspepsia, differences in scoring systems, and possibly some of the endoscopic criteria for 'normal.' The author concludes that these studies may not have an impact on the prescribing practice of the clinical gastroenterologist. However, the results may give pause to empiricists who feel obliged to treat patients with upper abdominal pain syndromes and no defined cause with a costly pharmaceutical regimen of multiple antibiotics and proton pump inhibitors. 3 references. •

Immunology of Helicobacter Pylori and Prospects for Vaccine Source: Gastroenterology Clinics of North America. 29(3): 671-685. September 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32821-9816. (800) 654-2452. Summary: Effective antimicrobial therapies have been developed to treat Helicobacter pylori infections; however, patient compliance with a complicated regimen that can cause unpleasant side effects has been less than ideal. An efficacious vaccine against Helicobacter pylori would provide a cost effective means of preventing numerous gastric diseases. This article reviews the immunology of H. pylori and prospects for a vaccine. Several H. pylori animal models have been developed for use in the development of prototype subunit H. pylori vaccines. Using murine (mouse), ferret, and nonhuman primate systems, prophylactic and therapeutic vaccines have been shown to be effective at providing protection or in significantly reducing the H. pylori load in the gastric mucosa. Many of these vaccine prototypes have been delivered orally. Recent studies investigating alternative routes of antigen delivery and more traditional adjuvant systems provide encouraging data that a vaccine might someday be extended for use in humans. A better understanding of the host immune response to H. pylori infection should allow investigators to develop immunotherapies to prevent the acquisition of infection and eradicate existing chronic H. pylori infection. 1 figure. 1 table. 85 references.

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Comparative Efficacy of New Investigational Agents Against Helicobacter Pylori Source: Alimentary Pharmacology and Therapeutics. 15(4): 487-492. 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: Emergence of antibiotic resistant Helicobacter pylori (a bacterium) has necessitated the identification of alternate therapies for the treatment of this infection. This article reports on a study undertaken to assess the in vitro (in real life use) of two agents still under investigation: DMG-MINO CL 344 (a derivative of minocycline) and davercin, a cyclic carbonate of erythromycin A. These agents were compared to older antibiotics (clarithromycin, azithromycin, minocycline, tetracycline, ofloxacin, ciprofloxacin, and cefixime) against clinical isolates of H. pylori. Testing was performed using the agar dilution method; Mueller Hinton agar containing 5 percent aged sheep blood was used. Twenty-one clarithromycin resistant and 16 clarithromycin susceptible

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clinical isolates of H. pylori, obtained from patients with duodenal ulcer, were used. Against clarithromycin susceptible isolates, all antimicrobial agents except the fluoroquinolones were highly effective. Against clarithromycin resistant H. pylori, the values showed that the tetracyclines and cefixime were the most effective agents. The fluoroquinolones and macrolides were ineffective. Macrolide cross resistance was detected. The authors conclude that macrolide cross resistance prevents the use of this entire class of antimicrobials when clarithromycin resistance is present. Tetracyclines and cefixime are possible alternative agents for the treatment of H. pylori infection in these patients. 2 tables. 33 references. •

One-Week Triple Therapy with Esomeprazole Provides Effective Eradication of Helicobacter Pylori in Duodenal Ulcer Disease Source: Alimentary Pharmacology and Therapeutics. 14(12): 1605-1611. December 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: Esomeprazole is the first proton pump inhibitor to be developed as an optical isomer for the treatment of acid related diseases. This article reports on a study of 1 week triple therapy with esomeprazole for eradication of Helicobacter pylori bacteria in duodenal ulcer disease. Patients with H. pylori infection, confirmed by C urea13 breath test (UBT), and no current ulcer, were randomized to double blind treatment with esomeprazole 20 mg twice daily (n = 224) or omeprazole 20 mg twice daily (n = 224), in combination with amoxicillin 1 gram twice daily and clarithromycin 500 mg twice daily for 1 week. A negative UBT at both 4 and 8 weeks after completing therapy indicated successful H. pylori eradication. Between group differences in eradication rates were not statistically significant. Both regimens were well tolerated, with an adverse event profile and frequency typical of proton pump inhibitor plus antibiotic combination therapy. The most commonly reported adverse events were diarrhea and taste changes, which were most likely attributable to amoxicillin and clarithromycin, respectively. The 90 percent eradication rate exceeds that of current recommendations and national guidelines. 4 figures. 3 tables. 17 references.

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Helicobacter Pylori 'Rescue' Regimen When Proton Pump Inhibitor-Based Triple Therapies Fail Source: Alimentary Pharmacology and Therapeutics. 16(6): 1047-1057. June 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: Even with the currently most effective treatment regimens, about 10 to 20 percent of patients will fail to obtain eradication of Helicobacter pylori infection. Therefore, in designing a treatment strategy, physicians should not focus on the results of primary therapy alone, but also on the final (overall) eradication rate. This review article focuses on rescue regimens undertaken in patients when the standard triple combinations of drugs (proton pump inhibitor plus two antibiotics) fail. The authors note that the choice of second line treatment depends on which treatment was used initially, because re-treatment with the same regimen is not recommended. Therefore, it is not necessary to perform culture after the first eradication failure. Assessment of the severity of H. pylori to antibiotics is suggested only after failure of the second treatment. Different possibilities of empirical treatment have been suggested. After failure of

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proton pump inhibitor-amoxicillin-clarithromycin therapy, quadruple therapy has generally been used. More recently, replacement of the proton pump inhibitor and the bismuth compound by ranitidine bismuth citrate has also achieved good results. After proton pump inhibitor-amoxicillin-nitromidazole failure, re-treatment with proton pump inhibitor-amoxicillin-clarithromycin has been proven to be effective. Finally, first line treatment should not combine clarithromycin and metronidazole in the same regimen, because of the problem of resistance to both antibiotics. Recently, rifabutinbased rescue therapies have been shown to constitute an encouraging strategy for eradication failures, as they are effective against H. pylori strains that are resistant to antibiotics. 1 figure. 1 table. 70 references. •

Gastric Outlet Obstruction Resulting from Peptic Ulcer Disease Requiring Surgical Intervention Is Infrequently Associated with Helicobacter Pylori Infection Source: Journal of the American College of Surgeons. 191(1): 32-37. July 2000. Contact: Available from Journal of the American College of Surgeons. P.O. Box 2127, Marion, OH 43306-8227. (800) 214-8489 or (740) 382-3322. Fax (740) 382-5866. Summary: Gastric outlet obstruction (GOO) secondary to peptic ulcer disease (PUD) requiring therapeutic intervention remains a common problem. The incident of Helicobacter pylori infection in this cohort has not been well defined. Pneumatic dilation (PD) has been proposed as first line therapy before surgical intervention. If H. pylori infection in patients with GOO is infrequent, PD may not offer permanent control without the need for long term antacid therapy. This article reports on a study undertaken to examine the incidence of H. pylori infection and surgical outcomes in patients undergoing resection for GOO. The records of all patients having resection (vagotomy and antrectomy) for benign disease from 1993 to 1998 for GOO at the University of Tennessee hospitals were reviewed retrospectively. Smoking history, NSAID use, weight loss, previous ulcer treatment, previous treatment for H. pylori, and previous attempts at PD were among the factors examined. Surgical complications and patient satisfaction were ascertained from inpatient records, postoperative clinical notes, and followup telephone surveys. During the study period, 24 patients underwent surgical resection. There were 16 men and 8 women, with a mean age of 61 years (range 40 to 87 years). Weight loss was documented in 58 percent and averaged 27 pounds. Five of 24 patients had previous attempts at PD, 3 of whom were H. pylori negative. All five had further weight loss after these failed attempts. Of the 24 patients reviewed, only 8 (33 percent) were H. pylori positive. There were no procedure related deaths. Long term clinical followup was possible in 16 of 24 patients, and all but one demonstrated dramatic clinical improvement by Visick score. The authors concluded that patients with H. pylori negative GOO resulting from peptic ulcer disease should be strongly considered for an early, definitive, acid reducing surgical procedure. 1 figure. 3 tables. 22 references.

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Are Genetic Influences on Peptic Ulcer Dependent or Independent of Genetic Influences for Helicobacter Pylori Infection? Source: Archives of Internal Medicine. 160(1): 105-109. January 10, 2000. Contact: Available from American Medical Association. Subscriber Services Center, P.O. Box 10946, Chicago, IL 60610-0946. (800) 262-2350. Fax (312) 464-5831. E-mail: [email protected]. Summary: Genetic factors play a role or roles in the etiology (cause or development) of peptic ulcer disease (PUD) and the acquisition of Helicobacter pylori infection. This

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article reports on a study undertaken to evaluate the relative importance of genetic and environmental influences as well as the importance of H. pylori on PUD. The cross sectional study included monozygotic (MZ) and dizygotic (DZ) twins, reared apart or together. A total of 258 twin pairs had information regarding H. pylori status and history of peptic ulcer. The intraclass correlations for PUD for MS twins reared apart and together and DZ twins reared apart and together were 0.67, 0.65, 0.22, and 0.35, respectively, which indicates that genetic effects are important for liability to peptic ulcer. The correlation coefficient for MZ twins reared apart (0.67) provides the best single estimate of the relative importance of genetic effects (heritability) for variation in liability to peptic ulcer disease, and structural model fitting analyses confirmed this result. The cross twin cross trait correlations for MZ and DZ twins were examined to determine whether genetic effects for peptic ulcer were shared with or independent of genetic influences for H. pylori. The results suggested that familial environmental rather than genetic influences mediate the association between PUD and H. pylori infection. The authors conclude that genetic influences are of moderate importance for liability to peptic ulcer disease. 3 tables. 33 references. •

Improvement in Atrophic Gastritis and Intestinal Metaplasia in Patients in Whom Helicobacter Pylori Was Eradicated Source: Annals of Internal Medicine. 134(5): 380-386. March 6, 2001. 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: Glandular atrophy and intestinal metaplasia (changes in the cells of the intestinal lining) are precancerous lesions; whether Helicobacter pylori infection or its eradication affects these lesions is controversial. This article reports on a study undertaken to determine whether eradication of H. pylori is associated with improvement in glandular atrophy and intestinal metaplasia after at least 1 year. The single blind prospective trial included 163 consecutive patients with dyspepsia and H. pylori infection, seen at an academic gastroenterology clinic in Japan. The intervention consisted of a 1 week course of a proton pump inhibitor and antibiotic therapy. In the 115 patients in whom H. pylori was eradicated, inflammation and mean neutrophil activity had decreased by 1 to 3 months, and both glandular atrophy in the corpus (the main body of the stomach) and intestinal metaplasia in the antrum had decreased by 12 to 15 months. Glandular atrophy in the corpus improved in 34 of 38 patients (89 percent) with atrophy before treatment, and intestinal metaplasia in the antrum improved in 28 of 46 patients (61 percent) who had metaplasia at baseline. In the 48 patients in whom eradication was unsuccessful, no significant histologic changes were observed. The authors conclude that in the year after successful H. pylori eradication, precancerous lesions improved in most patients. 1 figure. 1 table. 20 references.

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Helicobacter Pylori and Nonsteroidal Anti-Inflammatory Drugs Source: Gastroenterology Clinics of North America. 30(4): 937-952. December 2001. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32821-9816. (800) 654-2452. Summary: Helicobacter pylori and nonsteroidal antiinflammatory drugs (NSAIDs) cause most peptic ulcer disease. Because both of these factors are highly prevalent, defining the precise relationship between H. pylori and NSAIDs is important for theoretical and practical reasons. To date, there are data to suggest that H. pylori

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increases, has no effect on, or decreases ulcer risk in NSAID users. This confusion reflects a complex relationship between H. pylori and NSAIDs. The complexity is due partly to a wide spectrum of host response to H. pylori and NSAIDs. This article gives an overview of the pathogenetic mechanisms shared by H. pylori and NSAIDs on ulcer development, then reviews the clinical studies on the interaction between H. pylori and NSAIDs. The author emphasizes that better understanding of the design of these studies might resolve some of the controversies. Factors such as previous exposure to NSAIDs, a history of ulcer complication, concurrent use of acid-suppressant therapy, and the difference between NSAIDs, and low dose aspirin all affect the interrelationship between H. pylori, NSAIDs, and ulcers. 2 figures. 4 tables. 77 references. •

Relationship Between Persistence of Helicobacter Pylori and Dysplasia, Intestinal Metaplasia, Atrophy, Inflammation, and Cell Proliferation following Partial Gastrectomy Source: Digestive Diseases and Sciences. 44(2): 243-252. February 1999. Summary: Helicobacter pylori and partial gastric resection are risk factors for cancer. This article reports on a study to investigate the presence of H. pylori in postgastrectomy patients and to correlate that with alterations in mucosal architecture and cell proliferation. The study included 151 endoscopic biopsies from 22 patients (15 to 47 years of age, mean age 29.2 years), following partial gastrectomy with Billroth II reconstruction for peptic ulcer disease; each biopsy was examined for the presence of H. pylori using Giemsa staining. Sections were scored for grade of hyperplasia, intestinal metaplasia, dysplasia, inflammation, and atrophy. Immunohistochemistry for proliferative cell nuclear antigen (PCNA) was used to characterize cell proliferation. H. pylori was observed in 17 of 22 patients (77.3 percent) or in 57 of 151 biopsies (37.7 percent). Metaplasia was seen in 18 of the 22, chronic atrophic gastritis in 20 of 22 patients, and cystic glandular dilation in 21 of the 22 patients. The highest type of metaplasia in each patient was: four Type I, five Type IIA and nine Type IIB. Dysplasia was present in 16 biopsies from nine patients. H. pylori was more prevalent in intestinal metaplasia type I (44.8 percent of biopsies), than in type IIA (32.7 percent) or type IIB (25 percent). No H. pylori was detected in regions showing dysplasia or cystic glandular dilation. H. pylori colonization was associated with degree of inflammation and cell proliferation. In conclusion, H. pylori is commonly seen many years after gastrectomy, it is associated with an increased epithelial cell proliferation, and it is not present in areas of histologic markers of premalignancy (type IIB metaplasia and dysplasia). 4 figures. 5 tables. 42 references.

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Evaluation of Helicobacter Pylori Diagnostic Methods in Patients With Liver Cirrhosis Source: Alimentary Pharmacology and Therapeutics. 16(7):1283-1289. 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: Helicobacter pylori associated peptic ulcer is a frequent complication in patients with cirrhosis (scarring of the liver) and its morbidity rate (associated illness or disease complications) is high. In spite of this, diagnostic methods for H. pylori infection have not been fully evaluated in these patients. This article reports on a study undertaken to evaluate H. pylori diagnostic methods in patients with liver cirrhosis (n = 101). Results showed that 62 patients were positive for H. pylori and 35 were negative

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for H. pylori infection; four were indeterminate. The sensitivity and specificity were 90.4 percent and 100 percent, respectively, for antral histology; 100 percent and 100 percent for gastric body histology; 90.4 percent and 100 percent for antral immunohistochemistry; 96.2 percent and 96.7 percent for body immunochemistry; 85.7 percent and 97 percent for rapid urease test; 83.6 percent and 55.9 percent for serology; 96.4 percent and 97.1 percent for 13C urea breath test; and 75.4 percent and 94.1 percent for fecal antigen. The authors conclude that the most reliable tests for H. pylori infection in cirrhosis patients were the 13C urea breath test and gastric body histology. 1 figure. 4 tables. 28 references. •

Does Helicobacter Pylori Affect Gastric Mucin Expression? Relationship Between Gastric Antral Mucin Expression and H. Pylori Colonization Source: European Journal of Gastroenterology and Hepatology. 13(1): 19-23. January 2001. Contact: Available from Lippincott Williams and Wilkins. 241 Borough High Street, London SE1 1GB, UK 44(0)20-7940-7502. Fax: 44(0)20-7940-7574. Website: http://www.eurojgh.com/. Summary: Helicobacter pylori colonizes the mucous gel layer, the surface epithelium, and the glands of the stomach. It has previously been shown that H. pylori infection causes aberrant expression of gastric mucins MUC 5 and MUC 6. This study aimed to determine the distribution of MUC 5 and MUC 6 in the gastric antrum (the passage from the esophagus to the stomach, i.e., the first part of the stomach) of patients with dyspepsia, and to investigate changes in this pattern in the presence of H. pylori and after successful eradication. Gastric antrum biopsy specimens were examined by immunohistochemistry for mucin gene (MUC 5 and MUC 6) expression. The study included 49 patients positive for H. pylori, in 36 of whom successful eradication was performed, and 11 H. pylori negative patients. There was a gradient of MUC 5 expression, higher to lower, from the surface to the glands, which was more pronounced before eradication. Increased MUC 5 synthesis in the mucous neck cells and in the glands was found after H. pylori eradication. MUC 6 was synthesized in the glands more than in the mucous neck cells or foveola. MUC 6 was also secreted into the lumen and probably comprised the superficial part of the unstirred mucous layer. The authors conclude that the change in MUC 5 synthesis may reflect H. pylori colonization. 6 figures. 18 references.

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Fecal and Oral Shedding of Helicobacter Pylori from Healthy Infected Adults Source: JAMA. Journal of American Medical Association. 282(23): 2240-2245. December 15, 1999. Summary: Helicobacter pylori commonly infects humans; however, its mode of transmission remains unknown. This article reports on a study to determine how humans (the primary host for H. pylori) shed the organism into the environment. The controlled clinical experimental study of 16 asymptomatic H. pylori infected adults and 10 uninfected adults was conducted from February through December 1998 in a hospital in northern California. A cathartic (sodium phosphate, which causes defecation) and an emetic (ipecac, which causes vomiting) were given to all infected subjects, and an emetic was given to one uninfected subject. All vomitus samples from infected subjects grew H. pylori, often in high quantities. Air sampled during vomiting grew H. pylori from 6 (37.5 percent) of the 16 subjects. Saliva before and after emesis grew low quantities of H. pylori in 3 (18.8 percent) and 9 (56.3 percent) subjects, respectively. No normal stools

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and only 22 (21.8 percent) of 101 induced stools grew the organism, although 7 (50 percent) of 14 subjects had at least one positive culture (2 stool culture samples were contaminated by fungus and were not included). No samples from uninfected subjects yielded H. pylori. The authors conclude that H. pylori can be cultivated uniformly from vomitus and, occasionally, from saliva and cathartic stools. The organism is potentially transmissible during episodes of gastrointestinal tract illness, particularly with vomiting. 1 figure. 2 tables. 38 references. •

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 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.

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Can Helicobacter Pylori Serology Still Be Applied As a Surrogate Marker to Identify Peptic Ulcer Disease in Dyspepsia? Source: Alimentary Pharmacology and Therapeutics. 14(5): 615-624. May 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: Helicobacter pylori infection and associated peptic ulcer disease (PUD) has become less common in some countries. This article reports on a study undertaken to determine if H. pylori serology alone or combined with a history of ingestion of nonsteroidal antiinflammatory drugs (NSAIDs) and an age threshold can be used as an indirect ulcer test. The patients (n = 250; 121 males, mean age 52 years) were consecutive

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Australian patients referred for endoscopy. At endoscopy, eight biopsies were taken for rapid urease test (CLO) testing, culture, and histology. NSAID use over the prior 3 months was recorded. Results showed that 106 (42 percent) of the patients were seropositive for H. pylori; 48 (19 percent) patients had PUD (peptic ulcer disease), and 30 (12 percent) used NSAIDs. Serology alone had a sensitivity of 52 percent and a specificity of 60 percent for identifying PUD; the sensitivity and specificity were 60 percent and 55 percent, respectively, when combined with a history of NSAID use. Serology, regardless of NSAID use, would have saved 23 percent in endoscopy workload but would have missed 17 percent of PUD cases if an age threshold of less than 45 years was chosen for omitting endoscopy. The authors conclude that serology was a poor ulcer test despite an excellent performance for detecting H. pylori. A strategy combining serology and an age threshold with a history of NSAID use to reduce endoscopy workloads may not always be appropriate. 1 figure. 4 tables. 47 references. •

Update on the Management of Helicobacter Pylori Infection, Including DrugResistant Organisms Source: Journal of Gastroenterology and Hepatology. 17(4): 482-487. April 2002. Contact: Available from Blackwell Science. 54 University Street, Carlton South 3053, Victoria, Australia. +61393470300. Fax +61393475001. E-mail: [email protected]. Website: www.blackwell-science.com. Summary: Helicobacter pylori infection has many different clinical outcomes and not all infected persons need to be treated. Therefore, indications for treatment have to be clear, and several consensus guidelines have been formulated to aid the medical practitioner in this decision making process. This article offers an update on the management of H. pylori infection, including drug-resistant organisms. Triple therapy with a proton pump inhibitor (PPI), in combination with amoxicillin and clarithromycin, is the established treatment of choice. For patients with penicillin hypersensitivity, metronidazole can be substituted for amoxicillin. H. pylori resistance to metronidazole has been reported in up to 80 percent and resistance to clarithromycin in 2 to 10 percent of strains cultured. Resistance to either one of the antibiotics has been reported to result in a drop in effectiveness of up to 50 percent. To avoid the emergence of resistance to both key antibiotics, the combination of metronidazole and clarithromycin should be avoided where possible. For failed treatment, several strategies can be employed. These include ensuring better compliance with repeat therapy, and maximizing the efficacy of repeat treatment by increasing dosage and duration of treatment, as well as altering the choice of drugs. The author briefly discusses various options for 'rescue' therapies for patients who are refractory to treatment. 2 tables. 41 references.

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Long-Term Effects of Cure of Helicobacter Pylori Infection on Patients with Atrophic Body Gastritis Source: Alimentary Pharmacology and Therapeutics. 16(10): 1701-1708. October 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: Helicobacter pylori infection induces atrophic body gastritis (chronic inflammation of the stomach, associated with degeneration of the stomach mucosa), but the long-term effect of its cure on body atrophy is unclear. This article reports on a study undertaken to investigate the long term effects of H. pylori cure on gastric (stomach)

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morpho-functional parameters in patients with atrophic body gastritis. Forty patients with atrophic body gastritis were cured of H. pylori infection. At eradication assessment (6 to 12 months), in eight of the 40 patients, body atrophy was no longer observed, whereas in 32 of the 40 it remained substantially unchanged. In the 8 patients with reversed body atrophy, gastrinemia decreased significantly with respect to pretreatment values, and basal and stimulated acid secretion increased significantly after cure. In the 32 patients still presenting body atrophy, gastrinemia was similar to pretreatment values. At follow up, the eight patients with revered body atrophy continued with normal gastrinemia, but in the 19 patients with continued atrophy, both corporal atrophy and intestinal metaplasia remained substantially unchanged. The authors conclude that following successful treatment in patients with atrophic body gastritis and H. pylori infection, long-term histological investigations are crucial in order to detect reversed body damage or to confirm continued body atrophy. 4 figures. 2 tables. 35 references. •

Virulence and Pathogenicity of Helicobacter Pylori Source: Gastroenterology Clinics of North America. 29(3): 649-670. September 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32821-9816. (800) 654-2452. Summary: Helicobacter pylori infection is associated with multiple gastroduodenal (stomach and duodenum) disease manifestations. This article reviews many of the bacterial and host factors important in these diseases. The role of conserved and nonconserved H. pylori genes, genotyping, and effect on the epithelial cell cycle in the pathogenesis of disease are discussed. The authors also summarize the alteration of host physiological and immune response mechanisms and the molecules involved in the inflammatory cascade. Virulence (how strong it is and how much it affects the host) of H. pylori is based on factors that allow colonization and adaptation to the stomach environment, and the stimulation of mediators of inflammation that contribute to the physiologic and histologic (cell) changes that happen in the host (infected person). The complete DNA sequences for two H. pylori strain genomes have been published; however, whether these two DNA sequences are sufficient representation of the diversity of H. pylori genetics is unknown. The authors conclude that a better understanding of the role of H. pylori in apoptosis (sloughing off of mucosa) and cellular proliferation would enable clinicians to understand the bacterium's relationship to ulcer generation and stomach cancer. The development of animal models with H. pylori and other Helicobacter species has set the stage in which in vitro observations can be tested in the in vivo model. 1 figure. 1 table. 109 references.

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Bismuth-Based Multi-Drug Therapies in Helicobacter Pylori Eradication Source: Today's Therapeutic Trends. 18(3): 229-239. Third Quarter, 2000. Contact: Available from Communications Media for Education, Inc. P.O. Box 712, Princeton Junction, NJ 08550. (800) 221-3899 or (609) 799-2300. Fax (609) 275-8745. Summary: Helicobacter pylori infection of the gastric mucosa (stomach lining) causes progressive damage, with impairment of gastric function. In the United States, the presence of H. pylori infection has been shown to carry a lifetime risk of peptic ulcer disease of at least 16 percent and a 1 to 3 percent lifetime risk for gastric (stomach) cancer. Numerous treatment regimens have been used to eradicate H. pylori infection. As the organism readily develops antibiotic resistance to single antibiotics, development of multiple drug treatment regimens occurred. Bismuth containing triple therapies were

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the first treatment approach to prove successful, and they are the focus of this review article. Successful therapies have used both topical and systemic antimicrobials. The combination of a proton pump inhibitor (PPI), clarithromycin and amoxicillin; and the bismuth, metronidazole, tetracycline (BMT) combinations, are both available in convenient dose packs (Prevac and Helidac, respectively) that enhance patient acceptance and compliance. The BMT combinations offer a significant cost advantage. The authors conclude that bismuth compounds are safe and effective, and significant H. pylori resistance has not been described. The increasing incidence of clarithromycin resistance suggests that therapies containing bismuth will continue to be a cornerstone of anti H. pylori therapy. 1 table. 32 references. •

Current Therapy for Helicobacter Pylori Infection in Children and Adolescents Source: Canadian Journal of Gastroenterology. 13(7): 571-579. September 1999. Contact: Available from Pulsus Group, Inc. 2902 South Sheridan Way, Oakville, Ontario, Canada L6J 7L6. Fax (905) 829-4799. E-mail: [email protected]. Summary: Helicobacter pylori infects approximately 50 percent of the world's population and is a definitive cause of gastroduodenal disease (i.e., gastritis, duodenal and gastric ulcers) in children and adults. At each of four international conferences, the objective was to reach a consensus on the development of practical guidelines for the diagnosis and treatment of H. pylori infected individuals. However, it was not until the Canadian H. pylori Consensus Conference, held in November 1997, that the issues of H. pylori infection in children were addressed. This article reviews therapies for H. pylori infection in children. If it is accepted that gastric colonization by H. pylori is associated with pediatric gastroduodenal disease, then eradication of the organism must be the intent of the practitioner caring for the child infected with H. pylori. An ideal treatment for H. pylori in children has yet to be determined. This is due to problems with antibiotic resistance, a lack of research treatment trials conducted in children, and problems with drug side effects. Current H. pylori eradication therapy recommendations have been made by extrapolating findings from adult studies in combination with data available from small case series reported in pediatric patients. One chart offers six potential treatment options for H. pylori infections in children. Dual therapy containing regimens are not included as options, due to the clear superiority of triple therapy containing regimens. 5 tables. 87 references.

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Diagnosing and Managing H. Pylori Infections Source: IM. Internal Medicine. 19(7): 10-20, 25. July 1998. Contact: Available from Medical Economics. 5 Paragon Drive, Montvale, NJ 07645. (800) 432-4570. Summary: Helicobacter pylori is a bacteria that thrives in the acidic environment of the stomach, living in the mucous layer covering the gastric mucosa. This continuing education article updates physicians on the latest techniques for diagnosing and managing H. pylori infections. H. pylori has been strongly associated with gastritis, duodenal ulcers, gastric ulcers, and both gastric adenocarcinoma and gastric lymphoma. Diagnostic tests to determine if a patient is infected with H. pylori fall into two categories: noninvasive and nonendoscopic, or invasive and endoscopic tests. Diagnostic tests that do not require endoscopy include various methods of antibody detection and carbon-labeled urea breath tests. Those that involve endoscopy are the rapid urease tests, histology, and culture. The author stresses that the decision to test for H. pylori must be made with a firm resolve to proceed with treatment if the patient is

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infected. Treating H. pylori-positive duodenal and gastric ulcers produces a definitive benefit and is considered the standard of care. Furthermore, successful bacterial cure almost completely eliminates the risk of recurrent bleeding from gastric or duodenal ulcers. Even in patients who take NSAIDs (nonsteroidal anti-inflammatory drugs), H. pylori should be considered an important independent risk factor for ulcer recurrence and should therefore be treated. The author notes that complications of treatment regimens for H. pylori are usually mild and may include nausea, diarrhea, altered sense of taste, and vaginitis. Sidebars present four brief case histories, and their management. The article includes a recertification review self-test; the answers appear in the same journal issue. 4 tables. 19 references. •

Low Rates of Helicobacter Pylori Reinfection in Children Source: Gastroenterology. 117(2): 336-341. August 1999. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Helicobacter pylori is a bacterium that causes gastritis and is associated with duodenal ulcer disease in adults and children. Reinfection after treatment for H. pylori infection is uncommon in adults. It is more likely to occur in children because they acquire primary infection. This article reports on a study to determine whether children are likely to become reinfected with H. pylori and if there are any risk factors for reinfection. The prospective study included 52 children. Children, parents, and siblings underwent 13C urea breath tests. Details of family size and socioeconomic status were documented. The duration of followup was 103.8 patient years (mean was 24 months). Forty six (88.5 percent) of the index children remained clear of infection, and 6 (11.5 percent) children were reinfected. The mean age of those who became reinfected was 5.8 years (plus or minus 5.6 years) compared with 12.3 years (plus or minus 3.0 years) for those who remained clear of infection. Only 2 of 46 (4.3 percent) children older than 5 years of age were reinfected, although 80.8 percent had 1 infected parent and 65 percent of siblings were infected. Reinfection rate was 2.0 percent per person per year in children older than 5 years. Living with infected parents and siblings and low socioeconomic status were not risk factors for reinfection. In logistic regression analysis, age was the only risk factor for reinfection. The authors conclude that these findings also indicate that it is not necessary to treat all family members to achieve long term eradication of H. pylori. 1 figure. 3 tables. 33 references.

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Helicobacter Pylori and Clinical Risks: Focus on Gastro-Oesophageal Reflux Disease Source: Alimentary Pharmacology and Therapeutics. 16 (6 Supplement 3): 1-10. June 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: Helicobacter pylori is a stomach (gastric) pathogen that is a major cause of peptic ulcer disease, has a role in mucosa-associated lymphoid tissue (MALT) lymphoma, and is associated with gastric cancer. Yet, in a large proportion of the human population, H. pylori infection has no apparent adverse clinical consequences. Furthermore, recent research suggests that H. pylori may even confer protection against gastroesophageal reflux disease (GERD). This article summarizes a sponsored symposium held in Helsinki. The symposium was introduced by Professor P. Malfertheiner, with papers presented by Dr. H. J. O'Connor, Professor R.M. Genta, Dr.

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P. Unge, and Professor A.T.R. Axon. Emerging epidemiological and retrospective evidence suggests that the presence of H. pylori infection may provide some protection against GERD, but there is other evidence that shows no benefit of H. pylori for the protection of the esophagus. The presenters emphasize that prospective, multicenter studies are needed to explore the H. pylori-GERD relationship further, to avoid confusing potential benefits with known risks. 58 references. •

Recent Developments in the Epidemiology of Helicobacter Pylori Source: Gastroenterology Clinics of North America. 29(3): 559-578. September 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32821-9816. (800) 654-2452. Summary: Helicobacter pylori is found commonly throughout the world irrespective of how exotic the location. H. pylori remains among the most universal of infections; however, the understanding of some features of infection has changed. This review article on the epidemiology of Helicobacter pylori updates previous reviews and focuses on information made available in the last few years. Several studies of H. pylori have examined identification of new infections and loss of existing infections over time. These studies bring additional information to the many studies on prevalence, however, direct evidence of the major routes of transmission is still lacking. Oral oral, and oral fecal infection has declined rapidly in developed countries, which probably has contributed to declines in duodenal ulcer disease and gastric cancer. Apart from studies of transmission, the influence of H. pylori infection on upper gastrointestinal diseases is undergoing reappraisal. The author notes that the full health implications of the potential elimination of infection are unknown. 2 figures. 2 tables. 143 references.

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Gastritis and Helicobacter Pylori: Forty Years of Antibiotic Therapy Source: Digestion. 58(3): 203-210. May-June 1997. Contact: Available from S. Karger Publishers, Inc. 26 West Avon Road, P.O. Box 529, Farmington, CT 06085. Summary: Helicobacter pylori is now at the forefront of gastroenterology, particularly regarding its eradication as the treatment of gastroduodenal ulcer, whereas its role in gastritis is still widely ignored. The author notes that gastritis was the disease for which H. pylori was originally studied. This article reviews the 40 years of antibiotic therapy for gastrointestinal diseases, notably gastritis, and the application of this experience to present considerations for treatment. Forty years ago, it was shown for the first time that antibiotics can eliminate gastric ammonia production in humans; this suggested that this was due to eradication of bacterial urease activity. Researchers also found that the gastric juice ammonia concentration correlates with hypoacidity (low acid levels) or anacidity (no acid) in people with uremia and with mucosal inflammation in subjects with gastritis. In patients with nonalcoholic and alcoholic gastritis, the histology as well as the symptoms of gastritis were strikingly improved by antibiotic treatment. The beneficial effects of eradication of gastric urease activity and the resulting decreased ammonia production were also shown in patients with hepatic encephalopathy. The author concludes by emphasizing that broader studies and clinical applications of these earlier findings are now warranted. 7 figures. 62 references. (AA-M).

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13C-Urea Breath Tests are the Noninvasive Method of Choice for Helicobacter Pylori Detection Source: Canadian Journal of Gastroenterology. 13(8): 681-683. October 1999. Contact: Available from Pulsus Group, Inc. 2902 South Sheridan Way, Oakville, Ontario, Canada L6J 7L6. Fax (905) 829-4799. E-mail: [email protected]. Summary: Helicobacter pylori is recognized as the most important cause of duodenal and gastric ulcers. This article describes the use of the 13C urea breath test for the noninvasive identification of H. pylori infection. The 13C UBT is more accurate than serology (blood tests) with better positive and negative predictive values, is nonradioactive and safe, and can be used to diagnose H. pylori noninvasively both before and after eradication treatment. The test is simple to administer and can be done anywhere. It is particularly more effective in the under 50 years age group in which the 'test and treat' strategy is advocated. Thus, practitioners can conveniently identify patients who are truly positive for H. pylori, and treatment with antibiotics can be given appropriately. As such, the 13C UBT is advocated as the only reliable nonendoscopic means of detecting H. pylori. The authors conclude that, given the need for this test, it should be made more widely available, and reimbursement should be provided by health care plans. 2 figures. 27 references.

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Treatment of Helicobacter Pylori: An Overview Source: Alimentary Pharmacology and Therapeutics. 14(Supplement 3): 1-6. 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: Helicobacter pylori is recognized to be a serious pathogen, but there is still controversy as to who should be treated. This article reviews the arguments and some of the data advanced to support the differing views; the author briefly considers the currently used therapies and how they may best be employed. There is consensus for treatment of patients with H. pylori positive peptic ulcer and B cell lymphoma. Patients with lymphcytic gastritis and giant fold gastritis (Menetrier's disease) may also respond to treatment. Patients with functional dyspepsia have a 20 percent placebo response with a 5 to 10 percent 'eradication' response, results not dissimilar from empirical treatment with a proton pump inhibitor (PPI). A 'test and treat' policy for patients with uninvestigated dyspepsia remains controversial. Some clinicians have suggested that eradication of the H. pylori may increase the patient's risk of gastroesophageal reflux disease (GERD) or predispose patients to adenocarcinoma at the gastroesophageal junction (stomach cancer). However, PPI treatment without H. pylori eradication induces greater inflammation in the gastric corpus; this is the phenotype associated with non-cardia gastric cancer. A minority of clinicians believe the H. pylori should be eradicated in all individuals. The author concludes that, when choosing treatment, it is logical to start with a combination of antibiotics that, in the event of failure, will allow a second combination to be used without overlap. The author recommends the use of amoxycillin, clarithromycin, and a PPI for the first treatment, which then leaves the option of ranitidine bismuth citrate, tetracycline, and metronidazole, in the event of first line failure. 37 references.

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Helicobacter Pylori: An Emerging Infectious Disease Source: Nurse Practitioner. 25(8): 40, 43-44, 47, 50, 53-55. August 2000. Contact: Available from Nurse Practitioner. Circulation Department, P.O. Box 5053, Brentwood, TN 37024-5053. (800) 490-6580. Fax (615) 377-0525. Summary: Helicobacter pylori is the most common chronic bacterial infection in the world, colonizing the stomachs of more than 50 percent of the human population. The discovery of this bacterium has changed the concept of care and management for peptic ulcer disease (PUD), mucosa associated lymphomas, gastritis, and gastric carcinoma (stomach cancer). Although the mode of transmission is not definitively known, person to person contact is suspected. This article discusses H. pylori, the associated clinical syndromes and diseases, risk factors, and current pharmacologic management. In the United States, H. pylori prevalence increases by 10 percent with each decade of life. The infection is more prevalent in groups of lower socioeconomic status. Crowded living conditions, such as in institutions, increase the incidence and prevalence. Controversy exists regarding testing patients for H. pylori who present with complaints consistent with dyspepsia. Those who should be tested for H. pylori include patients who have a history of PUD and have not been treated for H. pylori in the past, and patients with a history of MALT lymphoma. A recent report suggests screening patients with a parental history of gastric cancer. For outpatient diagnosis, serology or a urea breath test can be used with high sensitivity and relatively low cost. A variety of treatment protocols may be used to eradicate H. pylori; however, only two are currently approved by the Food and Drug Administration. One regimen consists of amoxicillin, clarithromycin, and omeprazole for 14 days; the second regimen uses amoxicillin, clarithromycin, and lansoprazole for 10 days. Reinfection rarely occurs after successful treatment of H. pylori. A posttest with which readers can quality for continuing education credits is appended to the article. 3 figures. 2 tables. 44 references.

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Overexpression of Co-Stimulatory Molecules in Peripheral Mononuclear Cells of Helicobacter Pylori-Positive Peptic Ulcer Patients: Possible Difference in Host Responsiveness Compared With Non-Ulcer Source: European Journal of Gastroenterology and Hepatology. 13(1): 11-18. January 2001. Contact: Available from Lippincott Williams and Wilkins. 241 Borough High Street, London SE1 1GB, UK 44(0)20-7940-7502. Fax: 44(0)20-7940-7574. Website: http://www.eurojgh.com/. Summary: Helicobacter pylori is the principal cause of gastritis and peptic ulcer disease. However, H. pylori positive patients do not always have peptic ulcer. This study was carried out in order to determine the difference in host immune reaction to H. pylori between patients with peptic ulcer and those without. The study included 10 H. pylori positive patients with peptic ulcer, 10 H. pylori positive nonulcer patients, and 10 healthy volunteers who were examined for expression of surface molecules in peripheral blood mononuclear cells. The results showed more mononuclear cells expressed molecules ICAM-1, VLA-4, Leu-M3 in H. pylori positive ulcer patients than in nonulcer patients and healthy volunteers. There were also more cells expressing CD28, SLex, CD4, HLA-DR, and NU-B2 in H. pylori positive ulcer patients than in nonulcer patients and healthy volunteers. There were fewer cells expressing CD8 in H. pylori positive ulcer patients than in nonulcer patients and healthy volunteers. The authors conclude that H. pylori infection may cause immunological reactions which are reflected in peripheral mononuclear cells. However, the activity and characteristics of

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peripheral mononuclear cells, in terms of expression of adhesion molecules, may differ between ulcer and nonulcer patients who are infected with H. pylori. 8 figures. 31 references. •

Eradication of Helicobacter Pylori with Pantoprazole and Two Antibiotics: A Comparison of Two Short-Term Regimens Source: Alimentary Pharmacology and Therapeutics. 14(9): 1151-1157. September 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: High rates of Helicobacter pylori (a bacterium that is a causative factor in peptic or stomach ulcer disease) eradication can be achieved by combining proton pump inhibitors with two antibiotics. However, in the search for an optimal therapy, a direct comparison of different regimens is necessary. This article reports on an open study of 331 patients with duodenal ulcer who were screened and randomly allocated to either pantoprazole 40 milligrams twice a day, clarithromycin 500 milligrams twice a day and metronidazole 500 milligrams twice a day (PCM regimen) or pantoprazole 40 milligrams twice a day, amoxycillin 1000 milligrams twice a day, and clarithromycin 500 milligrams twice a day (PAC regimen) for 7 days. Both combinations were followed by a 7 day therapy with pantoprazole 40 milligrames alone. Eradication of H. pylori was assessed by use of a 13C urea breath test 4 weeks after the intake of the last medication. Eradication rates were 90 percent in intention to treat patients from the PCM and the PAC group. H. pylori was eradicated in 112 out of 117 per protocol patients of the PCM group (96 percent) and in 119 out of 126 patients of the PAC group (94 percent). Rapid relief from ulcer pain and a decrease in the mean intensity of other gastrointestinal symptoms was observed. Adverse events were reported in 69 patients; none of the adverse events were related to the intake of pantoprazole. Four serious adverse events, none related to the trial medication, were observed. The authors conclude that both pantoprazole based short term triple therapies are highly effective and well tolerated treatment regimens in the eradication of H. pylori. 3 figures. 1 table. 18 references.

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Helicobacter Pylori Infection, Gastritis and Gastric Cancer: Helicobacter Pylori Infection Among Japanese Children Source: Journal of Gastroenterology and Hepatology. 15(12): 1382-1385. December 2000. Contact: Available from Blackwell Science. 54 University Street, Carlton South 3053, Victoria, Australia. +61393470300. Fax +61393475001. E-mail: [email protected]. Website: www.blackwell-science.com. Summary: In Japan, there are few reports describing Helicobacter pylori infection among young children. This article reports on a study undertaken to identify risk factors associated with H. pylori in school aged children in Japan. Subjects were first grade students of three elementary schools (n = 310) and second grade students of a junior high school (n = 300). Personal information, such as students' medical history, parents' history, family size, siblings, and household pets, was collected using a questionnaire. Saliva samples and personal information were collected twice. Among the children, factors related to Helicobacter antibody in saliva included spending a longer period of time in a nursery school or kindergarten and a maternal history of stomach disease. Birth order, sleeping situation, and number of siblings were not factors that were significantly related to Helicobacter antibody in the saliva. Chewing food for the infant, family size, rooms in the household, sharing a bedroom during childhood, pets, a past

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history, and a paternal history were not related to positivity. The results indicate that transmission is person to person, mainly through close contact with other children and intrafamilial infection. H. pylori infection seems to occur frequently early in life, probably before 6 years of age. 2 tables. 29 references. •

Review Article. Helicobacter Pylori: Where Are We and Where Are We Going? Source: Alimentary Pharmacology and Therapeutics. 14(Supplement 3): 55-58. 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: In this article, the author offers a personal view on what has been achieved in Helicobacter pylori research and what the expectations might be for further developments. The author stresses that knowledge about the organism is already extensive. Particularly intriguing are the differences in genetic makeup in the various geographical regions. However, detailed knowledge on how the organism spreads is still lacking. The clinical spectrum of the disease in man is largely known, but as H. pylori is disappearing worldwise, the relative frequency of H. pylori negative ulcer disease is increasing. To what extent H. pylori disappearance and eradication is responsible for the decreasing incidence of gastric cancer remains uncertain. Antimicrobial therapy is dominated by proton pump inhibitor (PPI) triple therapy as first line, with quadruple therapy as second-line therapy. The long term consequences of the rising resistance to the 'key' antimicrobials (clarithromycin, metronidazole) are so far unknown and speculative. The author notes that quadruple therapy appears less influenced by antimicrobial resistance compared with the other treatment modalities. 12 references.

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Future of Helicobacter Pylori Eradication: A Personal Perspective Source: Alimentary Pharmacology and Therapeutics. 11(Supplement 1): 109-115. April 1997. Contact: Available from Mercury Airfreight International, Ltd. 2323 EF, Randolph Avenue, Avenel, NJ 07001. E-mail: [email protected]. Summary: In this article, the author presents a personal perspective on current issues in Helicobacter pylori eradication. The author notes that future changes in the use of H. pylori eradication therapy first will involve a decision-making process to determine which individuals require testing for the bacteria. Clearly, only persons who require therapy need to be diagnosed and, at present, the indications for therapy are constantly expanding. The author takes the view that everyone with H. pylori would be better off without the bacterium, but accepts that in many countries resources are inadequate to achieve this goal. Where antibiotic therapy for H. pylori fails because of a resistant organism, second treatment must include a different class of antibiotic. When a third therapy is contemplated, antibiotic sensitivity studies are usually necessary prior to therapy. In developing countries where reinfection with H. pylori is common, lesser goals than permanent cure might be appropriate. Thus, selected patients could have H. pylori suppressive therapy to prevent full expression of H. pylori-associated disease, or to prevent reinfection after an initial eradicative therapy. The author concludes that, after considering all these alternatives, a vaccination strategy, if safe and cost effective, is the ideal future therapy. 2 figures. 1 table. 30 references. (AA-M).

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Gastric Pathology Associated with Helicobacter Pylori Source: Gastroenterology Clinics of North America. 29(3): 705-751. September 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32821-9816. (800) 654-2452. Summary: In this article, the author reports on a study of approximately 8,000 gastric biopsy specimens, over a period of 20 years. The author has studied these cases in detail, with followup of 10 years in some cases. For much of this work, the author developed quantitative methods, particularly for the study of the antibacterial treatment of duodenal ulcers. The author discusses the range of changes seen in these biopsy specimens, the effect of treatment, and the relation of this work to that of other authors. The article discusses the history of Helicobacter infection and the histology of the normal stomach. The author examines the specific histological features related to Helicobacter pylori infection, including leukocyte infiltration of the epithelium, specific epithelial changes, and the morphology and distribution of the bacteria. Nonspecific changes, including atrophy, metaplasia, and stromal damage, are reported. Finally, the author describes special features: electron microscopy; changes after treatment; duodenal ulcer; other related conditions, including neoplasia; quantification of the histology; and the Sydney and Houston classifications. 27 figures. 7 tables. 23 references.

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In a World of Black and White, Helicobacter Pylori Is Gray Source: Annals of Internal Medicine. 130(8): 695-697. April 20, 1999. 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: In this commentary article, the author reviews the past 15 years of treatment for Helicobacter pylori infections, focusing on the question, 'In whom is the elimination of H. pylori beneficial?' The author first summarizes the consensus about the role of H. pylori in gastric ulcer, the use of diagnostic tests to confirm its presence, and the natural history of the organism. The author then summarizes emerging issues, commenting that H. pylori strains are highly diverse and the type of strain with which an individual patient is colonized affects the risk for disease. The author also ponders the problem of increased rates of gastroesophageal reflux disease (GERD), Barrett's esophagus, and adenocarcinomas of the lower esophagus and gastric cardia, even as rates of peptic ulcer disease and noncardia gastric cancers have been decreasing. The role of H. pylori in these epidemiologic changes still needs much investigation. The author discusses terminology (e.g., colonization versus infection), clinical dilemmas, and the present challenges for physicians treating patients with H. pylori infections. The author concludes by recommending that physicians undertake a search for H. pylori only in patients with peptic ulcer disease and gastric MALT lymphomas. In such patients, the benefits of treatment seem to outweigh the risks and costs. However, before treating other patients, physicians should wait to learn what ongoing research will demonstrate. 20 references.

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Review Article: Helicobacter Pylori Vaccines-the Current Status Source: Alimentary Pharmacology and Therapeutics. 14(9): 1107-1118. September 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.

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Summary: In this review article, the authors take a look at the current status in the development of a vaccine against the human pathogenic bacterium, Helicobacter pylori, a major etiologic factor (cause) of peptic ulcer disease and gastric adenocarcinoma. Various animal models are now in use from mice infected with H. pylori, through gnotobiotic pigs and primates, to ferrets naturally infected with their own Helicobacter, H. mustelae. A significant problem remains the requirement for a suitable mucosal adjuvant. Detoxification or the use of low doses of adjuvants already available may provide a solution, and new immune stimulating compounds have been tested with some success. New approaches include the delivery of Helicobacter antigens by DNA immunization, microparticles, or live vectors such as attenuated salmonella and the examination of alternative routes of vaccine administration. The phenomenon of post immunization gastritis and improvements in vaccine efficacy are also discussed. A major area of interest is the mechanism by which immunization actually influences Helicobacter colonization. This remains a mystery: antibodies appear to be unimportant whereas CD4 positive T cells are essential. Finally, the authors offer their viewpoint on whom should be immunized when a final vaccine becomes available. 63 references. •

Novel Therapies for Helicobacter Pylori Infection Source: Alimentary Pharmacology and Therapeutics. 13(1): 35-41. January 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: Increasing antibiotic resistance has begun to impair the ability to cure Helicobacter pylori (H. pylori) infection. This article reports on a study undertaken to evaluate orally administered novel therapies for the treatment of H. pylori infection. H. pylori infected volunteers received hyperimmune bovine colostral immune globulins, an oligosaccharide containing an H. pylori adhesion target, or recombinant human lactoferrin. Outcome was assessed by urea breath test or histological assessment of the number of H. pylori present. Results showed that none of the novel therapies appeared effective and no adverse events occurred. The authors conclude that, although in vitro data appeared promising, in vivo results were disappointing. Higher doses, longer duration of therapy, adjunctive acid suppression, or a combination could possibly yield better results. 3 figures. 1 table. 41 references. (AA-M).

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Pathogenesis of Helicobacter Pylori Infection Source: Current Opinion in Gastroenterology. 15(1): 66-71. January 1999. Contact: Available from Lippincott Williams and Wilkins Publishers. 12107 Insurance Way, Hagerstown, MD 21740. (800) 637-3030. Fax (301) 824-7390. Summary: Intensive investigation into Helicobacter pylori's interactions with the human host during the period of this review article (1998) has led to several important developments in the understanding of H. pylori pathogenesis. The authors note that direct evidence supports a central role for bacterial adhesion to host gastric epithelial (stomach lining) Lewis antigens. Adherence can result in activation of host signaling cascades, including tyrosine phosphorylation events. H. pylori induces an immune response that is skewed toward a T helper (Th) cell 1 phenotype, and an insufficient Th2 response is associated with the inability of the host to eradicate the organism. An area of active investigation has been the induction of epithelial apoptosis (sloughing off of the stomach lining), both in direct response to H. pylori and by T cell mediated pathways. Although the consensus is that the cagA gene product is not involved in pathogenesis,

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the presence of the cag pathogenicity island is associated with increased gastric inflammation and decreased epithelial repair. Interestingly, infection with cagA positive H. pylori appears to result in decreased prevalence of both gastroesophageal reflux disease and adenocarcinoma of the esophagus and cardia. However, this area of research is still controversial. 61 references (13 annotated). •

Helicobacter Pylori Eradication with Proton Pump Inhibitor-Based Triple Therapies and Re-Treatment with Ranitidine Bismuth Citrate-Based Triple Therapy Source: Alimentary Pharmacology and Therapeutics. 13(2): 163-168. February 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: It has been suggested that short term triple therapy with a proton pump inhibitor, plus clarithromycin and amoxycillin, be used as first choice in treating Helicobacter pylori infection, while eradication failure patients should be further treated with quadruple therapy. However, conflicting results have been reported using these treatment regimens in different countries. This article reports on a study in which a total of 278 patients with H. pylori infection were randomized to receive 1 week of triple therapy comprising clarithromycin 500 mg b.d., amoxycillin 1 g b.d., and either omeprazole 20 mg b.d. (OAC; 90 patients), or pantoprazole 40 mg b.d. (PAC; 95 patients), or lansoprazole 30 mg b.g. (LAC; 93 patients). H. pylori infection at entry, and eradication 4 to 6 weeks after therapy had ended, were assessed. When eradication did not occur, patients were given a 2 week treatment with ranitidine bismuth citrate 400 mg b.d., tetracycline 500 mg t.d.s., and tinidazole 500 mg b.d. (RBTT regimen). Eradication in these patients was assessed by a further endoscopy 4 to 6 weeks after conclusion of treatment. Six patients were lost to the follow up. At the end of the first course of treatment, the overall H. pylori eradication rate was 78 percent at 'intention to treat' (ITT) and 79 percent at 'per protocol' (PP) analysis, without any statistically significant difference between regimens, although a trend for better results with the omeprazole combination was observed. H. pylori eradication was achieved in 82 to 86 percent of 38 patients retreated with the RBTT regimen. The authors conclude that this short term triple therapy is not a satisfactory treatment for H. pylori infection. The 2 week triple therapy used as retreatment in eradication failure patients yielded more promising results. 2 figures. 3 tables. 34 references. (AA-M).

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Alteration of Histological Gastritis After Cure of Helicobacter Pylori Infection Source: Alimentary Pharmacology and Therapeutics. 16(11): 1923-1932. November 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: It is still disputed whether gastric (stomach) atrophy or intestinal metaplasia improves after the cure of Helicobacter pylori infection. If these condition improve, cure of the infection may reduce cancer risk. This article reports on a literature survey undertaken to clarify the histological changes after the cure of H. pylori infection. The authors reviewed 52 selected reports from 1,066 relevant articles. The extracted data were pooled according to histological parameters of gastritis based on the updated Sydney system. Activity improved more rapidly than inflammation. Eleven of 25 reports described significant improvement of atrophy. Atrophy was not improved in one of four studies with a large sample size (more than 100 samples) and in two of five studies with

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a long follow up period (longer than 12 months), suggesting that disagreement between the studies was not totally due to sample size or follow up period. Methodological flaws, such as patient selection, and statistical analysis based on the assumption that atrophy improves continuously and generally in all patients might be responsible for the inconsistent results. Five of 28 studies described significant improvement of intestinal metaplasia. The authors conclude that activity and inflammation were improved after the cure of H. pylori infection. Atrophy did not improve generally among all patients, but improved in certain patients. 5 tables. 65 references. •

Screening Dyspeptic Patients for Helicobacter Pylori Prior to Endoscopy: Laboratory or Near-Patient Testing? Source: European Journal of Gastroenterology and Hepatology. 10(10): 843-846. October 1998. Contact: Available from Rapid Science Publishers. 400 Market Street, Suite 750, Philadelphia, PA 19106. (800) 552-5866. Summary: It is unclear whether near-patient whole blood diagnostic tests for Helicobacter pylori are comparable in accuracy to laboratory based enzyme-linked immunosorbent assay (ELISA) tests for screening dyspeptic patients before endoscopy. This article reports on a study undertaken to compare two ELISA and two whole-blood tests to determine whether near-patient H. pylori diagnostic tests are an acceptable alternative to laboratory based ELISA tests for screening dyspeptic patients before endoscopy. One hundred and seven consecutive patients with dyspepsia (median age 32 years; range 16 to 45 years) were evaluated with Helico-G ELISA, Hmcap ELISA, and Helisal whole blood tests. A further 111 dyspeptic patients (median age, 51 years; range, 16 to 96 years) were evaluated with the Immunocard whole blood test only. The gold standard for infection was based on histology and the rapid urease test (CLO). Compared with the Helico-G test, both near patient tests had a higher false negative rate and lower sensitivity and negative predictive value. The Immunocard had a higher specificity than the Helisal; otherwise, both near patient whole blood tests showed similar performance. At a sensitivity of 95 percent, the Hmcap ELISA was more specific than the Helico-G ELISA and had fewer false positives. The near-patient tests would wrongly classify up to 40 percent of H. pylori positive dyspeptic patients and exclude them from endoscopy, compared with 5 to 6 percent for ELISA. The authors conclude that near-patient whole blood H. pylori diagnostic tests are less accurate and thus not an acceptable alternative to laboratory based ELISA tests. 1 table. 16 references. (AA).

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Cost of Diagnosing Helicobacter Pylori Infection Source: Alimentary Pharmacology and Therapeutics. 15(Supplement 1): 10-15. June 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: Noninvasive testing and treatment for Helicobacter pylori have been recommended for dyspeptic patients in primary care and this article reviews a number of recent studies have demonstrated the cost effectiveness of this approach. As the prevalence of H. pylori infection declines, the positive and negative predictive values of individual tests will change. Cost effectiveness is important in determining the appropriate test in individual populations. Recent studies have shown that the stool antigen test and the urea breath test have high sensitivity and specificity in the detection

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of H. pylori infection before and after therapy. Cost effectiveness studies have shown that when the prevalence of H. pylori infection is low or intermediate, serological tests have relatively poor accuracy compared with the stool test or the urea breath test. In populations with low or intermediate prevalence (less than 60 percent) these tests should be preferred to ELISA serology or office based whole blood test or serology. This is particularly true when the prevalence of H. pylori infection is less than 30 percent as is seen in many developed countries. When the prevalence of H. pylori infection is high (greater than 60 percent), low cost antibody tests are cost effective. 42 references. •

Management Strategies for Helicobacter Pylori-Seropositive Patients with Dyspepsia: Clinical and Economic Consequences Source: Annals of Internal Medicine. 126(4): 280-291. February 15, 1997. Summary: Noninvasive testing for Helicobacter pylori is widely available and has been considered as an initial management strategy for uninvestigated dyspepsia. However, data to guide clinicians in the management of patients with dyspepsia who are seropositive for H. pylori are lacking. This article reports on a study to examine the economic, clinical, and policy implications of alternative initial management strategies for patients with uninvestigated dyspepsia who are seropositive for H. pylori. Cost estimates were obtained from the Medicare reimbursement schedule and a health maintenance organization pharmacy; probability estimates were derived from the medical literature. Initial endoscopy costs an average of $1,276 per patient, whereas initial anti-H. pylori therapy costs $820 per patient; the average saving is $456 per patient treated. The financial effect of a 252 percent increase in the use of antibiotics for initial H. pylori therapy is more than offset by reducing the endoscopy workload by 53 percent. Endoscopy-related costs must be reduced by 96 percent before the two strategies become equally cost effective. In patients with nonulcer dyspepsia, the financial benefits of initial anti-H. pylori therapy are not substantially affected by varying the rates of H. pylori eradication, the complications of antibiotics, or the response of symptoms to cure of H. pylori infection. The authors conclude that, unless physicians are concerned about resistance to antimicrobial agents or the lack of proven benefit of anti-H. pylori therapy in nonulcer dyspepsia, the strategy outlined in this analysis can be used as a basis for management and policy decisions about H. pylori seropositive patients with dyspepsia. The article is accompanied by a related editorial. 4 figures. 6 tables. 86 references. (AA-M).

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Effects of Pumaprazole (BY841), A Novel Reversible Proton Pump Antagonist, and of Omeprazole, on Intragastric Acidity Before and After Cure of Helicobacter Pylori Infection Source: Alimentary Pharmacology and Therapeutics. 13(1): 27-34. January 1999. Contact: Available from Blackwell Science Ltd. Journal Subscriptions, P.O. Box 88, Oxford OX2 ONE, UK. 44(0) 1865 206180 or 206038. Fax: 44(0) 1865-206219. E-mail: [email protected]. Summary: Omeprazole (a proton pump inhibitor) produces a higher intragastric pH in the presence of Helicobacter pylori infection before cure than after cure. This article reports on a study undertaken to investigate whether this effect also occurs with pumaprazole (BY841), a reversible proton pump antagonist which, in contrast to omeprazole, does not require activation in the acid compartment of the parietal cell. In a randomized, crossover, double blind study, 24 hour intragastric (in the stomach) pH was measured in 13 H. pylori positive subjects before and after a 1 week course of

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omeprazole or of pumaprazole. The studies were repeated after the infection was cured. In the absence of drug administration, the median 24 hour pH values before cure did not differ from those after cure. However, the 24 hour pH values were higher before cure of the infection than after during both pumaprazole and omeprazole. Both before and after cure, there were no significant differences between the two drugs with respect to acid inhibition over the 24 hour period. The median decrease in acid inhibition after cure of the infection during pumaprazole was no different from that during omeprazole. H. pylori infection similarly augments the pH increasing effect of both drugs. This authors stress that this effect is related to H. pylori infection and not to an increased activation of acid inhibitory agents in the parietal cell compartment. 4 figures. 2 tables. 28 references. •

Treatment of Helicobacter Pylori Source: Current Opinion in Gastroenterology. 15(1): 72-78. January 1999. Contact: Available from Lippincott Williams and Wilkins Publishers. 12107 Insurance Way, Hagerstown, MD 21740. (800) 637-3030. Fax (301) 824-7390. Summary: Overwhelming evidence implicates Helicobacter pylori as a significant causative factor in many gastroduodenal diseases. This article reviews the advances made in the past year in the treatment of H. pylori. Effective multidrug antimicrobial regimens are available to cure the infection, so investigative efforts are focusing on cost effectiveness and treatment outcome in various populations. Potential associations between H. pylori and nongastric disorders are also being examined. Recognition that infection is largely acquired during childhood has emphasized the need to study pediatric issues. Posttreatment studies confirm the importance of the bacterium in pathogenesis and relapse of peptic ulcer disease (PUD). Antimicrobial resistance has a negative impact on cure of the infection and healing of gastroduodenal lesions. Methodology to evaluate H. pylori antimicrobial susceptibility has been standardized by the National Committee for Clinical Laboratory Standards, and minimum inhibitory concentration breakpoints to standardize resistance assays are being established. Surveillance of H. pylori antimicrobial resistance is underway in a Centers for Disease Control and Prevention (CDC) multisite project. The authors conclude that multidrug antimicrobial regimens are most effective in curing H. pylori infection. Triple therapy regimens with proton pump inhibitors (PPI) appear to be more effective, better tolerated, simpler, and associated with better compliance than other regimens. 39 references (7 annotated).

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Helicobacter Pylori and Risk of Ulcer Bleeding Among Users of Nonsteroidal AntiInflammatory Drugs: A Case-Control Study Source: Gastroenterology. 116(6): 1305-1309. June 1999. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Peptic ulcer complications related to use of nonsteroidal antiinflammatory drugs (NSAIDs) are among the most common serious adverse drug reactions. The role of Helicobacter pylori infection in causing or contributing to this gastrointestinal toxicity of NSAIDs is still unresolved. This article reports on a case control study of current users (n = 132) of NSAIDs (including acetylsalicylic acid, aspirin), admitted to the hospital because of bleeding peptic ulcer. The controls were 136 NSAID users who did not have gastrointestinal complications. H. pylori was diagnosed by either increased levels of serum immunoglobulin G or by 13C urea breath test. Fifty-eight (44 percent) case subjects had a bleeding gastric ulcer, 54 (41 percent) had a bleeding duodenal ulcer,

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12 (9 percent) had both gastric and duodenal ulcers, and 8 (6 percent) had hemorrhagic gastritis. H. pylori was present in 75 (57 percent) cases compared with 59 (43 percent) controls. The adjusted odds ratio of bleeding peptic ulcer among NSAID users associated with H. pylori infection was 1.81. H. pylori accounted for approximately 24 percent of bleeding peptic ulcers among elderly NSAID users. The authors conclude that NSAID users infected with H. pylori have an almost twofold increased risk of bleeding peptic ulcer compared with NSAID users without H. pylori infection. 2 tables. 23 references. •

Scope and Consequences of Peptic Ulcer Disease: How Important Is Asymptomatic Helicobacter Pylori Infection? Source: Postgraduate Medicine. 105(3): 100-102, 105-108, 110. March 1999. Summary: Peptic ulcer disease (PUD) is a worldwide problem, affecting 1 in 10 people. Similarly, Helicobacter pylori, the now undisputed culprit in most cases of PUD, is found virtually everywhere on the planet. Although the organism causes problems in only a minority of those who carry it, it is linked to a number of serious consequences. In this article, a panel of experts discusses the scope, risks, and relationships of H. pylori and peptic disease, cancer, and other disorders. Transmission is believed to be primarily person to person. The pathogen invariably damages the gastric mucosa, resulting in both structural and functional abnormalities. H. pylori causes histologic gastritis and is critical in the pathogenesis of the gastritis associated diseases: gastric ulcer, duodenal ulcer, gastric adenocarcinoma, and primary gastric lymphoma. Elimination of the infection results in healing of gastritis and cure of PUD. 2 tables. 28 references. (AA-M).

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Risk of Ulcer Bleeding in Patients Infected with Helicobacter Pylori Taking NonSteroidal Anti-Inflammatory Drugs (commentary) Source: Gut. 46(3): 310-311. March 2000. Contact: Available from BMJ Publishing Group. P.O. Box 590A, Kennebunkport, ME 04046. (800) 236-6265. Summary: This article reports on a study to determine whether Helicobacter pylori is an independent risk factor for bleeding peptic ulcer in users of nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin. The prospective matched case control study included 132 patients with a bleeding peptic ulcer (n = 124) or hemorrhagic gastritis (n = 8) at endoscopy who had taken an NSAID in the previous week, and 136 controls who had taken NSAIDs without gastrointestinal complications. The controls were recruited from rheumatology and geriatric outpatient clinics. H. pylori was present in 57 percent of cases and 43 percent of controls. The adjusted odds ratio of bleeding from a peptic ulcer owing to H. pylori infection in NSAID users was 1.81 and was similar in aspirin and nonaspirin NSAID users. Peptic ulcer bleeding was also statistically significantly associated with a history of previous ulcer bleeding, dyspepsia within the previous 3 months, and drinking alcohol, but not with smoking. The authors contend that about 16 percent of bleeding peptic ulcers in NSAID users could be attributed to H. pylori infection. NSAID users infected with H. pylori have an almost doubled risk of bleeding peptic ulcer compared with uninfected NSAID users. 12 references.

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Accuracy of the Stool Antigen Test in the Diagnosis of Helicobacter Pylori Infection Before Treatment and in Patients on Omeprazole Therapy Source: Alimentary Pharmacology and Therapeutics. 15(1): 73-79. January 2001.

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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 evaluate the Helicobacter pylori stool antigen (HpSA) test in the assessment of H. pylori infection and the effect of omeprazole treatment on its accuracy. In the first study, 140 patients with dyspepsia (heartburn, indigestion) were enrolled and defined as H. pylori positive if histology and rapid urease test, or culture alone, were positive. HpSA was performed on all patients and 13C urea breath test (UBT) on 87 patients. In the second study, 75 patients testing positive using both UBT and HpSA were given omeprazole 20 mg for 2 weeks (Group A) or omeprazole 40 mg for 2 weeks (Group B), or omeprazole, amoxicillin, clarithromycin OAC for 1 week (Group C). Results showed that 80 of 140 patients were H. pylori positive. The sensitivity and specificity of HpSA were 93.8 and 90 percent, similar to UBT (93.9 and 92.1 percent, respectively). Omeprazole significantly reduced both HpSA and UBT values, resulting in a decreased accuracy. Of 25 patients receiving 20 mg of omeprazole, HpSA gave 5 and 6 false negatives after 7 and 14 days treatment respectively, while UBT gave 4 and 7 false negatives after 7 and 14 days treatment. Of the 25 patients receiving 40 mg omeprazole, HpSA gave 7 and 9 false negatives after 7 and 14 days of treatment, while UBT gave 8 and 9 false negatives after 7 and 14 days of treatment. Two weeks after stopping omeprazole treatment, the HpSA and UBT were positive in all cases. The authors conclude that the H. pylori stool antigen test is valuable in the assessment of H. pylori infection. Short term omeprazole treatment decreases the accuracy of both HpSA and UBT in a similar manner. 3 figures. 1 table. 33 references. •

Helicobacter Pylori Gastritis and Gastric Physiology Source: Gastroenterology Clinics of North America. 29(3): 687-703. September 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32821-9816. (800) 654-2452. Summary: This article reviews Helicobacter pylori gastritis and gastric physiology. Helicobacter pylori gastritis (stomach inflammation) can alter stomach physiology, leading to increased or decreased acid secretion, depending on the pattern of gastritis present. These changes in physiology are related to the disease outcome, with increased acid secretion leading to duodenal ulcer disease and reduced acid secretion being a risk factor for gastric (stomach) cancer. Gastric acid secretion also affects the pattern of gastritis induced by the infection, with low acid secretion leading a pangastritis and possibly atrophy. This two way interaction between H. pylori gastritis and gastric acid secretion is important in understanding the role of H. pylori infection in the response to proton pump inhibitor therapy. This interaction explains the more profound control of gastric acid secretion in H. pylori positive patients and why rebound acid hypersecretion is confined to H. pylori negative subjects. 6 figures. 60 references.

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Endoscopic Methods for the Diagnosis of Helicobacter Pylori Source: Alimentary Pharmacology and Therapeutics. 11(supplement 1): 3-9. February 1997. Contact: Available from Mercury Airfreight International, Ltd. 2323 EF, Randolph Avenue, Avenel, NJ 07001. E-mail: [email protected].

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Summary: This article reviews endoscopic methods for the diagnosis of Helicobacter pylori. The authors note that at the time of endoscopy, certain findings (gastroduodenal ulceration and or antral nodularity) may be highly suggestive of H. pylori infection. Endoscopic acquisition of gastric biopsies, however, leads to a definitive diagnosis of infection on the basis of both direct and indirect tests. Direct tests include culture and histological detection (considered the gold standard). There are a variety of stains available for the detection of H. pylori; their choice is influenced by local expertise and the clinical situation. If at least three biopsies are obtained from nonadjacent gastric sites, incorrect assessment of H. pylori status should be rare. Indirect methods utilize the detection of urease. The three biopsy rapid urease tests commercially available in the United States have similar performance characteristics, except that two are gel tests requiring up to 24 hours to read, while one is a strip test that is read up to 1 hour. Specificity is excellent for these tests, while sensitivity is more variable. Rapid urease tests are the endoscopic tests of choice for initial evaluation due to their low cost. The authors note that diagnostic methods for H. pylori are of special interest because therapy for the infection is not 100 percent effective. Therefore, assessment of cure after treatment is important, especially in patients with either complicated ulcers or gastric MALT lymphomas. 1 table. 28 references. (AA-M). •

Role of Helicobacter Pylori in Extradigestive Diseases Source: Current Opinion in Gastroenterology. 15(Supplement 1): S29-S33. 1999. Contact: Available from Lippincott Williams and Wilkins Publishers. 12107 Insurance Way, Hagerstown, MD 21740. (800) 637-3030. Fax (301) 824-7390. Summary: This article reviews recent studies on the association between Helicobacter pylori infection and various extragastroduodenal (outside the stomach and duodenum) diseases, including cardiovascular, immunological, and miscellaneous other pathologies. The correlation between H. pylori and cardiovascular (heart) diseases appears to remain contentious, while association with some autoimmune diseases is supported by growing evidence. Recent studies have correlated H. pylori infection with functional vascular disorders, such as primary Raynaud's phenomenon and migraine. The mechanisms behind this phenomenon remain unknown, but some role for cytokines, prostaglandins, leukotrienes, and other vasoactive substances that are released as a consequence of H. pylori infection has been suggested. Finally, various Helicobacter species have been detected in the liver and bile; this important finding could lead to a revision of diagnostic and therapeutic approaches to various idiopathic diseases (those without a known cause) of the hepato-biliary tract. The author concludes that increasing evidence seems to support the existence of at least some extragastric manifestations of H. pylori infection. 46 references (18 annotated).

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Diagnosis of Helicobacter Pylori Source: Practical Gastroenterology. 25(4): 28, 30, 32, 34-37, 41. April 2001. Contact: Available from Shugar Publishing. 12 Moniebogue Lane, Westhampton Beach, NY 11978. (516) 288-4404. Fax (516) 288-4435. Summary: This article reviews the diagnosis of Helicobacter pylori infection, focusing on patient selection issues (which patients should be tested for this infection). There is a clear link between Helicobacter pylori infection and the pathogenesis (development) of peptic ulcer disease (PUD). Cure of this infection is the most cost effective means of managing patients with PUD. A consensus conference statement from the National Institutes of Health recommended that all patients with PUD and those on long term

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medical therapy for a history of PUD should be tested for H. pylori. The incidence of H. pylori infection in patients with gastric adenocarcinoma (stomach cancer), and non Hodgkins lymphoma is significantly higher than in controls. In addition, a recent medical position statement by the American Gastroenterological Association recommended that patients with dyspepsia (indigestion, heartburn) under the age of 45 to 50 years with no 'alarm features' undergo a test and treat strategy for H. pylori. In this strategy, patients undergo a non endoscopic test for H. pylori and those with a positive test receive antimicrobial therapy. The test and treat strategy may reduce the utilization of upper endoscopy (EGD) and costs associated with the care of patients with dyspepsia. The author reviews the nonendoscopic and endoscopic tests that can be used for H. pylori detection, including those used to prove cure of H. pylori infection after treatment. The author concludes that it is important to consider overall costs associated with testing (including costs for inappropriate therapy and its consequences or lack thereof) rather than only the acquisition costs associated with a specific test. 1 figure. 2 tables. 48 references. •

Extradigestive Manifestations of Helicobacter Pylori Infection: Fact and Fiction Source: Digestive Diseases and Sciences. 44(2): 229-236. February 1999. Contact: Available from Plenum Publishing Corporation. 233 Spring Street, New York, NY 10013. (212) 620-8468. Fax (212) 807-1047. Summary: This article reviews the extradigestive manifestations of Helicobacter pylori (H. pylori) infection. H. pylori infection is the main etiological factor for gastritis and peptic ulcer and has recently been found to have a potential role in several extraintestinal pathologies. The postulated role of H. pylori in the pathogenesis of extraintestinal manifestations is based on the facts that local inflammation has systemic effects, H. pylori gastric infection is a chronic process lasting for decades, and persistent infection induced a chronic inflammatory and immune response capable of inducing lesions both locally and remote to the primary site of infection. The authors review the available literature about extradigestive manifestations of H. pylori infection. Topics include vascular diseases and H. pylori infection, including coronary heart disease, primary Raynaud's phenomenon, functional vascular disorders, and primary headaches; autoimmune diseases, including Sjogren's syndrome, Schonlein-Henoch purpura, and autoimmune thyroiditis; skin diseases; and other diseases associated with H. pylori infection. 1 figure. 1 table. 70 references.

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Review Article: Non-Steroidal Anti-Inflammatory Drugs and Helicobacter Pylori Source: Alimentary Pharmacology and Therapeutics. 14(Supplement 3): 43-47. 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: This article reviews the impact of nonsteroidal antiinflammatory drugs (NSAIDs) and Helicobacter pylori, both well recognized causes of gastroduodenal mucosal damage. This damage is mediated through the effects of both agents on acid secretion, neutrophil activity and function, and prostaglandin metabolism. Clinical trials on the interrelationship between H. pylori, NSAIDs, and gastroduodenal mucosal injury have yielded conflicting results. The authors note that no consensus has been reached on what recommendations should be implemented with regard to H. pylori eradication in patients on long term NSAID therapy. Currently, the presence of H. pylori is identified

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at endoscopy and eradication of the bacterial infection is carried out in symptomatic patients. Asymptomatic patients remain a dilemma that requires further investigation. Clinical practice will continue to be tailored to a patient's individual requirements. Therefore, in patients on NSAID therapy and at risk of gastrointestinal hemorrhage, acid suppression therapy should be prescribed. 23 references. •

Lack of Effect of Treatment for Helicobacter Pylori on Symptoms of Nonulcer Dyspepsia Source: Archives of Internal Medicine. 159(19): 2283-2288. October 25, 1999. Contact: Available from American Medical Association. Subscriber Services Center, P.O. Box 10946, Chicago, IL 60610-0946. (800) 262-2350. Fax (312) 464-5831. E-mail: [email protected]. Summary: Prior studies have yielded conflicting results on whether or not Helicobacter pylori causes nonulcer dyspepsia. This article reports on a study undertaken to determine whether H. pylori infection causes nonulcer dyspepsia. The study enrolled 100 consecutive patients with nonulcer dyspepsia into a randomized, doubleblind, placebo controlled trial. Patients with peptic ulcer disease, esophagitis, hepatobiliary disease, irritable bowel disease (IBS), or predominately reflux related symptoms were excluded by history and upper endoscopy. H. pylori infection was determined by biopsy and histologic examination. Enrolled patients were randomized to a 14 day regimen of omeprazole (20 mg twice daily) and clarithromycin (500 mg three times daily) or placebo. Dyspeptic symptoms were assessed by use of a visual analog scale at baseline and at 1, 3, 6, and 12 months after treatment. Followup upper endoscopy with biopsy was performed 4 weeks after treatment. Compliance was measured by tablet counts. At 1 year, the change in dyspeptic symptoms was negative 24.0 in the omeprazole and clarithromycin group and negative 24.2 in the placebo group. Furthermore, patients with persistent H. pylori infection demonstrated a greater, but not significant, improvement in symptoms than those with successful eradication. The authors conclude that patients with nonulcer dyspepsia should not routinely be treated for H. pylori, since it is not a cause of this condition in most patients. 3 figures. 2 tables. 34 references.

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Eradication of Helicobacter Pylori Increases Gastric Acidity in Patients with Atrophic Gastritis of the Corpus: Evaluation of 24-h pH Monitoring Source: Alimentary Pharmacology and Therapeutics. 13(2): 155-162. February 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: Recent studies have shown that the eradication of Helicobacter pylori results in a gastric acid secretion that decreases to normal levels in patients with duodenal ulcer disease. This article reports on a study undertaken to evaluate the effect of eradicating H. pylori in a 24 hour study of gastric acidity in patients with atrophic gastritis of the corpus. Intragastric acidity was measured by continuous 24 hour pH monitoring, and the histology of the gastric antrum and corpus were evaluated in 14 H. pylori positive patients (10 men, 4 women; mean age 57 years)with histologically proven atrophic gastritis of the corpus before and 1 year after anti H. pylori therapy. H. pylori was absent in 13 of 14 patients 1 year after treatment. Both gastritis and atrophy scores were significantly lower after eradication therapy. The 24 hour medical pH and the percentage of 24 hour pH readings above 4.0 units were significantly decreased after

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eradication therapy. The authors conclude that improving the histology of the gastric antrum and corpus may lead to the normalization of gastric acidity. 3 figures. 1 table. 45 references. (AA-M). •

Helicobacter Pylori Antibiotic Resistance: Trends Over Time Source: Canadian Journal of Gastroenterology. 14(10): 895-899. November 2000. Contact: Available from Pulsus Group, Inc. 2902 South Sheridan Way, Oakville, Ontario, Canada L6J 7L6. Fax (905) 829-4799. E-mail: [email protected]. Summary: Resistance to antibiotics can be a major problem in the treatment of bacterial infections. As the use of antibiotics increases, bacterial resistance to these agents is rising and in many cases is responsible for the failure of treatment regimens. This review article considers the trends in H. pylori antibiotic resistance over time. Although the treatment of H. pylori infection requires the use of more than one antibiotic to obtain adequate eradication rates, the efficacy of the currently used antibiotic combinations has been shown to be decreased by resistance to one of the antibiotics. The use of antibiotics in regimens for the treatment of H. pylori is increasing in many countries, including Canada. This increase is both in the use of these antibiotics alone for the treatment of nongastrointestinal infections and in their use in association with proton pump inhibitors for the treatment of H. pylori infection. In several European and Asian countries, where resistance to antibiotics is being monitored, it has been demonstrated that H. pylori resistance to metronidazole and to clarithromycin increased throughout the 1990s. Thus far, the data available in Canada do not show increased resistance to either of these antibiotics. As for other antibiotics used in the treatment of H. pylori infection, such as tetracycline and amoxicillin, the rate of resistance to these agents is still very low and does not constitute a significant problem. However, because the efficacy of the regimens used in the treatment of H. pylori infection is compromised by resistance to the antibiotics used, it is important that H. pylori resistance rates in Canada and throughout the world continue to be monitored. 6 figures. 2 tables. 32 references.

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One-week Triple vs. Quadruple Therapy for Helicobacter Pylori Infection: A Randomized Trial Source: Alimentary Pharmacology and Therapeutics. 16(7):1261-1267. 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: Seven day triple therapy (omeprazole, clarithromycin, and amoxicillin) has become the treatment of choice for Helicobacter pylori infection. However, 7 days of classical quadruple therapy combining omeprazole, tetracycline, metronidazole, and bismuth may be an alternative to triple therapy. This article reports on a study undertaken to compare triple versus quadruple therapy for H. pylori eradication. The study included 339 patients with peptic ulcer and H. pylori infection. No significant differences between the triple versus quadruple therapy groups were found in the cure rates, compliance, or side effects. The authors conclude that one week triple and quadruple therapy show similar results when used as first line eradication treatment. 2 figures. 1 table. 33 references.

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Helicobacter Pylori Infection Source: New England Journal of Medicine. 347(15): 1175-1186. October 10,2002.

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Summary: Since the first culture of Helicobacter pylori 20 years ago, the diagnosis and treatment of upper gastroduodenal disease have changed dramatically. This review surveys scientific knowledge concerning H. pylori and focuses on the many aspects of this infection that are relevant to the clinician. The authors discuss epidemiology and transmission, pathogenesis, host responses to H. pylori, clinical outcomes of infection, diagnostic tests, treatment of H. pylori infection, first line therapies, proton pump inhibitor (PPI) based triple therapies, ranitidine bismuth citrate based therapies, bismuth based triple therapies, second-line therapies, and indications for therapy. Peptic ulcer disease is now approached as an infectious disease, in which elimination of the causative agent cures the condition. The role of H. pylori infection in gastric cancers is increasingly recognized, and its role in other diseases of the upper gastrointestinal tract is being evaluated. Effective antimicrobial therapy is available, although there is still no ideal treatment, and indications for therapy continue to evolve. 3 figures. 2 tables. 107 references. •

Helicobacter Pylori-Positive Functional Dyspepsia in Elderly Patients: Comparison of Two Treatments Source: Digestive Diseases and Sciences. 44(5): 863-867. May 1999. Summary: The association between Helicobacter pylori and functional dyspepsia is not well defined. The role of H. pylori in dyspeptic symptoms is still controversial. This article reports on a study undertaken to confirm the efficacy of H. pylori eradication by two different commonly used treatment regimens, as well as to examine the improvement of the dyspeptic symptoms by eradicating H. pylori. In the age group over 60 years, the authors treated 126 patients with bismuth plus metronidazole and amoxicillin (group A, 67 patients) versus omeprazole plus amoxicillin (group B, 59 patients). Two months after the end of therapy the authors observed an eradication rate of 66.1 percent in group A versus 64.3 percent in group B. All treated patients showed improvement in symptomatology. Although there was no significant difference between patients in whom H. pylori was or was not eradicated within the respective groups, when examining all H. pylori positive patients versus H. pylori negative posttreatment patients, there was a significant reduction in all four symptoms of functional dyspepsia measured. In conclusion, the authors suggest that patients treated with H. pylori eradicating therapeutic regimens have an improvement in functional dyspepsia symptoms. The authors prefer the dual therapy as compared to the triple therapy. The authors also note that eradicating treatment to eradicate H. pylori in the elderly patients with H. pylori related functional dyspepsia will reduce health care costs by reducing the number of subsequent visits. 5 tables. 15 references. (AA-M).

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Practical Advice On Eradicating Helicobacter Pylori Infection Source: Postgraduate Medicine. 105(3): 137-140, 145-148. March 1999. Summary: The days of putting patients with peptic ulcers on a diet of bland food and antacids are past. Today, curing ulcers is simply a matter of eradicating Helicobacter pylori infection. The authors of this article, the third in a series on peptic ulcer disease (PUD), question whether it is really that simple. The authors summarize combination regimens that have been found to be most effective against the organism and discuss what to do when such treatment fails. They also discuss issues to consider in preventing drug resistance and provide tips on improving patient compliance, which is vital to successful treatment. The important factors in selecting therapy are efficacy of eradication, prevention of resistance, avoidance or minimization of adverse effects, patient compliance, and cost. The most effective regimens include a bismuth preparation

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or antisecretory drug (proton pump inhibitor or H2 receptor antagonist) plus two antibiotics administered for 14 days. Dual drug therapies are not recommended. Triple drug regimens are more likely to eradicate H. pylori and less likely to generate resistant strains among surviving organisms. In general, cure of the infection should be confirmed 4 weeks after completion of the treatment. Antibiotic resistance is an important consideration in choosing therapy, and patients should be taught the importance of compliance. When treatment fails, antibiotic combinations should not be repeated. Considerations for anti H. pylori treatment in a managed care environment mirror those for good medical practice in general, with special attention to stringent cost control or outcomes driven measures. The authors include a patient care algorithm for treatment decisions in patients with suspected PUD associated with H. pylori infection. 1 figure. 1 table. 22 references. (AA-M). •

Cure of Helicobacter Pylori Infection in Atrophic Body Gastritis Patients Does Not Improve Mucosal Atrophy But Reduces Hypergastrinemia and Its Related Effects on Body ECL-Cell Hyperplasia Source: Alimentary Pharmacology and Therapeutics. 14(5): 625-634. May 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: The effects of Helicobacter pylori eradication on atrophic body gastritis are controversial. This article reports on a study undertaken to investigate the effect of triple therapy on atrophic body gastritis in H. pylori positive patients and its effect on morphofunctional gastric parameters. Consecutive patients (n = 35) with atrophic body gastritis with histological or serological evidence of H. pylori infection were treated. Before and 6 and 12 months after H. pylori eradication the patients were evaluated for fasting gastrinemia and pepsinogen I, basal and peak acid output, and detailed histological assessment including the ECL cell proliferative patterns. Six months after treatment, 25 out of 32 patients were cured (78 percent). Cure of infection was associated with improvement in both basal and stimulated acid secretion, as well as with reduction in hypergastrinemia. In contrast, the eradication had no effect on body corporal atrophy and intestinal metaplasia, or pepsinogen I levels. These results were confirmed at 12 months after eradication. A statistical inverse correlation was obtained between the corporal chronic infiltrate score and peak acid output values. A total of 53 percent of atrophic body gastritis patients showed a regression in severity of body ECL cell hyperplastic change. The authors conclude that cure of H. pylori infection in patients with atrophic gastritis reverses some adverse effects on gastric function and ECL cell hyperplasia. 3 figures. 2 tables. 38 references.

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Eradicating Helicobacter Pylori Infection Source: Patient Care. 35(7): 91-92, 94, 97-100. April 15, 2001. Contact: Available from Medical Economics. 5 Paragon Drive, Montvale, NJ 07645. (800) 432-4570. Fax (201) 573-4956. Summary: The eradication of Helicobacter pylori infection is now recognized as an integral component in the successful management of patients with peptic ulcer disease (PUD). The diagnosis of an active H. pylori infection can be made using the noninvasive urea breath test, serology, stool antigen test, or one of several biopsy based tests. H. pylori eradication is best accomplished with triple therapy consisting of a proton pump inhibitor (PPI) plus clarithromycin plus either amoxicillin or metronidazole given twice

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daily for 10 to 14 days. This regimen provides a cost effective means for reducing ulcer recurrence and complications. This article reviews the patient indications for H. pylori eradication and discusses general patient care management. The author notes that testing should only be conducted if eradication therapy will be used. Physicians should consider testing patients with recurrent dyspeptic symptoms, including epigastric pain (heartburn), abdominal discomfort, and nausea. The test should be matched to patient characteristics. Gastric mucosal (stomach lining) biopsy offers high sensitivity and specificity but is invasive. Serologic (blood) tests are the noninvasive approaches most commonly used. Antibiotic resistance to clarithromycin may slow treatment effectiveness. Confirmation of the successful eradication of H. pylori is not necessary in asymptomatic patients with uncomplicated peptic ulcer. Long term antisecretory therapy may be needed in patients who fail to respond to H. pylori eradication therapy and in those in whom antibiotic therapy may be too complicated or otherwise contraindicated. 2 tables. 25 references. •

Third Line Treatment for Helicobacter Pylori: A Prospective, Culture-Guided Study in Peptic Ulcer Patients Source: Alimentary Pharmacology and Therapeutics. 14(10): 1335-1338. 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: The first line treatment of Helicobacter pylori bacterial infection cures the infection in the majority of patients. However, failures are common and 5 to 25 percent of patients remain infected in spite of using current recommended regimens. Even after two courses of treatment, 2 to 5 percent of patients remain infected. This article reports on a prospective study undertaken to investigate the effectiveness of third line treatment of H. pylori infection in patients with ulcers. Two week quadruple, culture guided, combinations were used in 31 consecutive patients. Susceptibility to metronidazole and clarithromycin were studies by E test, and thereafter a predetermined treatment regimen was used. Compliance was evaluated by pill count, and eradication defined by negative urea breath test at 6 weeks. Two main quadruple regimens were used in 29 patients. In spite of good compliance, the combination of omeprazole, tetracycline, bismuth and clarithromycin (OTBC) showed an eradication rate of 36 percent (five patients out of 14). If amoxycillin was used in place of the clarithromycin, the rate was 67 percent (eight patients out of 12). The difference was not significant. No clinical factor was found to be associated with failure to eradicate. The authors conclude that third line treatment often fails to eradicate H. pylori infection. New strategies need to be developed and tested for this common clinical situation. 2 tables. 15 references.

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GERD and H. Pylori: Does It Matter? Source: Practical Gastroenterology. 25(7): 26, 31-32, 34, 36-37. July 2001. Contact: Available from Shugar Publishing. 12 Moniebogue Lane, Westhampton Beach, NY 11978. (516) 288-4404. Fax (516) 288-4435. Summary: The incidence of gastroesophageal reflux disease (GERD) and esophageal adenocarcinoma (cancer of the esophagus) have increased in recent years while the incidence of peptic ulcer disease (PUD) and distal gastric (stomach) cancer have declined. Given the simultaneous decline in Helicobacter pylori infection, it is tempting to propose a relationship between H. pylori infection and these opposing time trends. This review article puts into perspective the current understanding of the complex,

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incompletely understood relationship between H. pylori infection and GERD. While H. pylori infection clearly does not cause GERD, it may protect certain susceptible individuals from developing GERD and its complications. The most likely mechanism whereby H. pylori infection protects against GERD is by decreasing the potency of the gastric refluxate in patients with corpus predominant gastritis. A variety of implications of H. pylori infection on GERD treatment have also arisen in recent years. These focus on the risk of gastric atrophy while on proton pump inhibitor therapy and the efficacy of proton pump inhibitors before and after eradication of H. pylori. 4 figures. 20 references. •

Non-Helicobacter Pylori, Non-NSAID Peptic Ulcer Disease Source: Practical Gastroenterology. 25(9): 15, 18,20, 22. September 2001. Contact: Available from Shugar Publishing. 12 Moniebogue Lane, Westhampton Beach, NY 11978. (516) 288-4404. Fax (516) 288-4435. Summary: The majority of patients with peptic ulcers are infected with Helicobacter pylori bacteria but the organism may not always be responsible for the ulcer. Most patients have more than one risk factor for ulceration that then makes it difficult to establish the exact cause for the peptic ulcer. This article summarizes the current thinking in the etiology (cause) of peptic ulcer disease (PUD) and updates the reader on the prevalence and management of H. pylori, NSAID (nonsteroidal antiinflammatory drug) negative ulcer disease. Ulcer studies in the United States have found that approximately 20 percent of patients with duodenal ulceration have ulcer recurrence despite successful eradication of H. pylori. The phenomenon of non-H. pylori, nonNSAID mediate ulcer disease is also being increasingly recognized as defining a distinct subgroup of ulcer patients who have true idiopathic (with unknown cause) ulcer disease. The etiology for ulceration in these patients and their management is not well understood. The authors concludes that patients with an idiopathic duodenal ulcer have gastric (stomach) acid hypersecretion and are likely to have a more complicated course than their H. pylori-positive counterparts. 1 table. 18 references.

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Usefulness of Helicobacter Pylori Stool Antigen Test to Monitor Response to Eradication Treatment in Children Source: Alimentary Pharmacology and Therapeutics. 15(2): 203-206. February 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: The monitoring of the results of eradication treatment is a crucial step for patients with Helicobacter pylori gastritis. A noninvasive test for H. pylori antigens in stools (HpSA) was recently validated for children. This article reports on a study undertaken to evaluate the accuracy of HpSA in monitoring eradication treatment in children. In 60 children, H. pylori gastritis was diagnosed by endoscopy and the 13C urea breath test. The children were treated and returned for a followup 13C urea breath test 6 weeks after the end of treatment. Children were considered cured when the 13C urea breath test was negative. Stool were collected at baseline and at 2 and 6 weeks. Stool antigens were measured by HpSA. According to 13C urea breath test, 6 weeks after the end of treatment, 49 children were cured and 11 were still H. pylori positive. The sensitivity and specificity of HpSA on stools collected 2 weeks after therapy were 100 percent. At 6 weeks, specificity was 93.9 percent and sensitivity 100 percent. Results by visual reading were concordant with the plate reader in all but two cases at baseline.

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The authors conclude that HpSA is accurate for monitoring treatment in children as early as 2 weeks after therapy, when information is most useful and unachievable with other tests. In addition, the HpSA is more cost effective than the 13C urea breath test and it is not available everywhere. Results of the HpSA by visual reading are accurate, and this can make the test cheaper and more practical. 1 figure. 1 table. 8 references. •

Helicobacter Pylori-Positive Duodenal Ulcer: Three-Day Antibiotic Eradication Regimen Source: Alimentary Pharmacology and Therapeutics. 14(10): 1329-1334. 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: The most widely used treatments for ulcer healing and Helicobacter pylori eradication consists of a 1 to 2 week regimen of a proton pump inhibitor (PPI) plus two or three antimicrobials. This article reports on a study undertaken to evaluate the efficacy, safety, cost, and tolerance of a three day regimen with three antibiotics versus a 10 day treatment with a PPI inhibitor or versus a ranitidine bismuth citrate triple therapy. The study included 221 patients with endoscopically proven H. pylori positive duodenal ulcers. Recruited patients were assigned to one of four regimens: OAC (n = 55 patients) consisting of omeprazole, amoxycillin, clarithromycin; OACM (n = 56 patients), consisting of omeprazole, amoxycillin, clarithromycin, and metronidazole; RAC (n = 54 patients), consisting of ranitidine bismuth citrate, amoxycillin, and clarithromycin; or RACM (n = 56 patients) consisting of ranitidine bismuth citrate, amoxycillin, clarithromycin, and metronidazole. Fisher's exact test was used to compare data regarding healing and eradication in the four groups. The intention to treat eradication and ulcer healing rates for the RACM regimen were 95 percent and 98 percent, respectively. Statistically significant differences were observed, relating to the eradication and healing of ulcers, between RACM and either the RAC or OAC regimens. The authors conclude that the three day antibiotic therapy with amoxycillin, clarithromycin, and metronidazole, in addition to ranitidine bismuth citrate, is a very effective anti H. pylori regimen. 1 figure. 3 tables. 26 references.

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Failure of a 1-Day High-Dose Quadruple Therapy for Cure of Helicobacter Pylori Infection Source: Alimentary Pharmacology and Therapeutics. 13(2): 173-177. February 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: The optimal duration of treatment for eradication of Helicobacter pylori has still to be defined. A 1 day, high dose, quadruple therapy with a combination of amoxycillin (or tetracycline), metronidazole, a bismuth salt, and a proton pump inhibitor has led to eradication rates of 57 to 77 percent. This article reports on a study in which the authors hypothesized that by using clarithromycin in place of metronidazole and by increasing the dose of proton pump inhibitor, the efficacy of a this therapy could be improved. The authors focused on this aspect of the therapy because of the high frequency of metronidazole resistant strains of H. pylori in Europe. The authors originally intended to include 100 patients. The first planned interim analysis performed after follow up was completed for 30 patients and revealed H. pylori eradication rates of 80 percent (12 out of 15 patients) in the 7 day triple therapy group (amoxycillin 1000 mg

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b.d., clarithromycin 500 mg b.d., and lansoprazole 30 mg b.d.) and 20 percent (3 out of 15 patients) in the 1 day quadruple therapy group (amoxycillin 2000 mg q.d.s., clarithromycin 500 mg q.d.s., lansoprazole 30 mg t.d.s., and bismuth subcitrate 240 mg q.d.s. for 1 day); the difference was highly significant (P = 0.003). Because the efficacy of the 1 day treatment was so low, the study was stopped for ethical reasons. Eleven patients who failed with the 1 day treatment were given the 7 day triple therapy: the eradication rate was then 91 percent (10 out of 11 patients). The authors conclude that 1 day, high dose quadruple therapy with amoxycillin, clarithromycin, lansoprazole, and bismuth subcitrate is dramatically less effective than the classic 7 day triple therapy with the same antibiotics. 3 tables. 32 references. (AA-M). •

Furazolidone-Based Triple 'Rescue Therapy' vs. Quadruple 'Rescue Therapy' for the Eradication of Helicobacter Pylori Resistant to Metronidazole Source: Alimentary Pharmacology and Therapeutics. 16(7):1277-1282. 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: The optimal treatment of patients with Helicobacter pylori who are resistant to metronidazole has not been established. This article reports on a study undertaken to compare the efficacy of quadruple and furazolidone-based triple therapy in the eradication of H. pylori resistant to metronidazole. The study included duodenal ulcer patients (n = 70) in whom initial eradication therapy failed and who harbored H. pylori strains that are resistant to metronidazole. Patients were randomized to receive one of the following 7 day regimens: colloidal bismuth subcitrate, tetracycline, and furazolidone (BTF), or omeprazole, colloidal bismuth subcitrate, tetracycline, and metronidazole (OBTM). Duodenal ulcers were healed in nine of 10 (90 percent) patients in the BTF group and in all patients (12 of 12) in he OBTM group. A significantly lower rate of adverse events was observed in the BTF group than in the OBTM group (31.4 percent versus 60 percent, respectively) but there was no difference in terms of discontinuation of treatment. The authors conclude that the 1 week BTF regimen was as effective as the OBTM regimen, and produced less adverse events. Thus, it may be used in patients in whom resistance of H. pylori to metronidazole is suspected. 3 tables. 22 references.

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Helicobacter Pylori Infection and Gastric Outlet Obstruction: Prevalence of the Infection and Role of Antimicrobial Treatment Source: Alimentary Pharmacology and Therapeutics. 16(7): 1203-1208. 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: The prevalence of Helicobacter pylori infection in peptic ulcer disease complicated by gastric outlet obstruction seems to be, overall, lower than that reported in noncomplicated ulcer disease, with a mean value of 69 percent. However, H. pylori infection rates in various studies range from 33 percent to 91 percent, suggesting that differences in variables, such as the number and type of diagnostic methods used or the frequency of nonsteroidal anti-inflammatory drug (NSAID) use, may be responsible for the low prevalence reported in some studies. This article reviews these issues, including the prevalence of the infection and the role of antimicrobial treatment. The resolution of gastric outlet obstruction after the eradication of H. pylori has been demonstrated by

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several studies. The beneficial effect of H. pylori eradication on gastric outlet obstruction is observed early, just a few weeks after the administration of antimicrobial treatment. Furthermore, this favorable effect seems to remain during long term follow up. Nevertheless, gastric outlet obstruction does not always resolve after H. pylori eradication treatment and an explanation for the failures is not completely clear. The authors hypothesize that NSAID intake perhaps plays a major role in these cases. Treatment should start pharmacologically with the eradication of H. pylori, even when stenosis is considered to be fibrotic, or when there is some gastric stasis. Dilation or surgery should be reserved for patients who do not respond to medical therapy. 1 table. 29 references. •

Density of Helicobacter pylori Infection in Patients with Peptic Ulcer Perforation Source: Journal of the American College of Surgeons. 186(6): 659-663. June 1998. Summary: The prevalence of severe ulcer complications requiring emergency surgery has not been reduced, despite the common use of H2 receptor antagonists and proton pump inhibitors. This article reports on a study in which Helicobacter pylori (HP) infection and the severity of histologic change was investigated were evaluated semiquantitatively in patients with peptic ulcer who required surgery. The authors reviewed a total of 113 consecutive patients (98 men and 15 women) operated on for perforation, hemorrhage, or stenosis of gastroduodenal ulcer between 1986 and 1995. HP detection was by immunohistochemical staining and the severity of gastritis was evaluated by histologic examination using Rauw's criteria. Although the number of operations for gastroduodenal ulcer declined significantly, the rate of emergency operations for gastroduodenal ulcer increased from 60 to 90 percent, with the result that the frequency of operations for perforation or bleeding remained virtually constant while that for stenosis decreased significantly. HP infection was more prevalent in perforated ulcer (92 percent) than hemorrhagic ulcer (55 percent) or stenotic ulcer (45 percent). The authors conclude that perforated ulcer was associated with significantly more severe HP infection and gastritis changes than hemorrhagic or stenotic ulcer. 4 tables. 33 references. (AA-M).

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Epidemiology of the Antibiotic Resistance of Helicobacter Pylori in Canada Source: Canadian Journal of Gastroenterology. 14(10): 879-882. November 2000. Contact: Available from Pulsus Group, Inc. 2902 South Sheridan Way, Oakville, Ontario, Canada L6J 7L6. Fax (905) 829-4799. E-mail: [email protected]. Summary: The rate of Helicobacter pylori resistance to antibiotics determines the cure rate of treatment regimens containing such antibiotics. This article reports on a review of the literature, undertaken to determine the rates of H. pylori resistance to metronidazole and clarithromycin in Canada, and to determine whether these rates vary in different regions of Canada. Eleven studies that estimated H. pylori resistance to metronidazole and nine studies that estimated resistance to clarithromycin in Canada were identified. Rates of resistance for metronidazole and clarithromycin varied from 11 percent to 48 percent and 0 percent to 12 percent, respectively. Studies that obtained their estimates using the E test and those that did not clearly exclude patients who had undergone previous attempts at H. pylori eradication had higher estimates of resistance, accounting for this variability in results. The author concludes that the prevalence of primary H. pylori resistance in Canada appears to be 18 to 22 percent for metronidazole and less than 4 percent for clarithromycin. These rates appear to be consistent across the

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different regions studied in Canada, but many regions have not been studied. 2 figures. 23 references. •

Effect of Helicobacter Pylori Eradication Therapy on Dyspepsia Symptoms in Industrial Workers in Japan Source: Alimentary Pharmacology and Therapeutics. 15(6): 805-811. June 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: The relationship between Helicobacter pylori infection and non ulcer dyspepsia (heartburn, impaired digestion) is still controversial. The potential benefits and risks of the treatment could depend on local conditions, such as the prevalence of the infection and the local rates of gastric (stomach) cancer. This article reports on a study undertaken to evaluate the effects of H. pylori eradication therapy on non ulcer dyspepsia symptoms in industrial workers in Japan. A total of 615 employees of an industrial corporation were examined for H. pylori infection and symptom scores: 215 H. pylori positive non ulcer dyspepsia cases underwent eradication therapy. Symptom scores were also analyzed 12 months after the eradication therapy. Serum pepsinogen A and pepsinogen C levels were analyzed and chronic atrophic gastritis was serologically diagnosed. The symptom score improved significantly in the cured cases, but not in the non cured cases. The authors conclude that in both groups (cases with atrophic gastritis and cases with chronic gastritis only) the cure of H. pylori infection was effective in improving non ulcer dyspepsia symptoms. 1 figure. 3 tables. 35 references.

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Eradication Rates of Clarithromycin-Resistant Helicobacter Pylori Using Either Rabeprazole or Lansoprazole plus Amoxicillin and Clarithromycin Source: Alimentary Pharmacology and Therapeutics. 16(11): 1933-1938. November 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: The resistance of Helicobacter pylori to clarithromycin has become one of the primary reasons for eradication failure. This article reports on a study undertaken to compare the eradication rates of triple therapy using amoxicillin (A), clarithromycin (C), and rabeprazole (R) or lansoprazole (L) against clarithromycin-sensitive and clarithromycin-resistant strains of H. pylori. The study included 295 patients who were randomly divided into 4 groups and treated for 1 week: 147 cases were treated with RAC and 148 cases were treated with LAC. According to intention-to-treat and perprotocol analyses, the eradication rates were 88 percent and 91 percent with RAC and 78 percent and 81 percent with LAC, respectively. In addition, the eradication rates for clarithromycin-sensitive strains with RAC and LAC were 98 percent and 89 percent, respectively, and for clarithromycin-resistant strains with RAC and LAC were 8.1 percent and 0 percent, respectively. The authors conclude that the eradication rate was significantly higher with RAC than LAC. The eradication rate for clarithromycinresistant strains was low in both groups and an improved eradication rate could not be achieved by changing the dose of clarithromycin or proton pump inhibitor (PPI). 4 tables. 22 references.

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Increased Gastric Acid Secretion After Helicobacter Pylori Eradication May Be a Factor for Developing Reflux Oesophagitis Source: Alimentary Pharmacology and Therapeutics. 15(6): 813-820. June 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: The role of acid secretion in reflux esophagitis, which may develop after Helicobacter pylori eradication, is not well known. This article reports on a study undertaken to investigate the participation of altered gastric (stomach) acid secretion and the presence of hiatal hernia in the development of reflux esophagitis after eradication therapy for H. pylori. A total of 105 patients with H. pylori infection, but without reflux esophagitis at the time of eradication therapy, were followed prospectively for 7 months after the clearance of this microorganism. Gastric acid secretion was assessed by endoscopic gastrin test and the presence of hiatal hernia was assessed by endoscopy. Reflux esophagitis developed in 11 out of 105 (10.5 percent) patients when examined at 7 months after the eradication therapy. The incidence was correlated significantly with the increase in gastric acid secretion after the eradication of H. pylori and was significantly higher in the patients with hiatal hernia (20 percent) than in those without it (0 percent). The authors conclude that increased acid secretion after H. pylori eradication is an important risk factor of reflux esophagitis, especially in patients with hiatal hernia. 3 figures. 41 references.

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Favourable Effect of an Acidified Milk (LC-1) on Helicobacter Pylori Gastritis in Man Source: European Journal of Gastroenterology and Hepatology. 13(1): 25-29. January 2001. Contact: Available from Lippincott Williams and Wilkins. 241 Borough High Street, London SE1 1GB, UK 44(0)20-7940-7502. Fax: 44(0)20-7940-7574. Website: http://www.eurojgh.com/. Summary: The supernatant of Lactobacillus johnsonii La1 culture was shown to be bactericidal and to have a partial, acid independent suppressive effect on Helicobacter pylori in humans. This study investigated the effect of L. johnsonii La1 acidified milk (LC-1) on H. pylori infection in 53 volunteers infected with H. pylori. Volunteers were randomized to received either LC-1 or placebo 180 milliliters twice a day for 3 weeks. All subjects also received clarithromycin 500 milligrams twice a day (bid) during the last two weeks of acidified milk therapy. Esophagogastroduodenoscopy and biopsies were performed at inclusion and repeated 4 to 8 weeks after the end of the treatment. H. pylori infection was confirmed by urease test and histology. Results showed that LC-1 ingestion induced a decrease in H. pylori density in the antrum (the passage from the esophagus to the stomach, i.e., the first part of the stomach) and the corpus (the body of the stomach). LC-1 also reduced inflammation and gastritis activity in the antrum and of activity in the corpus. Clarithromycin eradicated H. pylori in 26 percent of the subjects; LC-1 did not improve the antibiotic effect. These results suggest that H. pylori infection and gastritis can be down regulated by LC-1. 4 tables. 33 references.

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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.

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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. •

Helicobacter Pylori Eradication and its Implications for the Future Source: Alimentary Pharmacology and Therapeutics. 11(supplement 1): 103-107. February 1997. Contact: Available from Mercury Airfreight International, Ltd. 2323 EF, Randolph Avenue, Avenel, NJ 07001. E-mail: [email protected]. Summary: This article addresses the eradication of Helicobacter pylori infections in humans. The rationale for eradicating H. pylori infection is its causal role in gastric malignancies and peptic ulcer disease. However, H. pylori are highly diverse and at least part of this variation involves characteristics related to pathogenicity. A large amount of evidence suggests that H. pylori infection of humans is ancient, and in general, the interaction is not terribly destructive. Current evidence indicates that fewer than 20 percent of all infected persons will develop any clinical consequences from their infection. However, the author stresses the need for better understanding of the risks associated with infection with particular H. pylori strains, and for limiting treatment to those situations in which the indications for eradicating H. pylori are clear cut. It is entirely possible that some H. pylori strains are commensals, and that others are symbionts. Eradicating those infections could ultimately cause more harm than good. The author concludes that it is too early to reach firm conclusions about whether all H. pylori infections need to be eradicated. 2 tables. 26 references. (AA-M).

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Transmission of Helicobacter Pylori from Stomach to Stomach Source: Alimentary Pharmacology and Therapeutics. 15(Supplement 1): 33-42. June 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 considers the mode of transmission of Helicobacter pylori, at present largely unknown and a matter of circumstantial evidence and speculation rather than fact. However, the principle evidence is of two sorts: the epidemiological data, providing evidence of possible risk factors associated with transmission, and the

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identification of potential sources from which H. pylori could be acquired. Evidence exists for several potential sources of infection and several possible modes of transmission, and it is feasible that the transmission of H. pylori varies according to the cultural and demographic circumstances. The author considers age factors, ethnicity, and socioeconomic factors. However, the most likely recognized source for H. pylori is the human stomach, although it is not known by what route the organism is transmitted to the stomach. The author reviews the evidence for the gastro oral route of transmission, fecal route and environmental sources, occupational exposure in hospitals, and food source animals and pets as a reservoir of infection. Evidence suggests close personal contact is important and that acquisition occurs mainly in childhood. 103 references. •

Role of Helicobacter Pylori Infection in Non-Ulcer Dyspepsia Source: Alimentary Pharmacology and Therapeutics. 11(supplement 1): 63-69. February 1997. Contact: Available from Mercury Airfreight International, Ltd. 2323 EF, Randolph Avenue, Avenel, NJ 07001. E-mail: [email protected]. Summary: This article considers the role of Helicobacter pylori infection in nonulcer dyspepsia. The author notes that it is currently unclear whether H. pylori infection plays a role in patients who fulfill the criteria for nonulcer dyspepsia. The author reviews evidence for H. pylori-induced changes in gastric emptying, gastrointestinal motility, gastric acid secretion, and gastric perception in patients with nonulcer dyspepsia. Problems in study design and execution of nonulcer dyspepsia treatment trials are covered. The author reviews the results of nonulcer dyspepsia treatment trials which have been performed in H. pylori-positive patients. To date, none of these studies has convincingly shown that cure of the H. pylori infection leads to a sustained improvement in symptoms. There is agreement that H. pylori infection does cause changes in gastric physiology. 55 references. (AA-M).

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Resistance of Helicobacter Pylori to Antibiotics Source: Alimentary Pharmacology and Therapeutics. 11(supplement 1): 43-53. February 1997. Contact: Available from Mercury Airfreight International, Ltd. 2323 EF, Randolph Avenue, Avenel, NJ 07001. E-mail: [email protected]. Summary: This article describes the resistance of Helicobacter pylori to antibiotics, a major reason for failure of the current regimens used to eradicate H. pylori. The author stresses that the definition of resistance is not simple, and the clinical relevance of in vitro results must be considered. The different methods of testing antibiotics cannot apply in all cases. Resistance to clarithromycin has a low prevalence rate (less than 10 percent) and its mechanism is well defined. Its clinical relevance is not questioned and, because of a clear occurrence of a bimodal strain population, the method for detecting resistance is not crucial. Resistance to nitroimidazoles is much more common, probably in the range of 30 percent or more in Europe. Neither the mechanism of action of metronidazole resistance nor its mechanism is well known. Metronidazole resistance was found to be clinically relevant when standard triple therapy was used. The relevance is questioned for triple therapies including a proton pump inhibitor, clarithromycin and metronidazole. More clinical data are needed in this field and the use of agar dilutions is recommended to assess the susceptibility of H. pylori to metronidazole. The mechanism of resistance to quinolones has been described but these

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compounds are not currently used for H. pylori infection. No resistance has yet been described for amoxycillin but continuous surveillance is needed in order to detect new cases, as was recently the case for tetracycline resistance. 2 figures. 5 tables. 39 references. (AA-M). •

Breath Testing in Health and Disease: Lactose Maldigestion, Bacterial Overgrowth, Intestinal Transit Time and Helicobacter Pylori Infection Source: Practical Gastroenterology. 23(4): 72, 74, 76, 78, 80. April 1999. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article describes the use of breath testing, a convenient and reliable method of evaluating lactose maldigestion, bacterial overgrowth, intestinal transit time, and H. pylori infection. These tests are inexpensive, noninvasive, and present little risk to the patient. The normal colonic flora produces hydrogen (H2) gas from food processed in the gastrointestinal tract. A portion of the H2 is absorbed and excreted by the lungs. In bacterial overgrowth, the bacteria are located more proximally and expired H2 will increase sooner after ingestion of food. Maldigested lactose, present in lactose intolerant patients, provides more substrate and consequently increases expired H2. Helicobacter pylori bacteria produce an urease that hydrolyzes urea producing carbon dioxide. If radiolabeled urea is given to a patient with an active infection, radiolabeled CO2 will be discharged from the lungs. The authors conclude that breath testing is an effective diagnostic aid that is well suited for the gastroenterologic and primary care clinic. 7 references.

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Understanding Disease Outcome Following Acquisition of Helicobacter Pylori Infection During Childhood Source: Canadian Journal of Gastroenterology. 13(3): 229-234. April 1999. Contact: Available from Pulsus Group, Inc. 2902 South Sheridan Way, Oakville, Ontario, Canada L6J 7L6. Summary: This article discusses disease outcome following acquisition of Helicobacter pylori infection during childhood. The article is taken from a presentation at the Canadian Helicobacter Pylori Consensus Conference held in June 1998 in Ottawa, Ontario. H. pylori causes chronic active (type B) gastritis in the overwhelming majority of infected individuals. Current research activities center around the relative contribution of virulence factors in the bacterium and host responses to the microbial infection in determining which subjects will go on to develop complications. These can include peptic ulceration, gastric cancers, and gastric lymphomas. The authors conclude that a likely possibility is that both the virulence of the infecting organism (H. pylori) and the host response to infection work in concert to determine which people will remain asymptomatic throughout their lifetime and which will develop complications. The authors call for the development of a reproducible model of peptic ulcer disease in an animal model of H. pylori infection. 2 tables. 75 references.

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Reinfection Versus Recrudescence in Helicobacter Pylori Infection Source: Alimentary Pharmacology and Therapeutics. 11(supplement 1): 55-61. February 1997. Contact: Available from Mercury Airfreight International, Ltd. 2323 EF, Randolph Avenue, Avenel, NJ 07001. E-mail: [email protected].

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Summary: This article explores reinfection versus recrudescence in Helicobacter pylori infection. Reinfection is defined as the acquisition of a new infection and recrudescence as the event of reappearance of H. pylori although initial posttreatment assessment tests were negative. Antimicrobial treatment of H. pylori is the proper management strategy in patients with ulcers. A high rate of H. pylori reinfection after successful eradication therapy however, may give rise to ulcer recurrence. The risk of reinfection, depending on the prevalence and the rate of acquisition of H. pylori infection, varies with socioeconomic status, age, and geographical location. The rate of reinfection may vary in a similar way. The available data in the literature reveal that reinfection by H. pylori is low or absent in developed countries and may be lower than the initial rate of acquisition. In addition, reported cases of H. pylori reinfection are often cases of recrudescent H. pylori infection. Acquisition rate in developing countries is high, so the reinfection rate is expected to be higher than in developed countries. However, studies discriminating reinfection from recrudescence are lacking. Therefore, more data from developing regions are needed to settle if 'cured once, cured forever' holds true. 1 figure. 1 table. 68 references. (AA-M). •

Review Article: Is Helicobacter Pylori Status Relevant in the Management of GORD? Source: Alimentary Pharmacology and Therapeutics. 14(Supplement 3): 31-42. 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: This article explores the growing interest in the relationship between Helicobacter pylori infection and gastroesophageal reflux disease (GERD). The authors note that this relationship is complex, as yet not fully clear, and probably based on multiple factors. The prevalence of H. pylori infection in patients with GERD is similar, but more often lower than in matched controls. There is a negative correlation between H. pylori infection and the severity of GERD. There are many hypothetical mechanisms by which H. pylori infection may protect from the development of GERD. Conversely, there are many possible mechanisms by which H. pylori infection could theoretically foster the GERD. Patients after H. pylori eradication may develop GERD, and this seems to suggest a protective role of H. pylori infection, but other possible explanations include weight gain after H. pylori eradication, changes in dietary habits and smoking, and preexisting GERD. Long term therapy of GERD in patients infected with H. pylori may lead to rapid progression of atrophic gastritis (stomach inflammation), intestinal metaplasia and dysplasia, and increase the risk of developing gastric (stomach) cancer. More recently, it has been shown that H. pylori infection may interfere with the acid suppressive therapies used for treating GERD. The authors propose that the progression of gastritis depends on the threshold of acid output at which H. pylori can flourish. Any decrease of acid secretion changes the behavior of H. pylori. During proton pump inhibitor (PPI) treatment, H. pylori redistribution occurs within the stomach. The authors also discuss Barrett's esophagus, as growing evidence is compiled on the associated risk of adenocarcinoma. The literature seems to demonstrate that the prevalence of H. pylori infection of the stomach in Barrett's esophagus patients is not different from that exhibited by controls, roughly one third of the subjects. Intestinal metaplasia (overgrowth) of the gastric cardia (the proximal part of the stomach) seems to be equally frequent in patients with and without GERD. The authors conclude that it appears unlikely that a causal relationship exists between H. pylori infection and Barrett's associated adenocarcinoma. 1 figure. 100 references.

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Helicobacter Pylori and Peptic Ulcer Disease: Bridging the Gap Between Knowledge and Treatment Source: Postgraduate Medicine. 103(3): 231-234, 236-238, 243. March 1998. Contact: Available from McGraw-Hill, Inc. 1221 Avenue of the Americas, New York, NY 10020. (612) 832-7869. Summary: This article looks at the latest diagnostic techniques and therapies used to identify and treat Helicobacter pylori associated peptic ulcer disease, with an emphasis on cost-effectiveness and patient compliance. H. pylori is widely accepted as the pathogenic cause of peptic ulcer disease, and studies show that its eradication cures infected patients. Combination antimicrobial therapy has been successful in not only curing the disease, but also significantly decreasing recurrence. However, only about one third of primary care physicians prescribe this therapy. Primary care physicians who do prescribe the treatment must better educate patients regarding compliance with the dosing schedule as well as the benefits of treatment. For example, patients should be advised that although the dosing schedule may be demanding, the treatment duration is short and the side effects are generally tolerable. Physicians may further motivate patients by explaining that once they have successfully completed treatment, they should be symptom-free with a low risk of ulcer recurrence. 3 tables. 32 references. (AAM).

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Update on Testing and Treatment for Helicobacter Pylori in Primary Care Patients with Uninvestigated Dyspepsia Source: Practical Gastroenterology. 26(3): 42,45-47, 50,52. March 2002. Contact: Available from Shugar Publishing. 12 Moniebogue Lane, Westhampton Beach, NY 11978. (516) 288-4404. Fax (516) 288-4435. Summary: This article offers an update on the testing and treatment for Helicobacter pylori in patients with dyspepsia (heartburn), a prevalent condition often seen in primary care practice. Multiple practice guidelines endorse testing and treatment for H. pylori as the initial step in the management of patients with uninvestigated dyspepsia. Recent clinical trials have provided support for this 'test and treat' approach over prompt endoscopy by demonstrating comparable clinical outcomes between these two strategies, with reduced costs and endoscopy rates with the test-and-treat strategy, but a slight compromise in patient satisfaction. The test-and-treat strategy appears to be costeffective even though many patients with dyspepsia have non-ulcer dyspepsia, in which H. pylori eradication yields little or no benefit. This cost-effectiveness advantage is explained in large part by the avoidance of endoscopy without adverse consequences in a large fraction of patients. Remaining questions include whether the test-and-treat strategy results in long-term cost savings, and how patient satisfaction and costeffectiveness should be balanced against each other in the care of patients with uninvestigated dyspepsia. 1 figure. 1 table. 13 references.

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From Bench to Bedside to Bug: An Update of Clinically Relevant Advances in the Care of Persons with Helicobacter Pylori-Associated Diseases Source: Canadian Journal of Gastroenterology. 14(3): 188-198. March 2000. Contact: Available from Pulsus Group, Inc. 2902 South Sheridan Way, Oakville, Ontario, Canada L6J 7L6. Fax (905) 829-4799. E-mail: [email protected].

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Summary: This article presents an update of clinically relevant advances in the care of patients with Helicobacter pylori associated diseases. The information was compiled after meetings at the XIth International Workshop on Gastroduodenal Pathology and Helicobacter Pylori (September 1998, Budapest, Hungary). The mode of transmission of H. pylori remains unclear, and it remains unknown why only a small proportion of infected individuals develop duodenal or gastric ulcer disease and even fewer develop gastric cancer. The role of H. pylori eradication in persons with uninvestigated dyspepsia remains controversial. New clinical trials of H. pylori treatment show symptom relief and improvement in the quality of life of persons with functional dyspepsia, especially in those with ulcer like or reflux like dyspepsia. Clearly, the move is toward symptom based management of persons with dyspepsia, with fewer endoscopies being needed in otherwise healthy young patients with dyspepsia. It remains controversial whether eradicating H. pylori in duodenal ulcer or functional dyspepsia increases the risk of subsequent development of gastroesophageal reflux disease. The 1 week proton pump inhibitor based triple regimens remain the gold standard of H. pylori therapy, but some of the ranitidine bismuth citrate plus two antibiotic regimens also achieve an 80 percent H. pylori eradication rate on an intention to treat basis. While the urea breath test remains the noninvasive test of choice, interesting new data are available on the use of stool antigen testing to diagnose H. pylori infection. The number of H. pylori associated gastroduodenal diseases grows to include possible liver, vascular, immune, and skin conditions. 2 tables. 157 references. •

Treatment of Helicobacter Pylori Infection Source: BMJ. British Medical Journal. 320(7226): 31-34. January 1, 2000. Contact: Available from BMA House. BMJ Fulfilment Department, Tavistock Square, London WC1H 9TD. 44(0)171 383 6270. E-mail: [email protected]. Summary: This article provides a basic framework for the treatment of Helicobacter pylori infection. The authors base their recommendations on basic bacteriological principles and on a regularly updated in-house database of all published therapeutic studies. The authors maintain that treatment to eradicate H. pylori in patients with a proved ulcer is both cost effective and benefits the patient and society. Several equally effective regimens are available, but even the best fail in 5 to 20 percent of patients. Antibiotic resistance is usually induced after failure, and initial regimens should not compromise future therapeutic possibilities. The authors recommend that physicians should choose two complementary regimens, which when used consecutively come close to 100 percent cure. Treatment should start with a regimen based on clarithromycin with a backup regimen based on metronidazole unless resistance is above 15 percent, in which case the order of therapies should be reversed. Triple regimens that combine clarithromycin and metronidazole should not be used as there is no valid empirical backup regimen after failure. In general, the likelihood of cure can be increased by increasing the length of treatment. 2 figures. 1 table. 30 references.

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Clinical Presentation of Helicobacter Pylori-Positive and-Negative Functional Dyspepsia Source: Journal of Gastroenterology and Hepatology. 15(5): 498-502. May 2000. Contact: Available from Blackwell Science. 54 University Street, Carlton South 3053, Victoria, Australia. +61393470300. Fax +61393475001. E-mail: [email protected]. Website: www.blackwell-science.com.

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Summary: This article reports on a study in which a questionnaire was used to record the clinical presentation of functional dyspepsia (heartburn) in relation to Helicobacter pylori infection in a consecutive series of patients sent for upper gastrointestinal endoscopy. Only patients without macroscopic abnormalities in their esophagus, stomach, and duodenum were included. The study questionnaire included two questions related to daily life, and the calculation of a symptoms score. In the study, 222 patients were H. pylori positive and 182 patients were H. pylori negative. Loss of weight was significantly more common in the H. pylori positive group. Patients with H. pylori infection had a significantly higher overall symptom score compared with H. pylori negative subjects. In addition, the severity of epigastric and nocturnal pain, heartburn, retrosternal (behind the breastbone) heartburn, and vomiting was significantly higher in H. pylori positive functional dyspeptic patients, and the influence on daily life and activities was significantly worse. The authors conclude that the combination of retrosternal pain, weight loss, food intolerance, and the absence of halitosis signified a 64 percent accuracy in predicting H. pylori infection. Although it was not possible to differentiate between H. pylori positive and H. pylori negative functional dyspeptics on the basis of clinical presentation and the number of complaints, overall symptom score and severity of several symptoms was significantly higher in the H. pylori positive group. 3 tables. 23 references. •

Treatment of Helicobacter Pylori Infection in Clinical Practice in the United States: Results from 224 Patients Source: Digestive Diseases and Sciences. 45(2): 265-271. February 2000. Summary: This article reports on a study that explored treatment success, compliance, and side effects for treatment of Helicobacter pylori in clinical practice. In all, 224 consecutive patients received H. pylori treatment: 97 received 2 weeks of bismuth subsalicylate, metronidazole, tetracycline four times a day with a H2 receptor antagonist twice a day (BMT); 89 received 1 week of metronidazole, lansoprazole, and clarithromycin twice a day (MLC); and 38 received 1 week of BMT with lansoprazole twice a day (BMT PPI). Cure rates were: BMT 81 percent, MLC 90 percent, and BMT PPI 87 percent. More patients who were prescribed a bismuth based regimen discontinued medications due to side effects, compared to MLC. Nausea was more common for BMT compared to MLC. In conclusion, treatment of H. pylori infection with a 1 week course of MLC achieves a high rate of cure in clinical practice. 5 tables. 40 references.

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Role of Antisecretory Drugs in the Treatment of Helicobacter Pylori Infection Source: Alimentary Pharmacology and Therapeutics. 11(supplement 1): 21-25. February 1997. Contact: Available from Mercury Airfreight International, Ltd. 2323 EF, Randolph Avenue, Avenel, NJ 07001. E-mail: [email protected]. Summary: This article reviews the role of antisecretory drugs in the treatment of Helicobacter pylori infection. The author notes that the efficacy of antibiotics against H. pylori is enhanced by the coadministration of antisecretory drugs. While proton pump inhibitors appear to have some direct effect on H. pylori and extreme hypochlorhydria has a deleterious effect on the organism, the most likely mechanism by which antisecretory drugs as a class provide this effect is by improving the efficacy of the antibiotics themselves. Although proton pump inhibitors are the most widely used antisecretory agents, H2 receptor antagonists also enhance antibiotic effects. The author concludes that it is possible to cure H. pylori infection with regimens that do not include

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antisecretory drugs. However, the addition of antisecretory drugs enhances the efficacy of almost all such regimens and, in patients with active peptic ulcers, speeds the relief of symptoms. The mechanisms by which antisecretory drugs enhance antimicrobial efficacy have not been clearly determined but are probably multiple. 3 tables. 36 references. (AA-M). •

Non-Endoscopic Tests in the Diagnosis of Helicobacter Pylori Infection Source: Alimentary Pharmacology and Therapeutics. 11(supplement 1): 11-20. February 1997. Contact: Available from Mercury Airfreight International, Ltd. 2323 EF, Randolph Avenue, Avenel, NJ 07001. E-mail: [email protected]. Summary: This article reviews the use of nonendoscopic tests in the diagnosis of Helicobacter pylori infection. The author notes that upper gastrointestinal endoscopy is expensive, uncomfortable for patients, and carries a small but finite risk. Nonendoscopic tests are cheaper and more convenient, and thus should be preferred in situations where the extra information yielded by an endoscopy is not needed. In this article, the two main types of noninvasive tests, urea breath tests (UBT) and antibody detection tests, are described, with special reference to recent advances. Other noninvasive tests are briefly mentioned, and finally, the place of noninvasive tests in treatment trials and clinical practice is discussed. For the UBT, either nonradioactive 13C or radioactive 14C is used as an isotopic marker. 14C-UBTs are cheaper and are safe, but licensing regulations may make them inconvenient. Some UBTs have been simplified by omitting the normal test meal and encapsulating the urea to avoid metabolism by oral bacteria. These modified tests need further validation, especially when used for assessing H. pylori status after treatment. Serological tests detect circulating IgG or IgA. They are of variable accuracy, the best performing as well as UBTs. Paired serum samples pretreatment and 6 months posttreatment accurately assess treatment success. Rapid inoffice tests appear less accurate and cannot be used for posttreatment assessment. In practice, for primary diagnosis of H. pylori infection, endoscopic tests are best because endoscopy allows assessment of treatment indications. Where indications already exist or taking biopsies is dangerous, UBTs or serology are suitable, but serology is cheaper and more convenient. After treatment, endoscopy is usually unnecessary and UBTs accurately assess H. pylori status at 4 weeks. Serology is an alternative only if results are not required before 6 months. 107 references. (AA-M).

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Treatment Strategies for Helicobacter Pylori Infection Source: American Family Physician. 55(8): 2765-2774. June 1997. Summary: This article updates readers on treatment strategies for Helicobacter pylori infection. Peptic ulcer disease is strongly associated with infection by H. pylori; more than 90 percent of duodenal ulcers and adenocarcinomas of the distal stomach are associated with H. pylori infection. Eradication of the organism effectively prevents relapses of gastroduodenal ulcers associated with H. pylori. In patients undergoing endoscopy, the rapid urease test is highly sensitive and specific in diagnosing H. pylori infection. Noninvasive diagnostic methods include serologic antibody measurements and urea breath testing. Empiric therapy may be tried if the diagnosis is suspected on a clinical basis. Traditional 14 day triple therapy with bismuth, metronidazole, and either amoxicillin or tetracycline has consistently produced eradication rates of approximately 90 percent. Compliant patients who suffer side effects after 1 week of therapy can stop treatment. Those who have not completed 1 week of therapy should be switched to an

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alternate regimen. Newer combination regimens have shown promise in a smaller number of studies. No single agent given as monotherapy has proved to be acceptably effective in clinical studies. 3 figures. 2 tables. 34 references. (AA-M). •

Helicobacter Pylori Eradication Did Not Change Ulcer Recurrence or Dyspepsia Rates in Patients Who Used NSAIDs (commentary) Source: ACP Journal Club. 130(2): 38. March-April 1999. Contact: Available from American College of Physicians-American Society of Internal Medicine (ACP-ASIM). 190 North Independence Mall West, Philadelphia, PA 191061572. Summary: This brief article offers a summary of a recent research study, with an accompanying commentary. The study was undertaken to determine whether Helicobacter pylori eradication in patients who use nonsteroidal antiinflammatory drugs (NSAIDs) can decrease dyspepsia (heartburn) without affecting the ulcer recurrence rate. The study comprised 285 patients who were 18 to 85 years of age, who required NSAID treatment, who had H. pylori infection of the gastric mucosa, who had peptic ulcers at baseline or in the previous 5 years, or who had moderate or severe NSAID associated dyspepsia. Patients were allocated to H. pylori eradication treatment twice a day with omeprazole, amoxicillin, and clarithromycin (n = 142) or to control treatment twice a day with omeprazole and placebo antibiotics (n = 143) for 1 week. All patients subsequently received omeprazole until endoscopy at week 4. No difference was found between groups in the number of patients who had treatment failure during followup. Fewer patients in the eradication group than in the control group were free of ulcers at 8 weeks (89 percent versus 100 percent). The author concluded that in patients who used NSAIDs, H. pylori eradication did not influence the rates of ulcer recurrence or dyspepsia over 6 months. The commentary discusses the results and concludes that it could still be argued that eradicating H. pylori is worth considering before ulcers form in patients who are about to start taking NSAIDs. 1 table. 1 reference.

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Helicobacter Pylori Infection in Nonulcer Dyspepsia: To Treat or Not to Treat? Source: Consultant. 39(2): 416. February 1999. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Box 4010, Greenwich, CT 06831-0010. Summary: This brief article summarizes two recent studies of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. The author notes that the results of these studies are contradictory. In the first study (McColl et al., 1998) the authors suggest that all patients with H. pylori infection and nonulcer dyspepsia be treated with omeprazole plus antibiotics, since it is not possible to predict which patients might benefit. In the second study (Blum et al., 1998) the rate of symptom relief among those with persistent H. pylori infection who had been given omeprazole and antibiotics was similar to that in persons in whom the infection was eliminated. The authors of this study remark that the role of H. pylori in nonulcer dyspepsia is still unclear and conclude that although the eradication of H. pylori infection may help prevent or cure peptic ulcer disease, it is not likely to relieve symptoms in patients with nonulcer dyspepsia. The author of this summary reports that consensus statements recommend diagnostic endoscopy for patients older than 45 years with dyspepsia, or patients of any age with unexplained weight loss, vomiting, dysphagia (swallowing difficulty), gastrointestinal bleeding, or anemia. Endoscopy is also recommended for patients of any age with dyspepsia who have a heightened risk of gastric cancer based on their

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ethnic, socioeconomic, or familial background. For patients younger than 45 years, the recommended approach is to perform serologic tests for H. pylori and prescribe eradication therapy for those with positive results. In all instances, dietary, emotional, and environmental triggers of nonulcer dyspepsia should be identified and managed. 3 references. •

Gastric Biopsy-Based Rapid Urease Tests for the Detection of Helicobacter Pylori: Progress, Advantages and Limitations. (editorial) Source: Journal of Gastroenterology and Hepatology. 17 (6): 629-632. June 2002. Contact: Available from Blackwell Science. 54 University Street, Carlton South 3053, Victoria, Australia. +61393470300. Fax +61393475001. E-mail: [email protected]. Website: www.blackwell-science.com. Summary: This editorial comments on a study reported in this same issue of the Journal of Gastroenterology and Hepatology on the use of gastric (stomach) biopsy-based rapid urease tests for the detection of Helicobacter pylori. The gastric biopsy based rapid urease test has many advantages over other invasive methods: the test is simple to perform and the results are easy to read; the test is relatively inexpensive; and the test provides a prompt result (positive results occur within 1 hour in 53 to 99 percent of cases with H. pylori infection, allowing the initiation of the therapy soon after endoscopy for these cases). However, the gastric biopsy-based rapid urease tests also suffer from several limitations: they are invasive; they are not accurate in monitoring the effectiveness of eradication therapy; and less accurate results (including false-negative results) may occur, particularly in patients who are receiving treatment with antimicrobial agents or antisecretory drugs, in patients with bleeding peptic ulcers, and in children or the elderly. 1 table. 47 references.

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Interactions Between Helicobacter Pylori and Gastroesophageal Reflux Disease Source: Diseases of the Esophagus. 11(4): 203-209. October 1998. Contact: Available from Harcourt Brace and Company, Ltd. Journal Subscription Department. Foots Cray, Sidcup, Kent, DA 14 5HP. Summary: This literature review explores the relationship between Helicobacter pylori and gastroesophageal reflux disease (GERD). The authors begin by noting the differences in nomenclature, particularly between European and American researchers; European terminology is used in this article. The authors discuss the research articles and summarize their conclusions. H. pylori colonization rates do not differ between patients with uncomplicated GERD and controls. Eradication of H. pylori infection in patients with duodenal ulcer disease may provoke the development of reflux esophagitis. Cardiac mucosa is as susceptible to H. pylori infection as antral and corpus mucosa. An inflammatory cell response to infection in cardiac mucosa is similar to that observed in antral mucosa. In patients with Barrett's esophagus, H. pylori infects gastric epithelium but not intestinal epithelium. In patients without endoscopic Barrett's esophagus, intestinal metaplasia at the gastroesophageal junction may result from H. pylori infection. 2 tables. 72 references.

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H. Pylori, GERD Should Be Treated As Separate Conditions Source: Gastroenterology and Endoscopy News. p. 7. January 2000. Contact: Available from McMahon Publishing Group. 545 West 45th Street, 8th Floor, New York, NY 10036. (212) 957-5300. Website: www.gastroendonews.com.

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Summary: This news article reports on soon to be published studies that support the contention that Helicobacter pylori infections and gastroesophageal reflux disease (GERD) should be treated as separate conditions. The article stresses that the relationship between H. pylori and GERD is complex and controversial. Epidemiologic evidence supports a protective role of H. pylori in GERD; the prevalence of H. pylori in patients with GERD is about 10 percent lower than in controls, and H. pylori positive patients are more likely to present with fewer cases of esophagitis than those who are H. pylori negative. Additional studies of H. pylori therapy suggest that eradication of the organism causes an increase in the incidence of GERD, but those studies have been challenged. The article refers to a study of a group of patients with active gastric and duodenal ulcers in which heartburn was decreased after 6 months of eradication therapy. The researcher interviewed concludes that H. pylori must be eradicated before initiating long term treatment of reflux esophagitis; however, reflux esophagitis will not necessarily increase after eradication. •

Helicobacter Pylori and the Risk and Management of Associated Diseases: Gastritis, Ulcer Disease, Atrophic Gastritis and Gastric Cancer Source: Alimentary Pharmacology and Therapeutics. 11(Supplement 1): 71-88. April 1997. Contact: Available from Mercury Airfreight International, Ltd. 2323 EF, Randolph Avenue, Avenel, NJ 07001. E-mail: [email protected]. Summary: This review article addresses the role of Helicobacter pylori and the effect of H. pylori eradication on gastritis, peptic ulcer disease, atrophic gastritis, and gastric cancer. The author emphasizes the various factors that influence the clinical course of this infection. H. pylori induces chronic gastritis in virtually all infected subjects. This inflammation can lead to peptic ulceration and atrophic gastritis in a considerable number of infected subjects. A minority eventually develops gastric cancer. The risk of such complications depends upon the severity of gastritis, which is determined by various host-and bacteria-related factors. Among bacterial factors, most of the evidence addresses the cagA pathogenicity island, the presence of which has been associated with more severe gastritis, peptic ulceration, atrophic gastritis, and gastric cancer. Among host factors, most of the evidence focuses on acid production in response to H. pylori infection. An increase in acid secretion limits H. pylori gastritis to the antrum at the risk of duodenal ulcer disease; a reduction allows more proximal inflammation at the risk of atrophic gastritis, gastric ulcer disease, and gastric cancer. Gastritis and atrophy negatively influence acid secretion. H. pylori eradication is required in peptic ulcer disease and may be advocated in patients on profound acid suppressive therapy; it has been shown to cure gastritis and prevent ulcer recurrence. The author concludes that further study is required to determine the efficacy of H. pylori eradication in the primary and secondary prevention of atrophic gastritis and gastric cancer. 3 figures. 193 references. (AA).

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Gastric Cancer and Helicobacter Pylori Source: Alimentary Pharmacology and Therapeutics. 16 (Supplement 4): 83-88. 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.

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Summary: This review article discusses gastric (stomach) cancer, the second most common cause of death from malignancy in the world. The pathogenesis of stomach cancer is comparatively well understood and its etiology (cause) multifactorial. Noncardia gastric cancer usually arises in a stomach that has been inflamed over a long period and where atrophy and intestinal metaplasia have supervened. The most common cause of gastric inflammation is infection with Helicobacter pylori. Colonization with this organism increases the relative risk of developing stomach cancer by about six. The likelihood of stomach cancer increases with the severity and extent of the gastritis. Severity is influenced by the virulence of the infecting organism, the genetics of the host, bile reflux, dietary factors, and the presence of hypochlorhydria which influences the extent, as well as the severity, of the inflammation. The only predisposing factor which can easily be manipulated is H. pylori infection, which can be successfully treated in 80 to 90 percent of cases using a 1 week therapeutic regimen. 1 table. 27 references. •

Review Article: The Control of Gastric Acid and Helicobacter Pylori Eradication Source: Alimentary Pharmacology and Therapeutics. 14(11): 1383-1401. November 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: This review article focuses on the gastric (stomach) acid pump as a therapeutic target for the control of acid secretion in peptic ulcer and gastroesophageal reflux disease (GERD). The mechnism of the proton pump inhibitors (PPT) is covered as well as their clinical use. The biology of Helicobacter pylori as a gastric resident is then discussed, with special regard to its mechanisms of acid resistance (i.e., how it survives in the seemingly hostile environment of stomach acid). The authors explore the properties of the products of the urease gene clusters, ureA, B, and uerI, E, F, G, and H, in order to explain the unique location of this pathogen. The dominant requirement for acid resistance is the presence of a proton gated urea transporter, UerI, which increases access of gastric juice urea to the intrabacterial urease 300 fold. This enables rapid and continuous buffering of the bacterial periplasm, allowing acid resistance and growth at acidic pH in the presence of urea. The authors also present a hypothesis for the use of combination therapy to eradicate H. pylori infections. 11 figures. 58 references.

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Is a One-Week Course of Triple Anti-Helicobacter Pylori Therapy Sufficient to Control Active Duodenal Ulcer? Source: Alimentary Pharmacology and Therapeutics. 15(7): 1037-1045. July 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: Triple therapy currently forms the cornerstone of the treatment of patients with Helicobacter pylori positive duodenal ulcer. This article reports on a study undertaken to establish whether prolonged antisecretory therapy is necessary in patients with active duodenal ulcer. A total of 77 patients with H. pylori positive duodenal ulcer were included in the prospective, controlled, double blind study. All patients received a 7 day treatment with omeprazole 20 milligrams twice daily (b.d.), clarithromycin 500 milligrams b.d., and amoxicillin 1000 milligrams b.d. Patients in the omeprazole group underwent an additional 14 day therapy with omeprazole 20 milligrams; patients in the placebo group received placebo. Endoscopy was performed

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upon inclusion in the study and after 3 and 8 weeks. After 3 weeks, the healing rate was 89 percent in the omeprazole group and 81 percent in the placebo group. After 8 weeks, the ulcer healed in 97 percent of the patients in the total group. H. pylori was eradicated in 88 percent of patients in the omeprazole group and in 91 percent in the placebo group. No statistically significant differences between the groups were found in ulcer related symptoms or in ulcer healing. The authors conclude that in patients with H. pylori positive duodenal ulcer, a 7 day triple therapy alone is sufficient to control the disease. 5 figures. 3 tables. 18 references. •

Outcomes Research in Helicobacter Pylori Infection Source: Alimentary Pharmacology and Therapeutics. 11(supplement 1): 95-101. February 1997. Contact: Available from Mercury Airfreight International, Ltd. 2323 EF, Randolph Avenue, Avenel, NJ 07001. E-mail: [email protected]. Summary: While the medical community has accepted the role of H. pylori in the pathogenesis of peptic ulcer disease, confusion persists among clinicians regarding when and on which patients to attempt H. pylori eradication. This article explains the role of outcomes research in helping clinicians to identify which patients benefit from H. pylori eradication and to determine the cost-effective strategies for their diagnosis, treatment, and follow up care. Economic evaluation of the impact of H. pylori infection has focused primarily on assessment of the patient with documented peptic ulcer disease, with particular attention to costs of pharmaceuticals. However, drug costs are only one portion of the total costs of management for patients with acid-related disorders and therefore must be put in the appropriate context. Additional aspects of patient benefit (e.g., patient satisfaction) and health care expenditures (e.g., over the counter medications, specialist visits, hospitalizations) must be included in an evaluation of the value of a particular diagnostic test, treatment, clinical guideline, or disease management strategy. As a result of the high quality and quantity of data emerging, the author concludes that H. pylori eradication is cost effective in selected patient populations: newly documented peptic ulcer disease; history of peptic ulcer disease and taking maintenance therapy; and suspected peptic ulcer disease using a serological test to guide initial treatment. The role of eradication in other areas, for example, patients with nonulcer dyspepsia and screening to prevent gastric cancer, remains to be seen. In addition to the performance of rigorous studies, researchers must respond to the 'information overload' on busy clinicians, by effectively disseminating their findings. If data generated from outcomes research are not integrated into everyday clinical practice, the enormous benefits associated with H. pylori eradication will not be achieved. 1 figure. 19 references. (AA-M).

Federally Funded Research on Helicobacter Pylori The U.S. Government supports a variety of research studies relating to Helicobacter pylori. 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

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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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 Helicobacter pylori. 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 Helicobacter pylori. The following is typical of the type of information found when searching the CRISP database for Helicobacter pylori: •

Project Title: A NOVEL METHOD TO DETECT HELICOBACTER PYLORI IN CHILDREN Principal Investigator & Institution: Wagner, David A.; Metabolic Solutions, Inc. 460 Amherst St Nashua, Nh 03063 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): In the avalanche of publicity surrounding H. pylori infection, children have been the one segment of the population that has been virtually ignored. However, there is a growing body of evidence that children, and especially minority children, are commonly afflicted with this disease. There are no FDA approved tests, other than the onerous endoscopic-based tests, to detect active H. pylori in children. We intend to address this need for a simple, minimally invasive and accurate diagnostic test for children. Metabolic Solutions has developed a test to determine the presence of active H. pylori infection that we named the Ez-HBT(TM). Although this is a blood test it should not be confused with serology tests that detect the presence of antibodies. The Ez-HBT(TM) is superior to antibody based tests because it detects the presence of gastric urease activity. Urease activity is only present when H. pylori have colonized the stomach. The test begins with the patient ingesting an oral dose of 13Curea (non-radioactive label). The enzyme urease associated with gastric H. pylori breaks urea down into 13CO2 and ammonia. This results in an increase in the ratio of 13C/12C in blood carbon dioxide if H. pylori are present in the stomach. H. pylori infection impairs a child's growth, ability to function in school and may have long term implications for gastric cancer. The simplicity of the Ez-HBT(TM) including no test meal, a tablet that can be dissolved in a glass of water and a single traditional venipuncture makes it an ideal and cost effective tool for identifying H. pylori infection in children. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ACETONE METABOLISM IN HELICOBACTER PYLORI Principal Investigator & Institution: Hoover, Timothy R.; Microbiology; University of Georgia 617 Boyd, Gsrc Athens, Ga 306027411 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Helicobacter pylori is a major human pathogen that colonizes the gastric mucosa, leading to gastric inflammation that can progress to chronic gastritis, peptic ulcer, gastric cancer or mucosal-associated lymphoma. The ability of H. pylori to establish a chronic infection in the human stomach indicates that it is well adapted to acquire the nutrients it needs for growth in this unique environment. Complete genomic sequences for two unrelated H. pylori strains, 26695 and J99, have greatly aided the understanding of the physiology of this bacterium. Both sequenced

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strains were reported recently to have the genes for a potential acetone carboxylase, an enzyme that initiates the metabolism of acetone by converting it to acetoacetate. Acetone is produced in the body upon the spontaneous decarboxylation of acetoacetate, one of the ketone bodies produced by the liver and used as an energy source when glucose is not readily available. Ketones are always present in the blood, with up to 185 grams of ketone bodies produced per day by the liver of a healthy adult. This proposal will test the hypothesis that H. pylori utilizes acetone as an important energy source for the bacterium in the gastric mucosa. The first specific aim of the proposal is to verify that H. pylori has a functional acetone carboxylase by expressing the protein in Escherichia coli, purifying it, and examining its ability to catalyze the carboxylation of acetone. The second specific aim is to determine if this enzyme is needed by H. pylori to establish a chronic infection in the gastric mucosa. The operon encoding the H. pylori acetone carboxylase will be disrupted and the resulting mutant strain will be examined for its ability to colonize the stomachs of mice and Mongolian gerbils. The proposed studies will expand knowledge of metabolic pathways in H. pylori, which will lead to a better understanding of how this pathogen establishes infections in humans and may provide new strategies for the prevention or treatment of H. pylori infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACID INDUCIBLE RESPONSES IN H PYLORI Principal Investigator & Institution: Mcgowan, Catherine C.; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-JUL-1999; Project End 30-JUN-2004 Summary: (Adapted from the Applicant's Abstract): Helicobacter pylori are curved Gram-negative bacteria that are now recognized as the cause of chronic superficial gastritis in humans, and this organism plays an important etiologic role in the pathogenesis of peptic ulcer disease and distal gastric adenocarcinoma. H. pylori colonizes the mucus layer overlying the gastric epithelium, where it is exposed to a wide range of pH values. Urease activity is required for H. pylori survival at low pH, and its presence is essential for colonization. However, little else is known about the mechanisms which allow H. pylori to survive in acidic environments. In previous studies, the investigators have used the strategy of subtractive RNA hybridization to identify an acid-inducible gene in H. pylori, wbcJ, that is essential for O-antigen expression and which contributes to acid survival of the organism. The long-term goal of this study is to isolate and identify additional acid-inducible factors in H. pylori which are required for establishment and maintenance of infection. The hypothesis of this study is that H. pylori possesses a regulated, inducible acid stress response system. The specific aims are 1) to study the transcriptional regulation of the acid-inducible H. pylori gene, wbcJ and to characterize its role in LPS biosynthesis and structure, 2) to identify other H. pylori genes whose expression is increased in response to acidic pH, and 3) to isolate acid-inducible promoters in H. pylori. To accomplish the first objective, analyses will be done to characterize the promoter region and genetic organization of wbcJ and its co-transcribed genes. Transcriptional wbcJ fusions then will be constructed using xylE to examine the expression of wbcJ under different environmental conditions in vitro. The LPS structure of wbcJ mutants will be analyzed to determine the role of this gene in H. pylori LPS biosynthetic pathways. The method of subtractive RNA hybridization will be used to isolate H. pylori genes whose expression is increased during growth at acidic pH. Genes identified by this approach will be cloned and disrupted using insertional mutagenesis, which will permit the study of their role in H. pylori acid survival and colonization. As an alternate strategy to identifying acid-

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regulated genes, we will employ the technique of differential fluorescence induction to enrich for promoters that are up-regulated following exposure to acidic pH, utilizing GFP and a fluorescence-activated cell sorter. The proposed work will further elucidate the mechanisms used by H. pylori to colonize and persist within the gastric environment and will lead to improved understanding of how H. pylori causes disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ASPIRIN, HELICOBACTER PYLORI, AND PEPTIC ULCER DISEASE Principal Investigator & Institution: Lew, Edward A.; Medicine; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2004 Summary: Aspirin and other non-steroidal anti-inflammatory drugs are widely used to treat pain and inflammation, and at low doses, aspirin is also increasingly being used for cardiovascular prophylaxis. However, these drugs have substantial gastrointestinal toxicity and a significant number of patients develop peptic ulcers and GI bleeding. Although infection with Helicobacter pylori is another major risk factor for ulcers, the relationships between aspirin and H. pylori in the development of ulcers remain highly controversial. It is unclear, for example, whether there is an addictive or synergistic interaction between these factors in conferring ulcer risk such that aspirin interacts with H. pylori to increase ulcer complications. Aspirin impairs mucosal protective mechanisms by decreasing prostaglandin production, whereas H. pylori promotes mucosal injury through cytokines and inflammation to form ulcers. Past studies have provided conflicting data on the ulcer risks associated with both factors but they have been limited by recall bias of aspirin use, selection bias, and small sample sizes with short follow-up. The primary goals of the proposed research are to determine the risk of peptic ulcers associated with the joint effects of low dose aspirin and H. pylori infection, the ulcer risk associated with low dose aspirin and a specific virulent strain of H. pylori, known as cagA+ H. pylori, and the risk of GI bleeding associated with low dose aspirin and H. pylori (especially cagA+ H. pylori strains) as compared to those without infection. We will have 80% power to detect a difference of 1.56 in the odds ratio, when comparing the association of aspirin use and ulcer formation in H. pylori positive and negative subjects. As the US population grows older, the chronic use of aspirin for cardiovascular prophylaxis and the subsequent development of ulcers are likely to increase, involving health care costs. The proposed study will provide important information to make an informed decision about aspirin related GI complications and whether H. pylori infected patients are at risk for ulcers and GI bleeding while on aspirin. These results may help identify high-risk patients and lead to strategies that will reduce ulcer complications among aspirin users. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AUTOIMMUNE GASTRITIS INITIATED BY HELICOBACTER INFECTION Principal Investigator & Institution: Lorenz, Robinna G.; Associate Professor; Pathology and Immunology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 30-JUN-2002 Summary: (Taken from the Investigator's Abstract) The bacteria, Helicobacter pylori, is a major pathogen which, in addition to infecting over half of the world's population, is linked to gastric and duodenal ulcer disease, mucosal-associated lymphomas, and adenocarcinoma. Infection with H.pylori initially leads to recruitment and activation of

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the non-specific innate immune response. These mononuclear cells secrete proinflammatory cytokines that directly affect the gastric epithelium, as well as recruit lymphocytes into the inflammatory focus. Very little is known about the characteristics of this immune infiltrate, its antigen specificity, or its role in subsequent development of gastric diseases; however, it has now been shown that infection with H.pylori can lead to the production of anti- parietal cell antibodies. This has led to the hypothesis that Helicobacter infection induces an autoimmune response that causes subsequent gastric epithelial cell destruction and pathology. A small animal model of Helicobacter infection, the H.felis mouse model, closely mimics the human disease and allows a careful analysis of the adaptive immune response to Helicobacter infection. The investigator has shown that it is the host T cell response that is crucial for the development of H.felis-associated gastric pathology. This has directed attention to the role of the cellular immune response, and its potential autoimmune nature, in the development of Helicobacter-associated gastric epithelial cell destruction and pathology. This grant application focuses on understanding the relationship between the cellular immune response to Helicobacter infection, and the development of subsequent gastric epithelial alterations. These changes in epithelial proliferation, differentiation, and cell death lead to clinical ulcer disease and increased metaplasia. In order to elucidate this immune/epithelial cell relationship and its sequelae, the investigators propose to identify the immune T lymphocyte subset critical for the development of Helicobacter- associated gastric pathology and to determine the mechanism by which Helicobacter-induced immune responses generate gastric epithelial pathology. The understanding of the basic mechanisms by which the host immune response to Helicobacter induces gastric epithelial pathology will lay the foundation for further studies on the regulation of the inflammatory response and the design of immunotherapies for Helicobacter infection and associated digestive diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BETA2 INTEGRIN SIGNALING IN HUMAN NEUTROPHILS Principal Investigator & Institution: Takami, Mimi S.; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 15-MAY-1999; Project End 31-MAR-2004 Summary: A variety of gastrointestinal disorders, that include H. pylori, NSAID induced gastritis and inflammatory bowel disease, involve the recruitment of leukocytes from the circulation to the site of injury. The severity of the mucosal injury in these disease processes has been directly correlated with the extent of the neutrophil infiltration. In addition, the persistent neutrophil infiltrate which is the hallmark of chronic H. pylori infection, has been implicated as a possible mechanism facilitating malignant transformation in the gastric mucosa. Central to the modulation of adhesion and migration of leukocytes in inflammatory processes such as these, is a subfamily of cell surface receptors, the beta2 integrins. Adhesion through beta2 integrins is a complex process that involves activation of the integrin through an inside out signaling mechanism, triggered by the engagement of well characterized receptors such as the chemokine receptors, IL-8, C5a, and N-Formylmethionlleucyl- phenylalanine (FMLP), cytokine receptors, such as TNF, and activation of Protein Kinase C. Integrin activation results in enhanced binding to ligand, and subsequently, generation of an outside-in signal cascade that may lead to changes in gene expression and cytoskeletal rearrangement, enabling the leukocyte to migrate to sites of injury, and facilitating the physiologic response of the cell. Recent reports have identified Interleukin-8 as an important epithelial-derived inflammatory mediator in both IBD and H. pylori gastritis.

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In neutrophils, I1-8 has been shown to induce chemotaxis, respiratory burst and granule release, and to enhance cellular adhesion. However, the specific effects of IL-8 on beta2 integrin activation and ligand binding have not been closely examined. In addition, while recent reports indicate that IL-8 activates the MAPK pathway through Ras/Rafmediated events, the relationship of these events to beta2 integrin function has yet to be elucidated. Our goal, within this proposal, is to delineate the signal transduction cascades involved in beta2 integrin activation, with a particular focus on the physiologic stimulus at the chemokine receptor. In addition, we will examine post-ligand-binding events, including protein tyrosine phosphorylation and protein-protein interactions that are central to the outside-in signaling cascade initiated by engagement of beta2 integrins on human neutrophils. We will examine the relationship of these events to the complex shape changes involved in aggregation and transmigration. And, as a biological model, we will explore the way in which exposure to Helicobacter pylori, may impact these signals and affect neutrophil adhesion and migration on epithelial surfaces. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOSENSOR FOR CONTAMINANT-FREE PLATELETS Principal Investigator & Institution: Elson, Edward C.; Opto-Gene, Inc. 7100 Baltimore Ave, Ste 203 College Park, Md 20740 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 30-NOV-2002 Summary: Development of a Bacterial Biosensor is proposed to ensure that platelets are sufficiently free of bacteria to be safely transfused into patients. Preliminary results with one prototype demonstrated that rRNA from Helicobacter pylori, a model bacterial pathogen for humans, could be detected by hybridization sandwich assay within two minutes and at 10/4 cells sensitivity. A second prototype with a long-period with alongperiod Bragg grating, which does not require a sandwich assay or signal fluorophore, showed that human IgG could be identified even in a crude bacterial lysate. Both prototypes work with either nucleic acids or proteins, can function as point-of-care devices, and are faster than commercially available tests. Each prototype will be modified and then tested two ways: first, by hybridization with a universal rRNA probe to detect bacterial contamination of platelets. Second, with receptor and/or antibody to detect extracellular release of soluble vascular endothelial growth factor (sVEGF) from platelets when bacteria are present. Each of the four possible configurations will be optimized and compared for sensitivity, specificity, ease of cooperation, potential cost, and other factors. The resulting instrument should prove a powerful and effective tool for rapid and direct determination of platelet safety and for other health related applications. PROPOSED COMMERCIAL APPLICATIONS: The risk of receiving bacterially contaminated platelets may be 50 to 250 times higher than the combined risk per unit of transfusion-related viral infection with HIV-1/2, HCV, HBV, and HTLV-I/II. About four million units of platelets are transfused globally every year. Medicare already adds a $35 premium to each unit of viral-cleansed blood product. By extrapolation, therefore, a minimal cost of $5 per unit to certify platelets as sufficiently free of bacteria would create an estimated $20 million market and would save 100 to 150 lives every year just in the United States alone. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOSYNTHESIS OF MEMBRANE GLYCOLIPIDS IN RHIZOBIUM Principal Investigator & Institution: Raetz, Christian R.; Professor & Chairman; Biochemistry; Duke University Durham, Nc 27706

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Timing: Fiscal Year 2002; Project Start 01-JUL-1995; Project End 30-JUN-2004 Summary: Lipopolysaccharides (LPSs) are remarkable glycolipids that comprise the outer surfaces of Gram-negative bacteria, including the symbiotic organism, Rhizobium leguminosarum. In Escherichia coli, the lipid A anchor of LPS is a hexa-acylated disaccharide of glucosamine, bearing phosphate moieties at positions 1 and 4'. The minimal LPS required for a growth of E.coli consists of lipid A and two extra sugars. Emerging genomic sequences indicate that the enzymes that make lipid A in E. coli are present in most other Gram-negative bacteria. Lipid A (often termed endotoxin) is also the active component of LPS responsible for the clinical complications of Gram-negative sepsis. Minor modifications in the structure of lipid A can have profound effects on pathogenesis. Some lipid A analogs are actually potent endotoxin antagonists. Compared to E. coli, the chemical structures of the lipid A and core domains of R. leguminosarum LPS are very unusual. R. leguminosarum lipid A lacks the and 4'phosphates, but is modified with galacturonic acid at position 4'. It is acylated with a peculiar 28 carbon fatty acid, and contains 2-deoxy-2-aminogluconate in place of the proximal glucosamine. The structure of R. leguminosarum LPS indicates the existence of novel enzymes for generating diverse lipid A and core species. It is now established that the first seven enzymes of lipid A biosynthesis are in fact the same in E. coli and R. leguminosarum. The differences arise in the later stages of the pathway. To date, enzymes identified as unique to R. leguminosarum include a 4'-phosphatase that is also a phosphotransferase, a 1-phosphatase, a long chain acyltransferase with its own acyl carrier protein, and three distinct core glycosyltransferases. Characterization of the R. leguminosarum system should provide insights into the function of lipid A-like molecules, including special roles during symbiosis in plants, and affords the opportunity to create novel lipid A hybrids that may have interesting adjuvant or antagonist activities. Some structural features of R. leguminosarum lipid A are seen in human pathogens. Legionella pneumophila lipid A contains a C28 chain, while Porphyromonas gingivalis and Helicobacter pylori lipid A lack the 4' phosphate. In the coming grant period, the specific aims are: I) cloning of the C28 acyltransferase of R. leguminosarum; II) analysis of the lipid A 4'-phosphatase/phosphotransferase, especially its ability to synthesize PtdIns-4-P; III) determination of the enzymatic basis for proximal unit diversity in R. leguminosarum lipid A; and IV) characterization of enzymes that incorporate the unique inner core sugars of R. leguminosarum LPS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BREATH AMMONIA METHOD FOR H. PYLORI DETECTION Principal Investigator & Institution: Putnam, David L.; Pacific Technologies 21806 Ne 1St Redmond, Wa 98053 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-MAY-2004 Summary: (provided by applicant): The project will develop a simple test for noninvasive diagnosis of active Helicobacter pylori infection in the stomach based on measuring ammonia in patients' breath. A novel highly sensitive optical technique will be used to measure breath ammonia, leading to an inexpensive diagnostic procedure that can be conducted in any general practitioner's office. An improved method of detecting gastric H. pylori is of clinical significance because the organism is the cause of most peptic ulcers and is associated with other gastrointestinal diseases including cancers. The new breath ammonia sensing method will be useful for diagnosis of infected patients, as well as for follow-up determinations of infectious status after therapy. Phase I results demonstrated 100 percent agreement with conventional 14Clabeled breath tests The research will optimize the clinical instrumentation, expand the

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scope of the Phase I clinical trial to a larger, more diverse patient set, and study test parameters that maximize the clinical diagnostic value of the test. This work will redisign the sensor and instrument as a logical and practical step to final product commercialization. Subsequent pre-market testing for commercialization will implement those instrument and test procedure and confirm their clinical efficacy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER SERO EPIDEMIOLOGY AMONG THE JAPANESE IN HAWAII Principal Investigator & Institution: Nomura, Abraham M.; Director; Kuakini Medical Center 347 N Kuakini St Honolulu, Hi 96817 Timing: Fiscal Year 2002; Project Start 15-SEP-1983; Project End 30-JUN-2004 Summary: (Adapted from the Investigator's Abstract) This is a sero-epidemiologic prospective study to identify biochemical markers related to common cancers occurring among 11,132 American Japanese subjects examined in Hawaii. Their unthawed serum, obtained many years prior to the diagnosis of cancer, will be used in the investigation. The proposal is focused on five specific cancer sites: prostate, colon, breast, stomach and urinary bladder. Eight specific aims will be addressed: 1) to determine whether low serum isoflavonoid levels increase the risk of prostate cancer; 2) to see if low serum selenium levels increase prostate cancer risk; 3) to determine whether high serum insulin level increases the risk of colon cancer risk in men; 4) to find out if low serum isoflavonoid levels increase breast cancer risk in women; 5) to determine whether men carrying the Helicobacter pylori Vac-A strains are at increased risk for stomach cancer; 6) to see if the presence of H. pylori serum markers increase the risk of total and causespecific mortality in men; 7) to find out if serum levels of vitamin A and carotenoids are inversely associated with urinary bladder cancer risk in men; 8) to determine whether low serum selenium levels increase urinary bladder cancer risk in men. The population base for aim 4 consists of 1787 women, born from 1900 to 1935 who were interviewed and examined from 1975-1977. The subjects for the rest of the aims are 9345 men born from 1896 to 1935, who were interviewed and examined from 1971 to 1976. A wealth of epidemiologic-based data was collected on these participants, and they have been under continuous hospital surveillance for cancer since their examination. Two types of study design will be used in this proposal: 1) prospective study (aim 6); 2) nested case-control study (the rest of the aims). It is estimated that the number of incident cases will be as follows: 376 prostate, 387 colon, 120 breast, 293 stomach, and 131 urinary bladder cancer cases. The number of cause -specific mortality cases should be at least 870 coronary deaths, 1277 cancer deaths and 4145 deaths among the men. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHEMOPREVENTION OF GASTRIC DYSPLASIA-LONG TERM FOLLOW UP Principal Investigator & Institution: Fontham, Elizabeth T.; Professor and Chairman; Louisiana State Univ Hsc New Orleans New Orleans, La 70112 Timing: Fiscal Year 2003; Project Start 08-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): While Helicobacter pylori is now established as a pivotal factor in gastric carcinogenesis, its mechanisms of action and timing in the premalignant process are the subject of research. This project builds upon a recently completed 6-year randomized chemoprevention trial in a high-risk region of Colombia. A significantly greater regression of premalignant lesions was observed in study

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participants who were treated and were cleared of H. pylori infection. Upon completion of the trial, participants who had not been in the anti-H. pylori treatment arm were offered standard triple therapy. Quarterly contact has been maintained with trial participants, and this project now proposes to evaluate the long-term effectiveness of anti-H. pylori treatment in an adult population in which the community prevalence of infection is greater than 90 percent. The specific aims of the study are to: 1. determine the proportion of subjects free of infection in 2002; 2. document the reinfection rates from 2002 to 2007 in subjects free of infection in 2002; 3. compare the H. pylori genotypes in persons receiving treatment and found to be free of infection during the follow-up phase with prior pre-treatment genotypes (1998); 4. determine the status of histopathologic lesions (progression; regression; no change) at the end of the follow-up phase (2006-7) in relation to their infection status over time and previous histopathology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COORDINATE REGULATION OF BACTERIAL VIRULENCE FACTORS Principal Investigator & Institution: Mekalanos, John J.; Professor; Microbiol & Molecular Genetics; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-MAY-1988; Project End 30-APR-2008 Summary: (provided by applicant): For the next funding period of AI-26289, our overall goal is to understanding the biology of five pathogenic microorganisms (Vibrio cholerae, Pseudomonas aeruginosa, Helicobacter pylori, Haemophilus influenzae, and Escherichia coli) in order to discover anti-infective strategies based on the use of small molecule inhibitors. These studies will be horizontally integrated by use of common technologies and genetic approaches. For example, we will use differential fluorescence induction (DFI) to define and study genes expressed in vivo or associated with virulence regulons of biological interest. Genomic microarrays will be used to measure gene expression at the global transcriptional level under various growth conditions, in various defined mutants, and under a series of imposed stresses. These stress challenges will include exposure to host milieu during infection, exposure to host cells, withdrawal of essential gene products through conditional expression, and exposure to toxic compounds, toxic protein aptamers, and inhibitory antibiotics. We will use a variety of methods including the new DNA-chip based "TraSH method" to identify genes required for bacterial growth and viability in vitro and in vivo. We will attempt to identify the function of new essential proteins by characterizing complexes they form with other proteins through micro liquid chromatography tandem mass spectrometry (microLCMS) analysis. Other proteomic projects will include the use of microLCMS to define proteins expressed on the surface of bacteria grown in vitro and in vivo. We will also explore the use of "protein chips" as a means of doing protein-protein interaction analysis and as a new tool for studying host immune responses. Computational methods will be used to mine expression and genomic databases for interesting potential virulence or essential gene products, which will then be analyzed genetically for attenuation in experimental animals. We will use the information we gain on essential processes in pathogenic bacteria to devise sensitive bioscreens that can detect small molecule inhibitors of these processes. Finally, we will screen diverse combinatorial compound libraries in high-throughput formats for "hits" that pharmacologically interfere with essential and virulence related functions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--GENETIC CHARACTERIZATION OF H PYLORIA STRAINS Principal Investigator & Institution: Schneider, Barbara A.; Louisiana State Univ Hsc New Orleans New Orleans, La 70112 Timing: Fiscal Year 2003; Project Start 08-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Helicobacter pylori (H.p.) gastritis is the most common chronic infection worldwide, affecting about half the world's population. In most infected persons, the bacteria produce few ill effects, but in a minority, ulcers and gastric cancer are associated with infection. Factors affecting the severity of results of infection are poorly understood. One factor likely to be important in controlling severity of symptoms is the virulence of the strain of H.p. This core laboratory will perform genotyping of major virulence factors of H.p. strains for the other laboratories of the program project. One key virulence factor is vacA, a secreted cytotoxin, which resembles an ion channel or transport protein. When the toxin binds to gastric epithelial cells, it is taken into the cells in vacuoles (hence the name). Subsequently the cells lyse, and the cell debris contributes to inflammation. The vacA gene contains 2 portions, one coding for a signal peptide, or s portion, and one coding for the middle or m portion. Both s and m are present in multiple alleles (s1a, s1b, s1c, s2, m1, m2a, and m2b), some of which are associated with more severe pathology. In addition, some strains of H.p. produce a cagA protein, which is a marker for a pathogenicity island, a group of 40 genes, which encode proteins, which enhance the virulence of the strain. Another virulence determinant is babA, which encodes an adhesion, which binds the bacteria to the surface of the gastric epithelial cells. This core laboratory will genotype clinical strains of H.p. for cagA, s and m regions of vacA, and babA. The laboratory will culture and genotype clinical strains of H.p. isolated from Colombian and New Orleans patients, and will serve all projects in the application. Genotyping will be performed by the line probe assay (LiPA) and with PCR using radioactive primers. In addition, we have developed and will employ for project 3, a method for performing genotyping from stool samples, which will greatly expand our abilities to genotype strains found in asymptomatic persons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CURE: DIGESTIVE DISEASES RESEARCH CENTER Principal Investigator & Institution: Rozengurt, Juan Enrique.; Professor of Medicine; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 15-JAN-1990; Project End 30-NOV-2004 Summary: (Taken from the application) The CURE: Digestive Diseases Research Center is composed of a cohesive group of physicians and basic scientists with strong independent grant-supported research programs in the biology of the gut, with special emphasis upon regulation of mucosal cell function and gut neuroscience. CURE first received NIDDK funding in 1974 as a center to study peptic ulcer disease and became a Digestive Disease Core Center in 1989. The research emphasis of the center is acquisition of new knowledge about cellular and physiological processes that control gut function and translation of this knowledge into development of therapy for patients with gastrointestinal diseases. CURE initially established its reputation for work in clinical peptic ulcer disease, physiological regulation of acid secretion, and parietal cell mechanisms for secreting acid. Demonstration that Helicobacter pylori is an essential factor in pathogenesis of ordinary peptic ulcer disease brought new aspects of mucosal cell biology into the forefront of research at CURE. The interests and activities of center members have evolved along with science in this area and now include several facets of

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gastrointestinal regulatory physiology and cell biology. CURE's new name reflects more appropriately the broad interests of its members, including gastroduodenal mucosal physiology and disease; intestinal transport, intestinal inflammation, nutrition, and pancreatic secretion; neurophysiology and neuroenteric disease; and hormones, receptors, and signal transduction. The five Biomedical Research Cores outlined in this proposal provide ready access to technology and to clinical and biological materials that are essential to the programs of center members. These cores provide custom antibody production, sophisticated peptide chemistry techniques, access to modem cellular imaging to study membrane proteins and their functions, animal models for studying physiology and pathophysiology, and access to a broad range of techniques and patients for clinical studies. The Administrative Core provides a wide range of administrative support for members and for center activities including a dynamic enrichment program. The Pilot and Feasibility Program has provided a successful mechanism for aiding development of new research programs by young investigators, and recipients usually have obtained independent funding. The center provides an optimal environment for cooperation and collaboration among its investigators, who have had a major impact on mucosal biology and on peptic ulcer disease over the past two decades and promise to have an even larger impact upon expanded research areas with continued support from the center. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOKINE IMMUNIZATION

RESPONSES

TO

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INFECTION,

Principal Investigator & Institution: Ernst, Peter B.; Professor; Internal Medicine; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2003; Project Start 01-SEP-1997; Project End 31-MAY-2007 Summary: (provided by applicant): Gastric immune responses interact with bacterial virulence factors to promote the pathogenesis of diseases associated with H. pylori infection. While helper T (Th) cells promote inflammation in response to H. pylori in both humans and mice, they are also essential for immunity in animal models. Effective immunity can be induced by vaccination although antibody responses are not necessary. Since/-/. pylori is a noninvasive pathogen, the "protective" Th cells are believed to modify epithelial cell gone expression such that the niche favoring colonization is disrupted. Th1 cells can augment expression of receptors that bind H. pylori and favor the epithelial damage that ensues. As such, they act as a "pathogenic" T cell. Either endogenous or exogenous ROS can regulate the expression of genes associated with Th1 cells. In contrast, Th2 cells, through the production ofIL-4, IL-5, IL-10, IL-13, IL-25 and TGF-Beta can antagonize the effects of Th1 cells. Tr1 cells, a recently described subset of Th cells, resemble Th2 cells by producing IL-5 and -10 but also produce IFN-gamma similar to Th1 cells. Importantly, Tr1 cells are present in the digestive tract and attenuate the host response to luminal antigen including the induction of colitis in animal models. Cytokines associated with Tr1 cells prevent the generation of ROS, the expression of genes associated with Th1 cells and their effects on bacterial binding and epithelial cell damage. These observations suggest that a "protective" response to vaccines will induce Tr1 cells, or related regulatory Th cells, that are responsible for limiting inflammation. How these cells are derived is unknown and their role in host defense has yet to be defined. This background leads to our general hypothesis that a relative imbalance in helper T cell subsets favors the stimulation of inflammation and epithelial damage in response to persistent infection with H. pylori. More specifically, oxidative stress associated with H. pylori infection selects for "pathogenic" Th1 responses that contribute

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to epithelial damage while a regulatory "protective" Th1 cell will favor tissue integrity and immunity. The overall objective is to define the T cell response to natural infection with H. pylori or immunization and elucidate the mechanisms governing lymphoepithelial cell interactions in disease versus immunity. This will be achieved in the following Specific Aims: 1). Define the factors selecting for "pathogenic" Th cells associated with H. pylori infection. 2). Identify T cell markers that are correlates of immunity. 3). Define mechanisms of host defense attributed to "protective" Th cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DETECTION OF H. PYLORI USING ELECTRICAL DNA SENSING Principal Investigator & Institution: Kelley, Shana O.; Chemistry; Boston College 140 Commonwealth Ave Newton, Ma 02467 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): This proposal describes the development of a new class of biosensors exploiting an intrinsic property of DNA: electrical conduction. The capability of dsDNA to conduct electricity, in combination with the ability to measure this conduction in short (