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

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

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

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

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

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Penicillin: 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: 0-597-84156-X 1. Penicillin-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 penicillin. 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 PENICILLIN................................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Penicillin ..................................................................................... 11 E-Journals: PubMed Central ....................................................................................................... 54 The National Library of Medicine: PubMed ................................................................................ 68 CHAPTER 2. NUTRITION AND PENICILLIN ...................................................................................... 91 Overview...................................................................................................................................... 91 Finding Nutrition Studies on Penicillin...................................................................................... 91 Federal Resources on Nutrition ................................................................................................... 96 Additional Web Resources ........................................................................................................... 96 CHAPTER 3. ALTERNATIVE MEDICINE AND PENICILLIN ............................................................... 99 Overview...................................................................................................................................... 99 National Center for Complementary and Alternative Medicine.................................................. 99 Additional Web Resources ......................................................................................................... 106 General References ..................................................................................................................... 108 CHAPTER 4. DISSERTATIONS ON PENICILLIN ............................................................................... 109 Overview.................................................................................................................................... 109 Dissertations on Penicillin......................................................................................................... 109 Keeping Current ........................................................................................................................ 110 CHAPTER 5. CLINICAL TRIALS AND PENICILLIN .......................................................................... 111 Overview.................................................................................................................................... 111 Recent Trials on Penicillin......................................................................................................... 111 Keeping Current on Clinical Trials ........................................................................................... 112 CHAPTER 6. PATENTS ON PENICILLIN .......................................................................................... 115 Overview.................................................................................................................................... 115 Patents on Penicillin .................................................................................................................. 115 Patent Applications on Penicillin .............................................................................................. 138 Keeping Current ........................................................................................................................ 151 CHAPTER 7. BOOKS ON PENICILLIN .............................................................................................. 153 Overview.................................................................................................................................... 153 Book Summaries: Federal Agencies............................................................................................ 153 Book Summaries: Online Booksellers......................................................................................... 154 The National Library of Medicine Book Index ........................................................................... 157 Chapters on Penicillin................................................................................................................ 159 CHAPTER 8. MULTIMEDIA ON PENICILLIN ................................................................................... 165 Overview.................................................................................................................................... 165 Video Recordings ....................................................................................................................... 165 Bibliography: Multimedia on Penicillin..................................................................................... 166 CHAPTER 9. PERIODICALS AND NEWS ON PENICILLIN ................................................................ 169 Overview.................................................................................................................................... 169 News Services and Press Releases.............................................................................................. 169 Academic Periodicals covering Penicillin .................................................................................. 171 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 173 Overview.................................................................................................................................... 173 U.S. Pharmacopeia..................................................................................................................... 173 Commercial Databases ............................................................................................................... 174 Researching Orphan Drugs ....................................................................................................... 175 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 179 Overview.................................................................................................................................... 179

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NIH Guidelines.......................................................................................................................... 179 NIH Databases........................................................................................................................... 181 Other Commercial Databases..................................................................................................... 184 APPENDIX B. PATIENT RESOURCES ............................................................................................... 185 Overview.................................................................................................................................... 185 Patient Guideline Sources.......................................................................................................... 185 Finding Associations.................................................................................................................. 188 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 191 Overview.................................................................................................................................... 191 Preparation................................................................................................................................. 191 Finding a Local Medical Library................................................................................................ 191 Medical Libraries in the U.S. and Canada ................................................................................. 191 ONLINE GLOSSARIES................................................................................................................ 197 Online Dictionary Directories ................................................................................................... 197 PENICILLIN DICTIONARY........................................................................................................ 199 INDEX .............................................................................................................................................. 275

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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 penicillin 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 penicillin, 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 penicillin, 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 penicillin. 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 penicillin, 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 penicillin. 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 PENICILLIN Overview In this chapter, we will show you how to locate peer-reviewed references and studies on penicillin.

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

Erythromycin and Amoxicillin? Source: Journal of the Tennessee Dental Association. 81(1): 34-36. Winter 2001. Contact: Available from Journal of the Tennessee Dental Association. 2104 Sunset Place, Nashville, TN 37212. E-mail: [email protected]. Summary: A large number of patients with odontogenic (arising in the teeth) infections are referred to the graduate and undergraduate oral surgery clinics at the University of Tennessee, College of Dentistry. These patients have often been placed on antibiotics by the referring dentist. Two of the more commonly prescribed antibiotics are erythromycin and amoxicillin. This article provides a brief review of the antibiotics most commonly used to treat odontogenic infections, and illustrates why erythromycin and amoxicillin may not be the best choice. Other drugs discussed include penicillin,

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cephalosporins, clindamycin, and metronidazole. The author concludes that two drugs that are effective alternatives in the penicillin allergic patient are cephalexin and clindamycin. They are bactericidal and effective against the oral streptococci and oral anaerobes that cause most odontogenic infections. 5 references. •

Etiology of Acute Otitis Media in Human Immunodeficiency Virus-Infected Children Source: Pediatric Infectious Disease Journal. 15(1): 58-61. January 1996. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 637-3030. Fax (301) 824-7390. Website: www.lww.com. Summary: Acute otitis media (AOM, middle ear infection) is one of the most common infections that are implicated as significant contributors to morbidity (illness) in HIV infected children. To decide on the best antibiotic therapy, tympanocentesis is indicated as the first line diagnostic procedure in these children, because unusual pathogens may play a role in advanced stages of deficient humoral or cellular immunity. This article reports the microbiology of 60 episodes of AOM diagnosed in 21 symptomatic HIV infected children (ages 9 months to 12 years) was compared with that of 121 episodes of AOM occurring in 113 immunocompetent HIV negative children (ages 6 months to 12 years). The prevalence of the three most common pathogens was similar in HIV infected and in normal children (56.5 percent versus 54.9 percent of the ears). Staphylococcus aureus was significantly more frequent in AOM diagnosed in severely immunosuppressed stages. A significantly lower proportion of middle ear effusions obtained in HIV infected children yielded no bacteria compared with normal children. Beta lactamase production among isolates of H. influenzae was a rare phenomenon, both in HIV infected and in normal children. No penicillin resistant S. pneumoniae was found. The authors conclude that in HIV infected children with absent or moderate immunosuppression, empiric antibiotic therapy should be based on the recommendations given for immunocompetent children of the same geographic area. In severe immunosuppressed stages, given the possible role of Staph. aureus, extended spectrum antibiotics should be considered. 2 tables. 19 references.

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Acute Otitis Media in Children: What Next When First-Line Therapy Fails? Source: Consultant. 38(11): 2681-2684, 2687-2690. November 1998. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Box 4010, Greenwich, CT 06831-0010. (203) 661-0600. Summary: Although amoxicillin continues to be the drug of first choice for patients with acute otitis media (AOM), the presence of drug-resistant pathogens may cause treatment failure. This article outlines strategies to be employed when first line therapy fails in children with AOM. Streptococcus pneumoniae is the most common pathogen found in middle ear fluid (MEF), followed by Hemophilus influenzae and Moraxella catarrhalis. Beta-lactamase inhibitors, such as clavulanate, are effective against H. influenzae and M. catarrhalis, but not against penicillin-resistant pneumococci. Trimethoprimsulfamethoxazole (TMP-SMX) and azithromycin show high levels of activity against all three common pathogens, as measured by their concentrations in MEF. The author concludes that azithromycin, amoxicillin and clavulanate combinations, and TMP-SMX appear to be reasonable choices for second-line treatment of AOM, based on their bacteriologic efficacy, cost, taste, ease of administration, and side effects. The author cautions that pneumococci resistant to penicillin may also be resistant to oral cephalosporins and TMP-SMX, so these drugs are best avoided in patients in whom resistance is suspected. 2 figures. 3 tables. 26 references. (AA-M).

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Survey of Antibiotic Use in Dentistry Source: JADA. Journal of the American Dental Association. 131(11): 1600-1609. November 2000. Contact: Available from American Dental Association. ADA Publishing Co, Inc., 211 East Chicago Avenue, Chicago, IL 60611. Summary: Antibiotics are important in the management and prophylaxis (prevention) of infection in patients at risk of experiencing microbial disease. As a result of the increase in antimicrobial resistance, the authors of this article conducted a survey to assess current antibiotic use in dental practices. The authors mailed a two page, pretested survey to all licensed dental practitioners in British Columbia, Canada. A total of 2,542 surveys were mailed; 19.9 percent were returned by fax or mail. Respondents were demographically consistent with all registered dentists in British Columbia. They reported writing an average of 4.45 prescriptions per week. Antibiotics prescribed after treatment primarily were penicillin and its derivatives. Recommended adult doses of penicillin were prescribed by 59.2 percent of respondents; recommended daily doses of amoxicillin were prescribed by 72.2 percent of respondents. The average prescription duration was 6.92 days. Respondents prescribed prophylactic antibiotics an average of 1.15 times per week for prophylaxis of bacterial endocarditis; 17.5 percent reported postoperative dosing for prophylaxis, ranging from a one to seven day prescription with an average of 6.91 postoperative doses. Preoperative antibiotics were prescribed for patients with a history of rheumatic fever or any heart murmur or prosthetic hip. Antibiotics were prescribed more frequently for surgical procedures and patients with AIDS than for other circumstances. In therapeutic use, approximately 85 percent of respondents followed appropriate prescription guidelines for dosing and duration of therapy. The authors conclude that appropriate and correct use of antibiotics is essential to ensure that effective and safe treatment is available and that practices that may enhance microbial resistance are avoided. 5 figures. 2 tables. 49 references.

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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

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of drugs. The author briefly discusses various options for 'rescue' therapies for patients who are refractory to treatment. 2 tables. 41 references. •

What Role for Antibiotics in Otitis Media and Sinusitis? Source: Postgraduate Medicine. 104(3): 93-99, 103-104. September 1998. Contact: Available from Postgraduate Medicine. P.O. Box 459, Hightstown, NJ 085209201. (609) 426-7070. Fax (609) 426-7087. Summary: Patients often expect to be given antibiotics for any illness affecting the ears and sinuses, regardless of whether such treatment is warranted. This article, the fourth of four articles on common ear, nose, and throat (ENT) problems, discusses the role for antibiotics in treating otitis media (middle ear infection) and sinusitis (sinus infection). The authors caution that bacterial resistance to antibiotics is rising. They outline the types of otitis media and sinusitis that should be treatment with antibiotics and the agents that are currently the most effective for each condition. The authors review the established classification and treatment guidelines for these conditions. First-line treatment for both uncomplicated acute otitis media and acute sinusitis is amoxicillin. Erythromycin ethylsuccinate and sulfisoxazole or TMP-SMZ may be used in patients who are allergic to penicillin. Beta-lactamase-stable agents should be given when no response occurs within 48 to 72 hours. In cases where penicillin-resistant pneumococcus is suspected, high-dose amoxicillin, with or without clavulanate, or clindamycin should be considered. Antibiotics are not indicated for initial treatment of otitis media with effusion (OME), but may be considered for effusions lasting longer than 3 months. Prophylactic antibiotics should be considered only for recurrent acute infections occurring three or more times within 6 months or four or more times with a year. 4 tables. 27 references. (AA-M).

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Life-Threatening Cervicofacial Infection in a Child with Hyperimmunoglobulin-E Syndrome Source: Journal of Oral and Maxillofacial Surgery. 59(5): 561-565. May 2001. Contact: Available from W.B. Saunders Company. Periodicals Department, P.O. Box 629239, Orlando, FL 32862-8239. (800) 654-2452. Website: www.harcourthealth.com. Summary: The hyperimmunoglobulin E (hyper IgE) syndrome (Job syndrome) is characterized by recurrent staphylococcal sinopulmonary (lungs) and skin abscesses, pneumonia with pneumatocele formation, and elevations of serum IgE. Job syndrome affects multiple systems including the dentition, the skeleton, connective tissues, and the immune system. This article presents a case report of the diagnosis and management of a youth with hyper IgE syndrome complicated by a periapical abscess leading to a life threatening deep space neck infection. The 16 year old boy with hyper IgE syndrome and a history of recurrent dental abscesses presented to the emergency department with a stated 1 day history of increased swelling, tenderness, progressive difficulty in swallowing, trismus (difficulty opening the mouth, 'lockjaw'), and a chronic cough. On further questioning, the patient stated that the right submandibular swelling had begun about 3 days before, and it had spread across the midline and elevated his tongue the last 2 days. The patient's medical history was significant for hyper IgE syndrome, chronic hepatitis C, chronic depression, and multiple episodes of pneumonia and pneumatoceles. He had a dental abscess 3 months before presentation, which was treated with oral penicillin. On physical examination, the lower right first molar was grossly carious (had a large cavity). The patient had severe swallowing difficulties and maximal incisal opening was approximately 15 mm. Radiograph showed a large

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periapical abscess involving the lower right first molar. The patient was urgently brought to the operating room for incision and drainage. The authors describe his postoperative care and recovery, including care at home postoperatively. The authors stress that treatment of children with hyper IgE syndrome with abscesses should begin early and be aggressive, with intravenous antibiotics and rapid surgical incision and drainage as indicated. The most successful treatment is lifelong administration of therapeutic doses of penicillinase resistant antibiotics to prevent staphylococcal infections. 2 figures. 10 references. •

Infectious Emergencies in Patients with Diabetes Source: Clinical Diabetes. 18(3): 102-105. 2000. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article discusses the features, diagnosis, and treatment of several serious infections that are strongly associated with diabetes, including soft tissue infections, urinary tract infections, and miscellaneous infections. Soft tissue infections include pyomyositis, necrotizing fasciitis, and malignant external otitis. Pyomyositis is a bacterial infection of the skeletal muscle that is characterized by fever, localized muscle pain, and swelling of the involved muscles. Useful diagnostic tools include computed tomography and magnetic resonance imaging scanning. Treatment involves the use of intravenous antibiotics with good Staphylococcus aureus coverage. Necrotizing fasciitis is a deep infection of the subcutaneous tissue involving destruction of fascia and fat. Surgical exploration is used to make a definitive diagnosis. Treatment consists of aggressive surgical exploration and debridement of nonviable tissue. Malignant external otitis occurs almost exclusively in people who have diabetes, particularly in those who have type 2 diabetes. The most common feature of this disease is otalgia. A diagnosis is made based on history and physical examination findings supported by radiological studies. Treatment usually involves the use of an antipseudomonal penicillin and an aminoglycoside for 4 to 6 weeks. Urinary tract infections include acute pyelonephritis and renal emphysema. Acute pyelonephritis is more common in people who have diabetes. Treatment involves a seven day course of cystitis therapy. Renal emphysema, which includes the distinct clinical entities of emphysematous pyelonephritis and emphysematous pyelitis, causes gas to occur in the kidneys. Therapy for the former condition involves antibiotic therapy and some form of surgical drainage, whereas treatment for the latter may involve antibiotics alone if no obstruction is present. Miscellaneous infections include rhinocerebral mucormycosis and emphysematous cholecystitis. Rhinocerebral mucormycosis is an extremely rare fungal infection occurring in people who have type 1 diabetes. Diagnosis is made based on the evaluation of biopsy specimens. Treatment involves administration of amphotericin B and surgical debridement. Emphysematous cholecystitis is characterized by gas in the gall bladder or pericholecystic tissues. Treatment is cholecystectomy. 56 references.

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Drug-Induced Acute Renal Failure: Keys to Recognizing and Treating Intrarenal Toxicity Source: Consultant. 37(6): 1592-1599. June 1997. Contact: Available from Consultant. Cliggott Publishing Company, 55 Holly Hill Lane, Box 4010, Greenwich, CT 06831-0010. Summary: This article helps readers recognize and treat drug-induced acute renal failure (ARF). Drug-induced acute tubular necrosis is a primary cause of ARF; it may

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result from the use of such agents as aminoglycosides, amphotericin B, and radiocontrast media. Suggestions are provided to reduce the risk of aminoglycoside toxicity: prescribe the shortest course possible, use once daily dosing, monitor serum concentrations, and avoid using these agents in patients with known risk factors. Radiocontrast media-associated ARF is most likely to occur with preexisting renal damage, especially in a patient with diabetes mellitus. Since sodium depletion is the most important risk factor for nephrotoxic injury with amphotericin B use, saline loading is recommended both before and during drug administration. Drug-induced acute interstitial nephritis, another important cause of ARF, has been associated with a number of antibiotics, especially penicillin and ampicillin; many patients recover with the removal of the offending agent. The authors provide three illustrative case reports. 6 tables. 17 references. (AA-M). •

Otosyphilis in a Patient with Human Immunodeficiency Virus: Internal Auditory Canal Gumma Source: Otolaryngology: Head and Neck Surgery. 112(3): 488-492. March 1995. Summary: This article presents a case report of a patient with progressive bilateral (both sides) sensorineural hearing loss (SNHL) and new onset dysequilibrium (loss of balance). A 42-year-old man presented after he had subjective hearing loss and tinnitus with intermittent disequilibrium. At his initial visit, audiometric examination revealed moderately severe sensorineural hearing loss in the high frequencies of the left ear and a mild to moderate, mixed hearing loss in the right ear. Magnetic resonance imaging (MRI) revealed a left internal auditory canal (IAC) mass lesion, and he was initially thought to have an acoustic schwannoma. However, on further evaluation, he was found to be infected with syphilis and HIV. The authors diagnosed the patient with otosyphilis with a left IAC gumma. Surgery was canceled because of the high probability of infectious involvement. The patient was given a 3-week course of benzathine penicillin G, 2.4 million units per week by intramuscular injection, and began taking azidothymidine (AZT). After six weeks, the patient had significant improvement in hearing bilaterally. The most recent audiogram, obtained approximately six months after diagnosis and four months after treatment, was entirely within normal limits. Despite developing AIDS and later dying of HIV encephalopathy, the patient had no subsequent auditory or vestibular symptoms or sequelae. 2 figures. 23 references. (AA-M).

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Management of Patients Susceptible to Bacterial Endocarditis and Related Infections Source: Journal of Dental Education. 57(11): 811-814. November 1993. Summary: This article reports on a study undertaken to determine the effectiveness of managing patients needing antibiotic prophylaxis for dental treatment in a non-random sample of four U.S. dental schools. The study also attempted to determine the extent to which the 1990 American Heart Association (AHA) guidelines were being applied. Based on a review of patient records, the 1990 AHA guidelines had been applied to 40 percent of the patients with cardiovascular findings who were identified as needing antibiotic prophylaxis. The author notes that the dental records of the patients reviewed in this study demonstrated a significant lack of detail concerning antibiotic prophylaxis. For 83 percent of the patients, it was impossible to demonstrate that the appropriate steps had, in fact, been taken. The author provides recommendations for improving recordkeeping. Forty-nine percent of patients taking prophylactic antibiotics who had multiple appointments received prophylaxis on two or more days during at least one week in the course of their dental treatment. The risk of penicillin resistant bacteria in

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the oral flora increases with repeated antibiotic use. The 1990 AHA guidelines addressed this issue and recommend that at least seven days elapse before starting another prophylactic coverage period for a patient who has just completed one. 3 tables. 12 references. •

Current Trends in Endodontic Treatment: Report of a National Survey Source: JADA. Journal of the American Dental Association. 127(9): 1333-1341. September 1996. Summary: This article reports on a survey of 360 general dentists and 291 endodontists, undertaken to obtain information on routine, nonemergency endodontic treatments adapted to clinical practice. The authors highlight frequent practices and recent advances in treatment modalities, including instrumentation, obturation, intracanal preparations, medications, and restorations. The authors identified a number of trends. They report that more clinicians are conducting cleaning and shaping procedures to levels closer to the radiographic apex, rather than the traditional 1mm level. There is less use of intracanal medicaments and greater use of warm gutta-percha obturation techniques. Single-appointment endodontic treatment is becoming much more common for all case types. While penicillin and erythromycin continue to be the most frequently prescribed antibiotics, there is greater use of NSAIDs, alone or in combination with narcotics, for the management of endodontic pain. Much of the information is presented in tabular format. 4 tables. 42 references. (AA-M).

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Perianal Streptococcal Dermatitis Source: American Family Physician. 61(2): 391-393. January 15, 2000. Contact: American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237 or (913) 906-6000. E-mail: [email protected]. Website: www.aafp.org. Summary: This journal article provides health professionals with information on the etiology, epidemiology, clinical presentation, differential diagnosis, and treatment of perianal streptococcal dermatitis. This skin condition is caused by group A beta hemolytic streptococci and occurs mainly in children between 6 months and 10 years of age. It is often misdiagnosed and treated inappropriately. Symptoms include perianal rash, itching, and rectal pain. Blood streaked stools may also be seen in one third of patients. Physical examination reveals a bright red, sharply demarcated, perianal rash. The differential diagnosis of perianal streptococcus dermatitis includes diaper dermatitis, candidiasis, psoriasis, seborrheic dermatitis, sexual abuse, pinworm infestation, local trauma from heavy wiping, and inflammatory bowel disease. A rapid streptococcal test of suspicious areas can confirm the diagnosis. Routine skin culture is an alternative diagnostic aid. Treatment with amoxicillin or penicillin is effective. Followup is necessary because recurrences are common. The article includes an illustrative case to remind physicians about the existence of this disorder. 1 figure and 9 references. (AA-M).

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High-Pressure Injection Injury of the Hand Source: Postgraduate Medicine. 108(1): 183-185,189-190. July 2000. Summary: This journal article uses a case report to provide health professionals with information on high pressure injection injury of the hand. A 20 year old man presented to an emergency department 2 hours after sustaining a minor laceration on the second

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digit of his left hand. Examination revealed a 2 centimeter laceration on the palmar surface of the finger and subcutaneous emphysema over the dorsum and anterior aspect of the hand. A hand radiograph showed the extensive presence of air under the skin and into the deep muscular tissue covering the anterior and posterior fingers. A diagnosis of high pressure injection of air into the subcutaneous tissue of the hand and forearm was made for this patient. Treatment involved administration of tetanous toxoid and one dose each of clindamycin hydrochloride and penicillin G. In addition, the hand was elevated and splinted. The patient was admitted to the hospital for observation, and he was discharged 4 days later. A discussion following the case presentation focuses on the clinical features and course of high pressure injection injuries, the pathophysiology of these injuries, the diagnosis of high pressure injection injuries, and patient management. 1 figure, 2 tables, and 11 references. •

Rashes and Fever: Sorting Out the Potentially Dangerous: Part 1: Spotting Diseases Associated With Macules and/or Papules Source: Consultant. 39(6): 1645-1648,1650,1655-1657,1661-1662,1667-1668. June 1999. Summary: This journal article, the first of three, provides health professionals with information on potentially dangerous diseases associated with macules or papules. A macular or papular rash may be the presenting manifestation of a number of benign as well as potentially dangerous or deadly diseases, including HIV infection, typhus, secondary syphilis, Lyme disease, and leptospirosis. A good history and physical examination and evaluation of the morphology of the rash are the keys to prompt, efficient diagnosis. Some dangerous disorders, including acute rheumatic fever, secondary syphilis, Lyme disease, and Letterer-Siwe disease, have unique cutaneous manifestations, including erythema marginatum, condylomata lata, erythema chronicum migrans, and seborrheic dermatitis-like eruption with papules and petechiae. Other diseases may present with nonspecific skin findings; however, painless, nonpruritic, erythematous macules and papules on the face and trunk point to HIV in a patient at risk for this infection. Still's disease is characterized by high spiking fevers and an evanescent erythematous, macular, or maculopapular eruption on the face, extremities, and trunk. Approaches to treatment include suppressive combination therapy for HIV infection, benzathine penicillin G for acute rheumatic fever and secondary syphilis, oral doxycycline for Lyme disease and leptospirosis, tetracycline for typhus, acetylsalicylic acid or a nonsteroidal anti-inflammatory drug for Still's disease, chemotherapy for Letterer-Siwe disease, and systemic corticosteroids for hypersensitivity syndrome. 7 figures, 3 tables, and 29 references. (AA-M).

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The Resurgence of Syphilis in the United States Source: Current Opinion in Infectious Diseases, 1991; Vol. 4. Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Prevention Services, Division of Sexually Transmitted Disease, 1600 Clifton Rd NE, Atlanta, GA, 30333, (404) 639-8002. Summary: This reprint of a journal article says that more cases of both primary and secondary syphilis were reported in 1989 than in any other year since 1949, and that the amount of infection is on the rise in spite of four decades of penicillin therapy. The rising incidence of drug use has been linked to the spread of the Sexually transmitted disease (STD). The article says that observations in patients coinfected with Human immunodeficiency virus (HIV) have raised questions about the adequacy of penicillin treatment. Efforts to control the epidemic have brought needed attention to improving

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health care delivery to persons at risk for syphilis. It examines the epidemiology of early syphilis infection, congenital syphilis, interventions, treatment, and the connection between syphilis and HIV.

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

Project Title: A PROTEOMICS

GENETIC

SCREEN

FOR

PROTEIN

EVOLUTION

AND

Principal Investigator & Institution: Cornish, Virginia W.; Chemistry; Columbia Univ New York Morningside 1210 Amsterdam Ave, Mc 2205 New York, Ny 10027 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2006 Summary: (provided by applicant): This grant application describes a cell-based assay for detecting molecular recognition and catalysis that can be used to evolve proteins with new functions. There is tremendous interest in being able to engineer proteins with new specificities and new activities for use as reagents for biomedical research, diagnostics and therapeutics for the health care community, and tools for the pharmaceutical industry. The screen builds from existing technology for dimerizing proteins inside a cell with dimeric ligands via the ligands' receptors (CIDs). By replacing one of the ligand-receptor pairs with potential binding partners, binding can be detected. By replacing the chemical linker between the two ligands with a bond and adding an enzyme, the assay can be used as a read-out for bond formation or bond cleavage. In Preliminary Results dexamethasone-methotrexate CIDs with non-cleavable and cleavable linkers have been developed. Aim 1 outlines our plans to evolve a protein receptor for estradiol that can be used in medical diagnostics for monitoring estrogen levels in women. We have developed a docking algorithm to pick several monomeric proteins from the PDB as the starting protein scaffolds. We plan to mutagenize these proteins using existing methods and then select for high affinity, specific receptors by screening for binding to estradiol and against binding to other common steroids. Aim 2 describes our plans to modify the yeast two-hybrid assay to detect catalysis and then evolve a penicillin-binding protein into a cephalosporinase enzyme. Penicillin-binding 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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proteins are the target of penicillin antibiotics and are believed to be the evolutionary precursors of cephalosporinases, the bacterial resistance enzymes that hydrolyze and inactivate these antibiotics. Because of the evolutionary relationship, the PBPs present a tractable first target for enzyme evolution. Moreover, this project should provide insight into how bacteria evolve antibiotic resistance and the mechanism by which the resistance enzymes hydrolyze the antibiotic. Finally, in Aim 3, we propose to develop a bacterial CID so that future protein evolution experiments can be carried out in bacteria. Bacteria have faster doubling times and higher transformation efficiencies than yeast, and so a bacterial CID system should facilitate the evolution experiments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AIR INFLATION EFFICACY--CORTICOSTEROID THERAPY OF OTITIS MEDIA WITH EFFUSION Principal Investigator & Institution: Alper, Cuneyt M.; Associate Professor; Children's Hosp Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, Pa 15213 Timing: Fiscal Year 2001 Summary: Otitis Media with Effusion (OME) is a common disease in the pediatric age group and remains refractory to current medical tretments. Middle ear (ME) pressure regulation is central to the maintenance of mucosal health, and dysregulation both promotes and is a consequence of OME. These considerations have generated a renewed interest in alternative non-invasive methods of maintaining stable ME pressures to prevent or treatment OME. In that regard, a variety of methods to introduce gas via the Eustachian tube, into the diseased ME has been described. However, the results of clinical studies are contradictory with reports of both no benefits of these procedures as well as high clinical cure rates for established OME. Theoretical considerations and experimental results show that the ME inflation protocols can be modified with respect to timing so as to optimize their expected physiological effect and thus their efficacy for treatment OME. However, in the absence of resolution of the underlying inflammation and/or restoration of good ME pressure regulating function, the disease is expected to recur quickly after termination of the inflation maneuvers. This is supported by the results of clinical studies that reported high recurrence rates upon discontinuing inflation. Consequently, a two-pronged intervention strategy including repeated ME air inflation to preserve ambient pressures and anti-inflammatory treatment to resolve the underlying mucosal inflammation may provide the best hope for curing persistent OME. That strategy is tested a proof-of-concept in this proposed clinical trial. Children with documented OME of at least two months duration will be randomized to receive antibiotic treatment + placebo inflation + placebo steroid (standard of care), or antibiotic + ME air inflammation + placebo steroid, or antibiotic + ME air inflation + oral corticosteroids for a one month treatment period. The cure rte for OME will be evaluated at the end of treatment and recurrence rates measured at 8 and 12 week follow-up visits. The hypotheses tested are that: 1) the two groups treated with air inflation will have comparable cure rates that are significantly greater than that of the antibiotic treatment group, and, 2) disease recurrence will be significantly greater in the group treated with inflation and placebo when compared to that treated with inflation plus corticosteroids. While primarily an evaluation of treatment efficacy for persistent OM, this study also represents a formal test of the predictive accuracy of the underlying model of disease pathogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANTIBIOTIC RESISTANCE IN A SUBGINGIVAL BIOFILM MODEL Principal Investigator & Institution: Walker, Clay B.; Oral Biology; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 30-APR-2007 Summary: (provided by applicant): We have developed biofilm models of the subgingival plaque on various supports (hydroxyapatite, nitrocellulose membranes, and glass) that are relative simple in concept, but yield reproducible results and mimic the complexity and the diversity of the subgingival microflora. These models appear to be useful for studying the development, maturation, and ultrastructure of the subgingival plaque. The hydroxyapatite model will be used to study the development of the subgingival microflora and the effects that antibiotics exert on the bacteria present. The biofilms grown on the membrane and glass supports will be used to microscopically study the ultrastructure of the biofilms by transmission electron microscopy and confocal laser scanning microscopy. We propose, after refining and validating the model, to use this model to determine the effects of antibiotics on biofilms grown from subgingival plaque collected from sites with periodontitis. These data will be compared to the effect of antibiotics on planktonic cultures of the predominant bacterial isolates present in the biofilm to determine differences in antibiotic susceptibilities in a biofilm relative to planktonic broth cultures. The second objective is to determine the effect of antibiotics, at concentrations obtained therapeutically, on developing biofilms and on a mature biofilms. This will provide a realistic approximation of the effect that antibiotics have on the periodontal flora when used as adjuncts to conventional scaling and root planing. The final specific aim will examine the transfer of antibiotic resistant determinants in the biofilm model. The horizontal transfer of tetQ, a major tetracyclineresistant determinant in the oral flora, will be investigated both within the normal biocommunity associated with the subgingival plaque and with exogenous tetracyclineresistant bacteria that are not normal inhabitants of the subgingival community but may occur as transients in this community. We believe the information derived from the experiments described will provide a better understanding of the subgingival flora and the effects that antibiotics may have on this flora. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANTIBIOTIC RESISTANCE IN THE ORAL STREPTOCOCCI Principal Investigator & Institution: Rogers, Jeffrey D.; Periodontics; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2003 Summary: (provided by applicant) The continuing increase in bacterial resistance to antibiotics is a significant worldwide problem. Although most research has focused on patterns of resistance in pathogenic organisms, the importance of commensal bacteria as reservoirs of antimicrobial resistance determinants is now beginning to be recognized. We seek a better understanding of antibiotic resistance genes, particularly those conferring beta-lactam resistance, in the oral streptococci. The discovery of altered penicillin-binding proteins (PBPs) as the basis of beta-lactam resistance in S. pneumoniae quickly led to the hypothesis that these pbp genes evolved by recombination with homologs from other streptococcal species, in particular the oral streptococci. This gave rise to mosaic sequences containing sequence blocks highly divergent from those of sensitive strains that encoded novel PBPs with decreased affinity for beta-lactam compounds. The contribution of such mosaic genes to the emergence of penicillin resistance is widely accepted. However, both the source and

14

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mechanism of dissemination of sequences giving rise to mosaic genes is not fully understood. We hypothesize that the genesis of mosaic low-affinity PBPs occurs in the oral streptococci through the accumulation and exchange of point mutations in pbp genes, and that the oral streptococci are a reservoir of antibiotic resistance genes that are exchanged between both commensal and pathogenic microorganisms. We will use the paradigm established for the PBPs of S. pneumoniae as a model for molecular studies of the pbp2x and pbp2b genes of the oral streptococci. Our analysis of pbp genes will be carried out in oral streptococcal isolates representing the species salivarius. This information will be extended to mixed growth studies that will document both the genesis and direct exchange of resistance genes between the oral streptococci, including S. pneumoniae, thus linking genetic exchange, the genesis of antibiotic resistance genes, and the role of the oral streptococci as a reservoir of antibiotic resistance determinants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIBIOTIC THERAPY IN TREATING PERIODONTAL DISEASES Principal Investigator & Institution: Paster, Bruce J.; Forsyth Institute Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: Ideally, therapies designed to control pathogenic oral microorganisms will suppress or abolish those organisms, leaving a stable host-compatible microbiota in place. At times, however, attempts to eliminate periodontal pathogens lead to undesired changes in the microbiota. Two of the most obvious are overgrowth of pathogenic species not commonly found din high numbers in the oral microbiota and the emergence of antibiotic resistant species. This Project will be concerned with the safety of therapies, particularly antibiotic therapies, employed to control periodontal infections. The immediate goal is to determine the consequences of antibiotic therapy on the composition and antibiotic resistance of the periodontal microbiota. The first aim is to determine how antibiotic therapy shift the composition of the subgingival microbiota by monitoring levels of 120 bacterial species using Checkerboard hybridization. Subgingival species in pooled subgingival plaque samples will be examined at baseline, at the completion of therapy, and at 1-year post therapy for 24 subjects treated by either scaling and root planing (SCR), SCR plus local tetracycline, or SCR plus systemic amoxicillin and metronidazole. The second aim will determine how antibiotic therapy affects antibiotic resistance genotype and phenotype of plaque bacteria. Twelve subjects in the three groups described for Aim 1 will have 60 colonies picked for each time point. The isolates will be identified by Checkboard hybridization of 16S rRNA sequencing, and the antibiotic resistance genotype will be determined by Southern hybridization. Antibiotic resistance phenotype will be determined by plate culture. Species that are resistant to multiple antibiotics will be identified and made available to collaborators examining resistance genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANTIMICROBIALS AGAINST CHLAMYDIA AND GC INFECTION: IN VITRO STUDIES Principal Investigator & Institution: Cooper, Morris D.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2001 Summary: Microbial pathogens which invade the genital mucosa have specific mechanisms which involve adherence, invasion, intracellular survival and exit as a means of production of pathogenicity. C. trachomatis is the most common sexually

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transmitted bacterial pathogen in this country causing about 4.5 million cases of chlamydia in men, women, and children. The majority of chlamydial infections in women are asymptomatic, sequealae of untreated infections are an important part of the pathogenesis of the disease. Infections due to N. gonorrhoeae, like those of C. trachomatis, remain a major cause of STDs. Further, they remain a major cause of pelvic inflammatory disease, tubal infertility, ectopic pregnancy and chronic pelvic pain in the United States. Epidemiologic data provide strong evidence that gonococcal infections facilitate the transmission of other STDs and studies have begun to elucidate the specific mechanisms through which this facilitation occurs(). In 1996, there were greater than 325,000 cases of gonorrhea reported in the United States. However, this rate has continued to decline since 1975 but still remains a significant cause of disease. Although adequate antimicrobial therapy exists for this infection rates are high (17 percent/100,000 population) and antimicrobial resistance is significant (29 percent of all isolates collected in 1996 were resistant to penicillin, tetracycline or both). Therefore, alternate methods of controlling the infection remains a high priority. Toward this end, we are aggressively pursuing antimicrobials which have potential as topical microbicides. Therefore, there is a critical need to find a microbicide that would interact with these pathogens either prior to or at the point of interaction with cells of the genital mucosa. We have decided to study a variety of chemical agents including detergents, bile salts and other compounds to determine their antichlamydial and antigonococcal activity in both in vitro assays using cell cultures and the human fallopian tube organ culture model. This proposal will address several questions which are central to the determination of useful microbicidal agents which will interrupt the interaction between the chlamydial elementary body and/or gonococci and receptors on the host cell surface. The specific aims of this proposal are: (1) To expand the human primary cell culture systems to evaluate in vitro the efficacy and cytotoxicity of potential topical antimicrobials to prevent infection of the genital mucosa by Chlamydia trachomatis and/or Neisseria gonorrhoeae. (2) Define the mechanism(s) by which select noncytotoxic candidate topical antimicrobials inhibit C. trachomatis and/or N. gonorrhoeae and (3) Isolate the HS glycosaminoglycans (GAGs) from human genital tract cells and organ cultures and identify fractions important for C. trachomatis adherence to cells. These studies should allow a detailed study of antimicrobials which will allow their potential as topical microbicides to be exploited. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HYDROLASE

AUTOPROTEOLYSIS

OF

N-TERMINAL

NUCLEOPHILE

Principal Investigator & Institution: Guo, Hwai-Chen; Biophysics; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2003 Summary: (Adapted from abstract): Lysosomal glycosylasparaginase hydrolyzes the amide bond joining carbohydrate to protein in Asn-linked glycoproteins. This enzyme joins the proteasome (Lowe et al., 1995; Groll et al., 1997) and penicillin acylase (Duggleby et al., 1995) as a class of amidases that catalytically use a processed Nterminal threonine or serine as both a polarizing base and a nucleophile. Another intriguing aspect of this enzyme is that a single chain precursor is processed by intramolecular autoproteolysis to yield the conserved N-terminal threonine and an active amidase (Guan et al., 1996). With crystals in hand, Dr. Guo proposes to determine the crystal structures of glycosylasparaginase precursor (proenzyme) to elucidate the mechanism of this intramolecular autoproteolysis, and activation process of enzyme

16

Penicillin

activity. Based on structural geometry and evolutionarily conserved sequence, the residues appearing to be important for autoproteolysis will be selected for site-directed mutagenesis. Mutant enzymes will then be subject to kinetic analysis, and/or further physical studies by circular dichroism (CD) or crystallography. Dr Guo will further investigate the role of dimerization in the intramolecular autoproteolysis. He has also crystallized the mutant proteins of reduced activity in their mature (autocleaved) form. By applying cryocrystallography techniques, he will attempt to stabilize the enzymesubstrate (or inhibitor) complexes for x-ray structure determination, to allow a more detailed examination of the enzymatic mechanism. The enzymatic activities and enzyme activation are central to much of physiology. Dr. Guo's work addresses the mechanisms of function at atomic resolution, and should contribute to an increased understanding of the essential biological processes. The broad, long-term objectives of this research plan are to understand the molecular basis of enzymatic mechanisms, as well as protein splicing. The tools employed are x-ray crystallography, CD, molecular biology, and protein chemistry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BACTEREMIA FROM DENTAL EXTRACTION VS. ORAL HYGIENE Principal Investigator & Institution: Lockhart, Peter B.; Chairman; Carolinas Medical Center Box 32861 Charlotte, Nc 28203 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2005 Summary: (provided by applicant): The use of antibiotic prophylaxis to prevent distant site infections (DSI) from oral pathogens remains a controversial issue in clinical practice. Little is known about the incidence, nature, magnitude, and duration (INMD) of bacteremia from naturally occurring or invasive dental procedures, or the impact of prophylactic antibiotics on the INMD. The major purposes of this prospective, randomized, clinical study of 300 subjects is to: 1) determine and compare the true INMD of bacteremia resulting from a highly invasive dental office procedure (single tooth extraction) and a minimally invasive and naturally occurring source of bacteremia (tooth brushing), from 10 specific oral pathogens (S. mitis, S. sanguis. S. Oralis. S. intermedius, S. mutans, S. Salivarius. F. nucleatum, A. Actinomycetemcomitans, E. corrodens and P. gingivalis) that have been reported to cause DSI; and 2) measure the effect of the American Heart Association's guidelines for amoxicillin prophylaxis on the INMD of bacteremia resulting from a single tooth extraction. Subjects will be randomized into three equal into three equal groups: extraction with amoxicillin, extraction with placebo, and tooth brushing. Blood for aerobic and anaerobic bacterial cultures and PCR will be drawn at six time points before, during, and following these oral procedures. INMD will be determined as follows: 1) incidence figures for each blood draw will employ a highly sensitive, broth-based blood culturing system (BACTEC); 2) nature will be determined by conventional methods of speciating pathogens cultivated by BACTEC, and we will improve the specificity of the oral pathogens from BACTEC with the use of gene sequence analysis; 3) magnitude of bacteremia will be determined by PCR for each blood sample; and 4) bacteremia duration will correspond to the presence of oral pathogens in sequential blood draws following tooth brushing and extractions. This study will provide a more complete understanding of the impact of invasiveness (i.e., brushing vs. extraction) and the degree of oral disease on the INMD. Additionally, we will have unique and critical data for the development of both future research and evidence-based guidelines concerning antibiotic prophylaxis for individuals currently felt to be at risk for DSI. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BECTA LACTAMASES AND DD PEPTIDASES ACTIVE SITE CHEMISTRY Principal Investigator & Institution: Pratt, Rex F.; Professor; Chemistry; Wesleyan University Middletown, Ct 06459 Timing: Fiscal Year 2001; Project Start 30-SEP-1982; Project End 31-JUL-2003 Summary: Bacterial resistance to beta-lactam antibiotics continues to become more prevalent and more clinically important. A large part of the resistance can be understood and investigated experimentally in terms of the chemistry of the interactions of beta-lactam antibiotics with the active sites of two groups of bacterial enzymes, the beta-lactamases on one hand, which catalyze the hydrolysis of the antibiotics, and the Dalanyl-D-alanine transpeptidase/carboxypeptidases on the other, which catalyze the synthesis an maintenance of the peptide cross-links of bacterial cell walls, and which are inhibited by beta-lactam antibiotics. There is now good reason to believe that all of these beta-lactam binding sites have much in common. An understanding o the structure and function of these sites and of the relationship between them is fundamental to future antibiotic design--both beta-lactam and otherwise. Th object of the proposed research is to explore further the chemical functionality and the substrate binding properties of a series of these active sites, using a number of modified substrates, novel inhibitors, and potential effecters. A mechanistic study of these sites, designed to determine the role of the functional groups present and the relationship between the proteinases, will be performed. Computational methods will be employed in order to interpre the results in terms of available crystal structures of these enzymes and to thus establish new guidelines to inhibitor design. In order to understand the structural and mechanistic basis of bacterial beta-lactam-resistance through mutation of transpeptidases, one important example of such beta-lactam-resistant enzymes, penicillin binding protein 2a of the methicillin-resistant Staphylococcus aureus (MRSA), will be studied in detail. These studies will lead to a clearer view of the chemistry of beta-lactamase and transpeptidase active sites, and thus to new directions in antibiotic design. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BETA LACTAMASE MUTATIONS IN ANTIBIOTIC RESISTANCE Principal Investigator & Institution: Palzkill, Timothy; Associate Professor; Microbiology and Immunology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2001; Project Start 01-JUL-1992; Project End 30-APR-2006 Summary: (provided by the applicant): Bacterial resistance to antimicrobial agents has increased in recent years and now represents a significant threat to successful antibiotic therapy. One example of this phenomenon is the development of resistance to B-Iactam antibiotics. B-lactam antibiotics, such as the penicillins and cephalosporins, are among the most frequently used antimicrobial agents. The most common mechanism of resistance to B-lactam antibiotics is the production of B-lactamases, which cleave the antibiotic, rendering it harmless to bacteria. Based on primary sequence homology, Blactamases have been grouped into four classes. Classes A, C and D are active-site serine enzymes that catalyze, via a serine-bound acyl-enzyme intermediate, the hydrolysis of the B-Iactam antibiotic. Class B enzymes require zinc for activity and catalysis does not proceed via a covalent intermediate. Because of the diverse range of substrate specificities of these enzymes, virtually all B-lactam antibiotics are susceptible to hydrolysis. Clearly, the design of new antibiotics that escape hydrolysis by the growing collection of B-lactamase activities will be a challenge. It will be necessary to understand the catalytic mechanism and basis for substrate specificity of each class of B-lactamase.

18

Penicillin

The goal of this work is understand how the amino acid sequence determines the structure, catalysis, and substrate specificity of the IMP-I B-lactamase of class B and the P99 class C B-lactamase. This will be achieved by randomizing amino acid positions in the active-site pocket of each enzyme to sample all possible amino acid substitutions. All of the random substitutions will then be screened to identify those substitutions that alter the substrate specificity of the enzyme. Enzymes containing substitutions that alter substrate specificity will be purified and characterized biochemically. The sets of random substitutions will also be screened using phage display methodology to identify residues critical for catalysis. A further goal of this proposal is to use the detailed knowledge of the interface between B-lactamase inhibitory protein (BLIP) and Blactamase, in combination with random mutagenesis and phage display, to create derivatives of BLIP that bind and inhibit B-lactamases and penicillin binding proteins. The new' BLIP derivatives will be characterized biochemically and structurally. The information gained from these studies will be useful for the rational design of new antibiotics and inhibitors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BETA-LACTAMASE ANTIBIOTIC RESISTANCE OF B ANTHRACIS Principal Investigator & Institution: Zhang, Hong-Zhong; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2005 Summary: (provided by applicant): Recent anthrax-related bioterrorism incidents highlight the need for effective antimicrobial agents for treatment and prevention. Penicillin antibiotics has been historically the first choice for this purpose. However, concerns for drug resistance have resulted in recommendations that these drugs no longer be considered as drug of choice. This application proposes to define the biochemical and molecular basis of resistance to beta-lactams, as well as the potential for resistance to emerge in B. anthracis. The aims of the proposed experiments are: 1) to determine whether one or both of the two putative B-lactamase genes code for a Blactamase and 2) to identify regulatory genes controlling B lactamase gene expression. Specifically, individual Beta-lactamase gene will be cloned and expressed. Encoded protein will be purified and in vitro biochemical studies will be performed to determine its substrate profile and inhibitor specificity. Candidate regulatory genes as identified by genome scanning will be cloned and their sequence will be determined. Mutants of regulatory genes will be constructed using genetic manipulation to assess the function of each gene product. The result of this study will elucidate the molecular mechanism underlying the resistance of Bacillus anthracis to penicillin antibiotics and inform decisions about the clinical utility of Beta-lactam antibiotics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOSYNTHESIS OF BETA LACTAM ANTIBIOTICS Principal Investigator & Institution: Townsend, Craig A.; Professor; Chemistry; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 01-SEP-1978; Project End 31-MAR-2004 Summary: Penicillin and related beta-lactam antibiotics have been a mainstay in the treatment of infections for 50 years. However, their effectiveness, like other known classes of antibiotics, has come under increasing challenge from the rise of multiply drug-resistant pathogenic bacteria. Efforts have intensified to understand mechanisms of resistance and to overcome them. Structural modification through genetic

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manipulation of their biosynthetic pathways is a promising approach to produce variants of known antibiotics by cost-effective fermentation and semi-synthetic methods. Continuation of a program to investigate beta-lactam antibiotic biosynthesis is proposed in this application. Three of the four known classes of these antibiotics will be studied: (1) clavulanic acid, a potent inhibitor/inactivator of beta-lactamase enzymes and a wide-spread source of resistance, (2) the nocardicins, a family of monocyclic betalactams, and the metabolically related monobactams, and (3) the carbapenems, represented clinically by thienamycin and its derivatives, but most simply by carbapen2-em-3-carboxylic acid. With the recent isolation of biosynthetic gene clusters for at least one member of each of these four principal groups, work is poised to advance rapidly in an integrated research plan using techniques ranging from organic synthesis and enzymology to molecular biology and macromolecular structural methods. Clavaminate synthase will be examined in mutagenesis experiments to identify ligands to the catalytic iron, substrate analogues will be prepared to elucidate the controlling factors in hydroxylation vs. oxidative cyclization chemistry mediated by this protein and as probes in spectroscopic studies of the iron binding site. The newly discovered betalactam synthetase active in this pathway will be examined in detail kinetically and for its substrate tolerance, and the poorly understood transformations at the end and beginning of the pathway will be investigated in both gene disruption, and overexpression experiments. The recently discovered nocardicin gene cluster will be studied with emphasis on determining how the presumed precursor peptide is assembled and the beta-lactam formed. Possible evolutionary cross-over between clavulanic acid and the carbpenems will be examined particularly with respect to an apparent similarity of beta-lactam synthesis. These insights will be extended to examination of beta- lactam formation in the prephytotoxin tabtoxin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BROAD SPECTRUM BETA-LACTAMASE INHIBITORS Principal Investigator & Institution: Buynak, John D.; Associate Professor; Alamx, Llc 101 N Wilmot Rd, Ste 600 Tucson, Az 85711 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 30-JUN-2003 Summary: (Adapted from the application): Penicillin-resistant bacteria pose a serious threat to human welfare. This project will generate new products designed to defeat resistant microorganisms. The most prevalent cause of bacterial resistance involves the destruction of the antibiotic with the enzyme B-lactamase. There are more than 255 known B-lactamases, which have been grouped into four classes: A through D. Historically, class A has been the most clinically important. However, the incidence of class C-mediated infections has increased dramatically in the past decade. Often such resistant infections can be defeated through the co-administration of an antibiotic and a B-lactamase inhibitor. However, current commercial B-lactamase inhibitors are effective only against class A enzymes. We have now identified and patented lead compounds which are simultaneously effective against both class A and class C B-lactamases. This project will develop those leads into viable commercial products. Collaborations with a number of academic researchers and pharmaceutical companies are in place, allowing access to representative B-lactamases as well as microbiological evaluations of these inhibitors. The objective is to develop products which have a broader spectrum than commercial antibiotic/inhibitor combinations. This will include either better overall activity or better activity against a subclass of clinically important organisms not targeted by current commercial products. PROPOSED COMMERCIAL APPLICATION:

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Penicillin

These inhibitors can be combined with the commercial beta-lactam antibiotic to broaden the spectrum of the antibiotic. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPLEX PHENOTYPES OF MUTIPLE MUTANTS OF E COLI Principal Investigator & Institution: Young, Kevin D.; Professor; Microbiology and Immunology; University of North Dakota 264 Centennial Drive Grand Forks, Nd 58202 Timing: Fiscal Year 2001; Project Start 01-MAR-2000; Project End 30-APR-2004 Summary: Some biological traits are mediated by combinations of genes or proteins whose interactions are so complicated that we can not predict an organism's phenotype even with an intimate knowledge of its genotype. The twelve penicillin binding proteins (PBPs) of Escherichia coli form a model system for the study of such "complex phenotypes." The PBPs synthesize, modify and maintain the rigid peptidoglycan layer of the bacterial cell wall and are the targets of our most important single class of antibiotics, the beta-lactams. Nonetheless, despite decades of work, we do not know the detailed biological functions of these enzymes nor can we describe the biochemical pathways by which they operate. This information is becoming increasingly important with the rise of antibiotic resistant organisms. Our long term objective is to explain the structure, synthesis, and function of bacterial peptidoglycan so that more rational antimicrobial strategies can be devised. Therefore, we constructed 192 E. coli strains from which were deleted every possible combination of eight different PBPs. This comprehensive set of mutants allowed us to show that such a combinatorial genetic strategy produces results impossible to classic genetic approaches. Preliminary screening of the mutants revealed unusual and unanticipated phenotypes, including: capsule production, morphological aberrations, phage resistance, resistance to antibiotic- induced lysis, and temperature sensitivity. In most cases, the traits did not appear in cells with fewer than three or four mutations, and these phenotypes depended in a complex way on the combinations of active PBPs. We propose to complete the screening of this set of mutants for traits likely to be affected by a alterations in the peptidoglycan-e.g., in antibiotic-or chemically-induced autolysis, phage resistance, protein secretion, and in the morphogenesis of extracellular structures. In addition, analytical techniques will be adapted so that phenotypic predictions can be made from knowledge of the genotype in complex situations. Three significant results can be anticipated. First, we will identify new phenotypes in basic cellular processes in which the PBPs and peptidoglycan play fundamental biological roles. Second, we will understand better how the PBPs maintain the bacterial cell wall and how beta-lactam antibiotics induce its destruction. And third, the compilation of extensive and defined datasets will allow us to develop appropriate tools to investigate complex relations between genotype and phenotype. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMPREHENSIVE SICKLE CELL CENTER Principal Investigator & Institution: Wang, Winfred C.; Member; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAR-2008 Summary: (provided by applicant): The mission of St. Jude Children's Research Hospital (SJCRH) is to find cures for children with catastrophic illnesses through research and treatment, a mission that is directly relevant to the 700 children and adolescents cared for in our Comprehensive Sickle Cell Center. We seek to offer a broad range of

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therapeutic options. Namely, supportive care, chronic transfusion, drug therapy or stem cell transplantation, to our patients and in so doing to implement effective clinical research protocols to evaluate these options. Project N, the Network (Inter-Center) Proposal, seeks to test combination "chemotherapy" for reducing the frequency of pain crises through a Phase III trial of hydroxyurea and magnesium vs. hydroxyurea and placebo in pediatric and adult patients. In Project 1, a formal Phase I trial of magnesium will be conducted in pediatric patients, and then a Phase II trial will examine the effect of this combination on prevention and/or reversal of central nervous system abnormalities, on red blood cell properties and on nutritional status. In Project 2, we seek to test the feasibility of using parental donors for haploidentical stem cell transplantation to extend potentially curative therapy to more children with sickle cell disease. Project 3, utilizes a murine model of sickle cell disease to explore pathogenesis of pneumococcal infection in the children followed in our Center to examine the effects of penicillin prophylaxis, vaccines and specific antimicrobial therapy on the frequency of antibiotic tolerance and/or resistance. In Project 4, lentiviral vectors designed to express a gamma-globin gene at high levels will be optimized in a murine model of sickle cell disease and we will test the concept of in vivo drug selection to amplify a minority, genetically modified hematopoietic population to achieve effective gene therapy. Project 5 is focused on understanding the regulatory mechanisms that modulate the relative levels of expression of the gamma- and Beta-globin genes in maturing erythroblasts. Activities are integrated through the functions of the Clinical Core, a Patient Services Core and a Central Nervous System Assessment Core. Our Sickle Cell Scholars will have the opportunity to develop a translational research career through mentoring with a focus in the clinic and/or laboratory. Thus our Comprehensive Sickle Cell Center effectively integrates clinical, translational and basic research and thereby fosters multidisciplinary collaborations directed toward the goal of finding effective therapy and ultimately a cure for sickle cell disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPUTATIONAL INSIGHTS INTO BACTERIAL RESISTANCE: ANTIBIOTICS Principal Investigator & Institution: Massova, Irina; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001 Summary: We are investigating the intrinsic reactivity of beta-lactams for understanding the mechanisms of action and inactivation of beta-lactamases and penicillin-binding proteins. Ab initio quantum mechanical calculations using a polarizable continuum model to estimate solvation effects have been utilized to analyze the hydrolysis and methanolysis of selected beta-lactams and simple amides. The roles of four-membered ring strain, reduced amide resonance, substituent and ring fusion effects on hydrolysis and methanol-mediated hydrolysis of these compounds have been studied by reconstructing the corresponding reaction pathways in gas and solution. Insights into this reactivity could prove very useful in the design of novel potent antimicrobials. The Computer Graphics Laboratory facilities has been used for visualization of the molecules. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CONTROL OF AUTOLYSIS IN PNEUMOCOCCI Principal Investigator & Institution: Tuomanen, Elaine I.; Chair, Professor; St. Jude Children's Research Hospital Memphis, Tn 381052794

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Timing: Fiscal Year 2001; Project Start 01-JUL-1997; Project End 30-JUN-2002 Summary: Regulation of bacterial autolytic enzymes (cell wall hydrolases) is a highly spohisticated physiological task. Antibiotics such as pencicillin induce bacteriolysis by interfering with the control of the endogenous autolytic enzymes, indicating the major chemotherapeutic relevance of autolysins. Although the binding of antibiotics to cell wall synthetic enzymes has been very well characterized, it is unknown how this event leads to deregulation of autolytic enzymes. It is this aspect ofantibiotic activity, revealed as the tolerant phenotype, that is the focus of this proposal. Bacteria which stop growing in response to penicillin but fail to lyse and die are termed tolerant. This property ensures bacterial survival and is the first step for most strains on the way to development of antibiotic resistance. Mechanistically, tolerance arises beyond the level of the drug binding to the vacteria (the site where resistance arises). Classically, tolerance has been induced in the lab by knock out of the lethal autolysin. Much of this physiology has been studies in pneumococci becuase it contains only one major autolytic enzyme, this providing a simple, model system from which to learn of elements in the autolytic cascade. Tolerance has also been described in clinical isolates of pneumococci, but, the mechanism of tolerance is unknown since the autolytic enzyme is present and functional but is apparently, not triggered to act in the presence of penicillin bound to the bacterium. This proposal seeks to aply a newly developed genetic strategy to identify genetic elements important in control of autolytic activity. A library of insertionally inactivated mutants has been screened for mutants in which loss of function of a gene renders the bacteria tolerant to penicillin despite the presence of normal autolytic enzyme. The genes involved in generation of the tolerant phenotype will be characterized. One mutant of particular interest harbors an inactivation in a histidine kinase, suggesting a possible signalling pathway important for the triggering of lytic activity. Very recent analysis of this mutant indicates it is also defective for natural transformation of DNA suggesting a programed link between autolysis and transformation. This will provide information important to the development of new potential antibacterial agents and perhaps suggest why bacteria in the clinical encironment choose to reggulate autolytic activity rather than dispense with sucidal autolysins in the face aof antibiotic pressure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEGRADATION REACTIONS IN SPORE GERMINATION Principal Investigator & Institution: Setlow, Peter; Professor; Biochemistry; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806 Timing: Fiscal Year 2001; Project Start 01-SEP-1978; Project End 31-AUG-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECT OF ANTIBIOTICS ON ORAL BIOFILMS IN VIVO Principal Investigator & Institution: Haffajee, Anne D.; Senior Member of Staff; Forsyth Institute Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 30-JUN-2003 Summary: Biofilms found on mammalian tissue surfaces contain complex mixtures of bacterial species growing within a glycocalyx matrix. Species in biofilms have shown remarkably greater resistance to antibiotics than when grown in a planktonic state. Surprisingly little is known about the effect of systemically administered antibiotics on the microbial composition of naturally occurring, complex biofilms. Thus, the long-term

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objective of this proposal is to determine the effect of antibiotics on the microbial composition of biofilms as they exist in vivo and to determine if the proportion and nature of antibiotic resistant taxa is affected. Subgingival biofilms that occur on teeth will be employed as a model system because of their complexity, ready accessibility and known microbial composition. Specific Aim 1 will examine the effects of 3 systemically administered antibiotics on the microbial composition of subgingival biofilms in adult humans with periodontitis. All subjects will receive scaling and root planing and will be randomly assigned to one of 4 groups of 36 subjects each receiving one of doxycycline, amoxicillin, metronidazole or control. 28 subgingival biofilm samples will be taken in each subject at baseline, at selected time points while the agent is being taken, the same time points after cessation of the agent as well as at 3, 6 and 12 months. These samples will be evaluated individually for their content of 40 subgingival species using checkerboard DNA-DNA hybridization. Data will be evaluated longitudinally and compared with clinical parameters. Specific Aim 2 will examine the proportion and nature of subgingival species that are resistant to 4 mug/ml of the test antibiotic at the same time points. Subgingival biofilm samples will be plated on media with and without the test antibiotic and resistant isolates identified using DNA probes. Data from this investigation will indicate the kinetics of suppression of species in subgingival biofilms during antibiotic administration, the kinetics of repopulation after antibiotic withdrawal as well as the nature and proportion of subgingival species that are resistant to the antibiotics at different time points. The data should indicate the effects of antibiotics on the microbial composition of complex ecosystems such as those found in biofilms and be useful in guiding and interpreting in vitro studies of mechanisms of antibiotic resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE ENGINEERING AND COMBINATIONAL BIOLOGY Principal Investigator & Institution: Jarrell, Kevin A.; Pharmacol & Exper Therapeutics; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2001; Project Start 15-MAR-2001; Project End 28-FEB-2002 Summary: (Investigator's Abstract): The research program described in this application is focused on the development and implementation of new gene engineering methods. The methods that are being developed are particularly suited to the manipulation of modular genes, such as peptide synthetic genes. Our goal is to break the modular genes up into their component modules, and use those modules as building blocks for the assembly of novel new modular genes. To achieve this goal, we have developed two new approaches to gene engineering. Both approaches will be optimized and implemented during the funding period. The first approach involves the use of ribozymes(i.e., enzymes comprised of RNA) as tools for chimeric gene assembly. The second approach involves the use of RNA-overhang cloning (ROC) and NA-overhang cloning (DOC) to create chimeric genes. Finally, the ribozyme method will be combined with the ROC and OCmethods to create a new gene engineering system that takes full advantage of the strengths of the individual approaches. Efficient gene engineering methods are of fundamental importance for both basic and applied research on topics directly relevant to human health. For example, the gene engineering methods described here will be used to create combinatorial gene libraries that encode chimeric peptide synthetase genes. Naturally occurring peptide synthetases are known to synthesize important antibiotics, such as penicillin and vancomycin. Furthermore, the immunosuppressant cyclosporine is produced by a peptide synthetase. The chimeric peptide synthetase genes generated during the course of this project should encode

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hybrid enzymes that synthesize novel biologically active-molecules. A long-term goal of this project is to screen chimeric gene libraries to identify enzymes that synthesize novel compounds at could be developed as drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC CONTROL OF NUTRITIONAL STARVATION IN YEAST Principal Investigator & Institution: Fink, Gerald R.; Professor of Molecular Genetics, Mit; Whitehead Institute for Biomedical Res Biomedical Research Cambridge, Ma 02142 Timing: Fiscal Year 2001; Project Start 01-JUL-1984; Project End 30-NOV-2003 Summary: Experiments are designed to determine the mechanism by which gene expression is controlled by ploidy in the yeast Saccharomyces cerevisiae. This work has implications for abnormal cell growth in humans because tumor cells with aberrant cell control often contain an abnormal number of chromosomes. Although hyperploidy is usually viewed as a consequence of aberrant cell cycle control, this proposal suggests that hyperploidy itself may cause the abnormal expression of key molecules required for cell proliferation. Gene arrays will be used to determine the molecular basis for the ploidy control of gene transcription in isogenic yeast strains whose ploidy varies from haploid to tetraploid. One set of experiments is designed to identify the role of G1 cyclin transcription in the ploidy control of cell size and cell proliferation. These studies will determine whether ploidy control is itself cell cycle regulated. As polyploid cells are much more sensitive to nutritional starvation that their euploid counterparts, the genes responsible for the differences in euploid and polyploid growth control will be identified. The role of heterozygosity at the mating type locus and chromosome pairing in the response of polyploids to nutritional starvation will be ascertained. The promoter of one of the genes known to be transcriptionally controlled by ploidy will be analyzed to identify cis-acting sequences that respond to ploidy control. Another screen is designed to identify the trans-acting genes that mediate ploidy control. Salt resistance, a ploidy sensitive phenotype, will be used to screen for suppressors of the ploidy dependent phenotype. In addition the cellular basis for salt sensitivity will be elucidated. A third set of experiments identifies the role of the Rim1 transcription factor in stationary phase metabolism. This yeast homolog of a known fungal regulator of penicillin production is proposed to control stationary phase metabolism in Saccharomyces. A fourth set of experiments focuses on the role of dipthamide, a conserved posttranslational modification of elongation factor2 in cellular regulation. dph mutants have a stationary phase defect that is again more severe in diploids that in haploids. The experiments proposed will lead to a deeper understanding of the role of ploidy in aberrant cell proliferation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC EXCHANGE AND ORAL BACTERIA Principal Investigator & Institution: Wang, Bingyan; State University of New York at Buffalo Suite 211 Ub Commons Amherst, Ny 14228 Timing: Fiscal Year 2001 Summary: Our investigation will focus on genetic exchange among oral bacteria, especially among periodontopathic organisms. The transfer of genetic information between different organisms has been inferred from nucleotide sequence comparisons. The ecological benefits of genetic exchange include the expansion of metabolic versatility and resistance to hazardous environments. Some transformable bacteria have acquired antibiotic resistance by horizontal genetic exchange of fragments of

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chromosomal genes, such as penicillin-resistant penicillin-binding proteins in Streptococcus pneumoniae. The application of molecular biology techniques with oral microorganisms should permit the opportunity for an in vitro assessment of gene transfer. The specific aim of our investigation is to understand the role of genetic exchange as a risk factor in human oral infections such as periodontal diseases. Little information exists on gene transfer between the bacterial flora associated with periodontal diseases. Among the periodontopathic organisms, T. denticola, P. gingivalis, and F. nucleatum are the focus of our present investigation. The recent development of a gene transfer system in T. denticola in Dr. Kuramitsu's laboratory now makes it feasible to study whether the genetic information from T. denticola can be transferred in vitro to P. gingivalis or to F. nucleatum. We are also planning to determine if the exchange of genetic information can occur between T. denticola and oral streptococci, since the latter forms the majority of gram positive early colonizers of the tooth surface. Both in vitro bacterial culture and biofilms will be used to evaluate gene transfer from T. denticola to different bacteria. Information obtained from this study could elucidate the potential role of gene transfer between oral bacteria in the etiology of periodontal diseases. Key words: Genetic exchange, biofilms, periodontal disease Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC SYSTEM TO STUDY VIRULENCE IN BACTEROIDES Principal Investigator & Institution: Malamy, Michael H.; Professor; Molecular Biol & Microbiology; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2003; Project Start 01-JAN-1983; Project End 30-APR-2004 Summary: (provided by applicant): This study will focus on factors that allow the obligate anaerobe B.fragilis, although a component of the normal colonic microbiota, to be a successful pathogen. These include its ability to withstand an aerobic environment (aero-tolerance) during early stages of infection; the presence of systems to import heme into the cell for the heme-dependent pathways of central metabolism and defense against reactive oxygen species; the ability of B.fragilis to remove sialic acid residues from host components, and its virtuosity in obtaining nutrients for growth in vivo from complex oligosaccharides and glycoproteins. Specific aims include: 1, to continue to study factors that allow B.fragilis to withstand prolonged oxygen challenge (aerotolerance): We propose that activities in the B.fragilis periplasm serve as the initial line of defense to combat the formation of reactive oxygen species (ROS), protect sensitive targets from ROS challenges and to reverse ROS damage. In addition we have identified specific functions (superoxide dismutase, SOD), and an extensive gene cluster (the Bat operon) that are required for aerotolerance. We will test the hypothesis that the Bat operon plays an important role in exporting reducing potential from the cytoplasm to the periplasm. 2. Acquisition of iron and heme is important for B.fragilis growth in vitro and in vivo. We will study the process of heme uptake in B.fragilis by the heme permease systems whose genes and functions we have described. We will also continue to study the heme-dependent, and Fe-S cluster-containing enzymes in the dual pathways of central metabolism to establish their roles in aerotolerance and in providing energy during oxygen challenge. 3. to investigate the composition, functions and control of operons for the acquisition of growth substrates from the infected host. We will focus on the operon containing the neuraminidase (nanH1) gene and several other glycohydrolases capable of converting the complex Lewis antigen found on the surface of many human cells to individual monosaccharides. We will continue to define the operon for NANA utilization, the NanL1 operon. Is neuraminidase a virulence factor because it supplies NANA for B.fragilis growth, or because its activity alters the surface

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of host cells during infection, or both? 4.We will develop additional tools to define changes in macromolecular synthesis and stability of DNA, proteins and membranes during 9 oxygen challenge. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IRON ACQUISITION AND PNEUMOCOCCAL INFECTION Principal Investigator & Institution: Tai, Stanley S.; Howard University 2400 6Th St Nw Washington, Dc 20059 Timing: Fiscal Year 2001 Summary: Children under two years of age, the elderly, and individuals with underlying disease are to great risk of developing pneumococcal otitis media, septicemia, meningitis, and pneumonia. Antibiotic prophylaxis and vaccination are the two major methods to treat and prevent invasive pneumococcal infections. However, the success of antibiotic treatments has been limited by the recent isolation of penicillinor multi-drug resistant pneumococci. The current pneumococcal vaccine, a mixture of capsular polysaccharide of 23 most prevalent of possible 84 stereotypes, only elicits type-specific antibodies and can not provide protection against infection of other Streptococcus pneumoniae serotypes not used in the vaccine preparation. To control pneumococcal disease would require a new knowledge about the biology of S. pneumoniae. The long range goal of this investigation is to study how S. pneumoniae survives in infected animals where most of iron molecules are sequestered by ironbinding proteins, such as hemoglobin, transferrin, and lactoferrin. Iron limitation restricted the growth of S. pneumoniae and the limited growth could be restored by the addition of hemin or hemoglobin. Pneumococcal cells have a great ability to bind hemin. Several hemin binding proteins have been identified in the cell lysate of S. pneumoniae with the major species migrated as a molecular mass of 43 kDa. The specific aims of this proposal are employing genetic and immunological methods to seek answers to the following question: 1). What is the genetic determinant of 43-kDa hemin binding protein? 2). What roles does 43-kDa HBP play in the hemin acquisition of S. pneumoniae? 3) What roles does 43-kDa HBP play in S. pneumoniae infection in experimental animals? Results generated from the proposed studies not only will provide us with basic information about the iron acquisition of S. pneumoniae, but will allow us to gain insight into the pathogenic mechanism of S. pneumoniae disease. The knowledge obtained in this study will have practical applications as well in designing effective therapeutic strategy and agents for the control of pneumococcal disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MEASUREMENT AND THERAPY OF UNIVESTIGATED DYSPEPSIA Principal Investigator & Institution: Rabeneck, Linda; Department Chairman; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2001; Project Start 29-SEP-2001; Project End 31-JUL-2002 Summary: The candidate for this NIH K24 award is a gastroenterologist and Associate Professor of Medicine at Baylor College of Medicine (BCM), where she holds joint appointments in the Gastroenterology (GI) and Health Services Research Sections. Dr. Rabeneck began her full-time academic career in 1990, upon obtaining her MPH degree at Yale University, where she trained as a Robert Wood Johnson Clinical Scholar. She has been successful in obtaining VA and NIH support for her work, and has achieved national recognition for outcomes research in digestive diseases. Dr. Rabeneck recently held a 3-year VA. HSR&D Advanced Research Career Development Award, which

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facilitated her career development by providing relief from heavy clinical responsibilities. With this NIH K24 award, Dr. Rabeneck seeks to expand her mentoring activities and enhance her research skills. Dr. Rabeneck has a strong record of mentoring junior individuals and is committed to training the next generation of clinical investigators focusing on patient-oriented research. Dr. Rabeneck's plans over the 5 years of this award are to: 1) continue and expand her current mentoring of trainees and junior faculty; 2) establish a GI/MPH Track within the BCM GI Fellowship Program; and 3) establish a GI Epidemiology/Outcomes Research Group at BCM. This proposal makes use of the following outstanding resources: 1) Houston VA HSR&D Center of Excellence, one of 11 such programs in the U.S., a consortium of over 22 MD and PhD investigators; 2) a new NIH P30 award for BCM's Center for Gastrointestinal Development, Infection, and Injury, on which Dr. Rabeneck serves as Director, Clinical Core; 3) BCM's NIH K30 funded Clinical Scientist Training Program; 4) the University of Texas-Houston School of Public Health; 5) Research Endoscopy Unit; and 6) GI Mucosa Pathology Laboratory. Dr. Rabeneck's research focuses on the measurement and therapy of uninvestigated dyspepsia. Project #1, which makes use of previously collected data, will evaluate the relationships between three dimensions of dyspepsia (pain intensity; non-pain symptoms; satisfaction), and explore new methods for the analysis of outcome data. Project #2 is a multicenter randomized controlled trial of 330 H. pylori-infected patients presenting with dyspepsia without alarm features at 5 primary care sites in Houston. Patients will be randomized to combined antimicrobial-antisecretory therapy versus antisecretory therapy alone versus prompt endoscopy. The patients will be followed over 1 year. The trial will examine the hypothesis that combined antimicrobialantisecretory therapy is more efficacious than either prompt endoscopy or antisecretory therapy alone. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM PNEUMONIAE

OF

CAPSULAR

TRANSFORMATION

IN

S

Principal Investigator & Institution: Nesin, Mirjana; Pediatrics; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2001; Project Start 01-JUL-1997; Project End 30-JUN-2004 Summary: Streptococcus pneumonia is one of the most common invasive bacterial pathogens in children. The increase( incidence of pneumococcal diseases has been complicated by the appearance of multidrug resistant isolates, low levels of serotypespecific antibodies in young children and the absence of routine, effective immunization. Understanding the mechanisms of acquisition and spread of multidrug resistant microorganisms and their interaction with the immune system during colonization and invasion in order to design novel approaches for therapy of these infections is the long term career goal of this candidate. In the sponsor's laboratory the applicant has been studying the molecular epidemiology of penicillin resistant, pediatric isolates of S. pneumonia. Results of these studies have lead to the hypothesis that multidrug resistant defenses through capsular transformation. The proposed project would involve creating mutants in the genes for the capsular of S. Pneumonia and clarifying the mechanisms by which capsular transformation occurs in vivo. Information about this process improve our understanding of the strategies pneumococci have developed for colonization and infection and the essential criteria for successful immunization and therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MENINGOCOCCAL LIPOOLIGOSACCHARIDE & MUCOSAL PATHOGENESIS Principal Investigator & Institution: Stephens, David S.; Director; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2001; Project Start 01-JAN-1993; Project End 31-DEC-2002 Summary: The long-term objectives of this research program are to help define the genetic, structural and pathogenic basis of meningococcal endotoxin (lipoligosaccharide[LOS]). The recent dramatic increases in meningococcal infections in part of the United States and the emergency of penicillin-resistant meningococcal, emphasize pathogenesis. The principle investigator s approach utilized novel genetic techniques for meningococcal(e.g., Tn916 mutagenesis), biochemical and physical analysis of LOS structure; and human tissue assays to assemble a detailed model of meningococcal LOS and to provide insights into how Los influences pathogenesis. This application is directed at understanding the structural-functional relationship of the meningococcal LOS inner core, Flu (GlcNAc) Hep2KD02LipidA. LOS inner core structure is predicted to influence LOS assembly, human immune recognition of the meningococcus and interactions with soluble and cellular human proteins. In Specific Aim 1, genetic determinants that are responsible for LOS inner core oligosaccharide chain synthesis and heterogeneity in serogroup B meningococcal will be characterized: (1) by investigation of the ace (alpha chain elongation) operon which contains the UDPGlu: heptosyl (ll) lipooligosaccharide alpha 1, 2 N- acetylglucosamine transferase (rfaK) and the putative UDP-Glu heptosyl (1) lipooligosaccharide beta 1, 4 glucosyltransferase (IgtF); (2) by study of alpha chain initiation, and additions of phosphate derivatives and saccharides to Hepll; and (3) by understanding the deep rough Tn916 mutant 469 (KD02LipidA) at both genetic and structural levels. In Specific Aim 2, the role of Los in two important events that occur during group B meningococcal infection will be investigated. They propose that the LOS inner core, in particular the Hepll structure, facilitates group B meningococcal entry into human nasopharyngeal epithelial cells. In addition, genetically and structurally defined LOS mutants will be used to determine how expression of hep2KD02-Lipid A LOS enhances sensitivity of encapsulated meningococcal to killing by classical pathway complement-mediate mechanisms of human serum. Such data has application to the design of meningococcal vaccines currently in development (e.g. inclusion of truncated LOS molecules in outer membrane vesicle vaccines), and should provide insights into the unique features of meningococcal endotoxin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: METALLO BETA LACTAMASE FROM X MALTOPHILIA Principal Investigator & Institution: Crowder, Michael W.; Chemistry and Biochemistry; Miami University Oxford 500 E High St Oxford, Oh 45056 Timing: Fiscal Year 2001; Project Start 01-DEC-1997; Project End 30-NOV-2002 Summary: Enzymes that hydrolyze beta-lactams and cephalosporin antibiotics are called beta-lactamases, and their production by bacteria is the most common way that bacteria become antibiotic-resistant. The Zn(II)- containing beta-lactamases constitute an ever-growing and troubling class of beta-lactamases which contain 2 moles of Zn(II) per mole of enzyme, hydrolyze all known penicillin and cephalosporin antibiotics, are not inhibited by clavulanic acid, and have no known inhibitor of activity. The long-term objective of the proposed research is the rational design and preparation of irreversible inhibitors of the Zn(II)-containing beta-lactamases. Given the apparent structural and

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mechanistic differences among the metallo-beta-lactamases, this objective can only be realized after detailed characterization of a member from each distinct subclass of metallo-beta-lactamases. Similarities between the enzymes can then be identified and exploited for the rational design of an inhibitor. This proposal involves the study of the structurally-distinct, biomedically-important beta- lactamase (L1) from X maltophilia. The specific aims of this proposed research are: (1) detailed structural characterization of the metal binding sites of metal-substituted forms of the X. maltophilia beta- lactamase using spectroscopic, mutagenesis, and binding studies, (2) elucidation of the mode of action of the enzyme with several penicillin and cephalosporin antibiotics using steadystate and pre-steady state kinetics studies, (3) identification of the overall reaction mechanism used by Ll and of any stable reaction intermediates using mathematical simulations of kinetics rate profiles and results from biochemical studies, (4) integration of structural and mechanistic results to identify key aspects of the enzyme that can be targeted for the development of novel reaction- or structure-based inhibitors, and (5) examination of the possible inhibition properties of compounds, when once hydrolyzed produce reactive, exocyclic methylene groups. It is hoped that this novel integration of kinetics, biochemical, simulations, and spectroscopic studies can be used as a general strategy for the preparation of new antimicrobial agents and a better way to combat the ever-increasing prevalence of antibiotic resistance in bacteria. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METALLOPROTEIN BASED INTERFACIAL SYSTEMS Principal Investigator & Institution: Mabrouk, Patricia A.; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2001 Summary: The long term objectives of the project are characterization of the enzymatic activities and gene products involved in synthesis of the peptidoglycan cell wall of bacterial endospores and examination of the role of each type of peptidoglycan structural modification in determining endospore resistance properties. The specific aims are 1) to determine the structure of the endospore peptidoglycan in the first stages of its synthesis and to track the structure to its final form in the dormant spore, 2) to identify changes in synthesis of this structure produced by mutation or loss of each penicillin-binding protein, autolysin, and sporulation-associated gene product, and 3) to purify and characterize in vitro the enzymatic activities involved in peptidoglycan side chain cleavage and muramic lactarn production. Knowledge of principles of endospore resistance properties, dormancy, and longevity may contribute to better decontamination methods and to methods for storage and transport of drugs and vaccines. Peptidoglycan synthesis in general is an attractive target for antibiotic action, further studies of this process will contribute to methods for identification of new antibiotics. Peptidoglycan is purified from sporulating cultures of Bacillus subtilis by chemical and enzymatic treatments, digested with muramidase, and analyzed using high-pressure liquid chromatography (HPLC) using methods previously developed for analysis of dormant spore peptidoglycan. Novel muropeptides are identified using amino acid analysis and mass spectrometry. Appearance and loss of peptide side chain alanine and glycine residues, muramic lactarn production, and changes in peptide crosslinking are quantified throughout the sporulation process. The analysis will be repeated using strains with altered or absent penicillin-binding proteins, autolysins, and sporulation-associated gene products. The cwlD and other gene products found to be associated with muramic lactam production will be assayed in vitro using extracts of sporulating cells or following over-expression in B. subtilis or Escherichia coli.

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Penicillin

Immature peptidoglycan samples from mutant strains and purified muropeptides will serve as substrates in these assays. Reaction progress will be monitored using the HPLC method and by development of a more rapid capillary electrophoresis method. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MINIMIZING ANTIBIOTIC RESISTANCE IN COLORADO (MARC) Principal Investigator & Institution: Gonzales, Ralph; Associate Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2005 Summary: A broad-based coalition of stakeholders has collaborated to reduce excess antibiotic use in Colorado by developing and disseminating clinical practice guidelines and practice profiles to 2600 primary care physicians throughout the state. Whether, how much and what type of public and patient education to employ on large-scale efforts to decrease unnecessary antibiotic use is not known. The Minimizing Antibiotic Resistance in Colorado (MARC) Project is designed to evaluate the independent and combined marginal impact of two common mechanisms of public and patient education in clinician prescribing behavior: 1) household and office-based materials, and 2) mass media (television, radio, newsprint, web site). The following specific aims will examine the processes and outcomes of care related to each intervention strategy. Results from this project will inform state and federal efforts to improve ambulatory antibiotic prescribing practices. Specific Aim IA: Develop and implement community educational interventions using (1) household and office-based materials, and (2) mass media. Specific Aim IB: Measure and assess changes in antibiotic prescription rates for pharyngitis in children, and bronchitis in adults, using commercial MCO and Medicaid administrative data from physician practices. Specific Aim IIA: Conduct household surveys in and outside the intervention communities to measure the impact of each education strategy on public knowledge, attitudes, behavior and self- efficacy. Specific Aim IIB: Conduct a clinician judgment analysis to measure the impact of each education strategy on clinician decision making and empowerment relating to episodes of care for pharyngitis and bronchitis. Specific Aim IIIA: Conduct a survey of patients and parents to measure the impact of decreased antibiotic use on duration of illness and satisfaction with care, for children with pharyngitis and adults with bronchitis. Specific Aim IIIB: Using active surveillance data from the Colorado Department of Public Health and Environment (CDPHE), compare the incidence of invasive penicillin-resistant S. pneumoniae infections in and outside the intervention communities. Specific Aim IIIC: Conduct a net-cost analysis of the different levels of community education. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MODELING ANTIMICROBIAL RESISTANCE IN COMMUNITIES Principal Investigator & Institution: Huang, Susan S.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-JUL-2001 Summary: This project will use data from an ongoing multi-community trial to identify individual and community level risk factors that are associated with nasopharyngeal colonization with Streptococcus pneumoniae in young children. We will conduct a cross-sectional study to evaluate how community-level characteristics, in addition to individual risk factors, aid in describing the likelihood of colonization with resistant strains. We will further use the identified risk factors in a mathematical transmission model to predict proportional resistance in a community and evaluate changes in

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proportional resistance based upon alteration of modifiable risk factors. Our specific aims include: 1) Determination of individual and community-level risk factors associated with nasopharyngeal colonization with Streptococcus pneumoniae in young children, regardless of susceptibility pattern. 2) Determination of individual and community-level risk factors associated with nasopharyngeal colonization with penicillin-resistant Streptococcus pneumoniae in young children. 3) Development of a mathematical transmission model that can predict the rate of change in pneumococcal prevalence based upon identified individual and community-level risk factors, and alteration of these risk factors within the transmission model to predict their effects on future pneumococcal prevalence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR TARGETS IN PEPTIDOGLYCAN SYNTHESIS Principal Investigator & Institution: Davies, Christopher; Assistant Professor; Biochem and Molecular Biology; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): The murein sacculus is a mesh of cross-linked peptidoglycan strands that confers rigidity to the bacterial cell wall. Beta-lactam antibiotics, which target the essential transpeptidases (penicillin-binding proteins or PBPs) that cross-link the peptidoglycan strands, are important compounds in the treatment of bacterial diseases. Unfortunately, the emergence of multiple mechanisms of antibiotic resistance threatens to make these and other antibiotics obsolete in the treatment of bacterial infections. Along with other pathogenic bacteria, antibiotic resistance in Neisseria gonorrhoeae is a growing problem. Penicillin and tetracycline, once the antibiotics of choice for treatment of gonococcal infections, are no longer be used due to the emergence of resistant strains. Moreover, increasing numbers of strains are now resistant to the fluoroquinolones, one of the two antibiotics current recommended in the treatment of gonorrhea. Clearly there is an urgent need to develop new antimicrobials directed both against well-known molecular targets, such as PBPs, but also against novel targets. In this proposal we describe structural and biochemical studies of three enzymes involved in peptidoglycan metabolism: a D-Dcarboxypeptidase from E. coli (PBP 5) that serves as a model system for elucidating PBP function, an essential transpeptidase (PBP 2) from N. gonorrhoeae that is the lethal target of current beta-lactam antibiotics, and a lytic transglycosylase, MltA, also from N. gonorrhoeae, that serves as the lynchpin of the cell wall synthesizing complex. Each of these proteins has been selected to address one or more of the following aims: (a) to understand the biology of peptidoglycan synthesis, (b) to explore their interactions with antibiotics, (c) to elucidate the molecular basis for antibiotic resistance and (d) to examine their potential as targets for drug development. Studies on PBP 5 will elucidate the mechanism by which this enzyme hydrolyzes substrate and will provide a better understanding of PBP-antibiotic interactions in general. The molecular basis for antibiotic resistance in PBP 2 will be investigated by structural studies of the native enzyme and of a mutant isolated from a penicillin-resistant strain. The role of MltA as part of a multienzyme complex mediating peptidoglycan synthesis as well as its suitability as a novel target for antimicrobials will be examined by solving its crystal structure. These studies will provide a framework for future studies aimed at structurebased drug design and will provide substantial insight into the mechanisms of peptidoglycan synthesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEW INHIBITORS FOR THE PENICILLIN BINDING PROTEINS Principal Investigator & Institution: Gutheil, William G.; Associate Professor; Pharmaceutical Sciences; University of Missouri Kansas City Kansas City, Mo 64110 Timing: Fiscal Year 2001; Project Start 01-MAR-1999; Project End 28-FEB-2003 Summary: Bacterial infections, a major cause of death and morbidity prior to the development of modern antibiotics during the first half of this century, continue to pose a serious threat to public health due to the emergence and spread of increasingly antibiotic resistant bacteria. Penicillin- binding proteins (PBPs) are cell wall synthesizing enzymes that are the targets of the beta-lactam antibiotics. Each bacterial species has a number of PBPs, E. coli having at having at least eight. These enzymes can be divided into two groups, high molecular weight (HMW) PBPs, and low molecular weight (LMW) PBPs. HMW PBPs are lethal targets for the beta-lactam antibiotics, whereas the LMW PBPs are not lethal targets. The LMW PBPs give detectible activity against cell wall related substrates, whereas the HMW PBPs do not. Enzymatic assays against cell wall related substrates therefore do not exist for the most medically important PBPs. Even for LMW PBPs, currently available assay methods are inadequate. As observed by Waxman and Strominger (1983) "The absence of a simple, rapid and sensitive assay has made detailed kinetic and enzymological studies of purified CPases (PBPs) slow and difficult". In preliminary studies precise and sensitive UV-vis based coupled enzyme assays have been established for PBP activity, for both D-Ala and D-Lac based substrates, and used to partially characterize the activity of E. coli PBP5 amd the previously uncharacterized N. gonorrhoeae PBP3. These assays are substantially more precise than previously described PBP assays. A synthetic approach to D-Ala based substrates has been developed and significant progress toward the synthesis of D-Lac substrates has been made. The proposed research is directed towards: 1) the development of high sensitivity PBP assays, 2) the determination of PBP substrate specificity with synthetic cell wall related substrates, 3) the characterization of PBP steady-state kinetics using precise assays, and 4) preparation and testing of several possible new classes of PBP inhibitors. These studies will established improved methods for the study of the PBPs, determine essential features of PBP substrate specificity, and use this information to design new PBP inhibitors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PENICILLIN INTERACTIVE PROTEINS OF STAPHYLOCOCCUS AUREUS Principal Investigator & Institution: Chambers, Henry F.; Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: Methicillin-resistant strains of Staphylococcus aureus are a major clinical problem. They are multiple drug resistant, but ineffectiveness of penicillins and betalactam antibiotics is the real problem, as these are drug of choice to treat staphylococcal infections. The objective of this research is to further knowledge of mechanisms of methicillin resistance. Resistance is determined by several proteins that interact with penicillin. The interactions among these proteins are critical, but poorly understood. Knowledge of these interrelationships may lead to new drug discovery and new and more effective approaches to therapy./ Resistance is mainly due to production a novel low affinity penicillin bind protein, PBP 2a, a well wall synthetic enzyme. PBP 2a seems to substitute for all other PBPs. mecA, the gene encoding PBP 2a, is regulated by the same regulatory genes that control production of inducible beta-lactamase. Another

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type of penicillin interactive protein, a penicillin sensory signal transducer BlaR1, signals the cell to express PBP 2a and beta-lactamase, which together mediate all betalactam resistance in staphylococci. BlaR1 appears to be a PBP fused to an intracellular Zn++ metalloprotease, and as such may represent a completely new type of transmembrane signaling system. There are three aims. Aim1. To determine the intracellular pathway by which penicillin binding to BlaR1 signals induction of betalactamase and PBP 2a. The effect of specific mutations in BlaR1 on signaling will be determined to prove whether or not Blar1 is a metalloprotease. Putative consensus motifs of this superfamily of proteins will be targeted. The relationship between BlaR1 activation and proteolysis of BlaI, the repressor of the beta-lactamase regulon, will be defined. Aim 2. To identify PBPs, structural determinants, and other elements that interfere with PBP 2a mediated resistance. Effects of PBP deletion and mutations on PBP 2a mediated resistance will test whether PBP 2a can substitute for other PBPs and where essential functions reside within the molecule. The curious phenomenon of negative selection for expression of PBP 2a that we observed in mec naive cells also will be examined. Aim 3. To determine when during the cell cycle PBPs are expressed and where they are localized. An electron microscopic method for immunolocalization of specific myc-targeted PBPs in the cell will be developed. To augment information about where PBPs localize, when they are expressed during the cell cycle will be determined by Northern blotting. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PENICILLIN-BINDING PROTEINS, MECHANISM AND INHIBITION Principal Investigator & Institution: Mobashery, Shahriar; Professor; Chemistry; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (Applicant's Description) Penicillin-binding proteins (PBPs) are a group of enzymes involved in a number of functions in the assembly and regulation of bacterial cell wall. These enzymes are the targets of beta-lactam antibiotics for inhibition of bacterial growth. A multidisciplinary approach has been outlined for the study of PBPs, which builds on the mechanistic findings from this laboratory presented as Preliminary Results. Pour Specific Aims are outlined. Specific Aim 1 details the plans for cloning, expression and large-scale production of two PBPs, one from Escherichia coli (a Gramnegative bacterium) and another from Staphylococcus aureus (a Gram-positive bacterium). These proteins will be used in the biochemical studies and also will be provided to Professor Judy Kelly of the University of Connecticut for crystallization. Specific Aim 2 describes our design and proposed syntheses for two cephalosporins that are incorporated with structural components of the cell wall (peptidogylcan). These cephalosporins, in conjunction with one that is already synthesized, are proposed as mechanistic probes for the transpeptidase reaction carried out by certain PBP in the last step of cell wall biosynthesis (cross-linking of cell wall). Biochemical and structural experiments are detailed for the use of these cephalosporins as probes of mechanisms for PBPs. An assay for the cell wall cross-linking reaction of the transpeptidases (a PBP) is described in Specific Aim 3. The enzymic reaction is biochemically dissected into the acylation and deacylation steps, for each of which a quantitative assay method is described. These methodologies will allow investigations of the mechanistic details of these PBPs. Furthermore, a series of four peptidoglycan derivatives have been proposed to investigate the requirements for a minimal substrate for the transpeptidation reaction of the PBPs. Specific Aim 4 details the search for novel non-f3-lactam inhibitors for PBPs.

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Penicillin

These molecules will be synthesized and their potential PBP inhibitory and antibacterial activities will be investigated in both in vivo and in vitro experiments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PENICILLIN-RESISTANT NEISSERIA GONORRHOEAE (CMRNG) Principal Investigator & Institution: Nicholas, Robert A.; Pharmacology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 01-APR-1996; Project End 31-MAY-2006 Summary: Antibiotic resistance in Neisseria gonorrhoeae remains a very important problem. Penicillin and tetracycline, which were once the antibiotics of choice for treatment of gonococcal infections, are no longer used due to the preponderance of strains resistant to these agents. Resistance to currently recommended antibiotics is also increasing. My laboratory is interested in the mechanisms of chromosomally-mediated antibiotic resistance in the gonococcus, especially those that promote high- level resistance and subsequent treatment failure. Intermediate- level chromosomallymediated resistance to penicillin and tetracycline is due to three resistance loci. These include the penA gene encoding altered forms of penicillin-binding protein 2 (PBP 2), the mtr loci conferring resistance to hydrophobic agents, and the penB gene, which decreases outer membrane permeability. The genes involved in mediating high-level penicillin resistance, however, have been difficult to identify. Our work during the last funding period has identified two resistance genes, ponA and penC, which together mediate high- level penicillin resistance, and a third gene, tetGC, which confers highlevel tetracycline resistance. This proposal outlines experiments to clone and characterize the penC and tetGC genes and to elucidate the mechanisms by which they increase resistance. In addition, we propose experiments that follow up on our structure/function studies of the penB gene product, porin IB, to understand how mutations in this protein increase both penicillin and tetracycline resistance. We also propose studies to complete our work on the crystal structure of penicillin- binding protein 2 (PBP 2), an essential penicillin target, and several mutant forms that display a lower affinity for beta- lactam antibiotics. In addition, we will engage in new structural studies of wild-type and mutant forms of porin IB to explicate in molecular detail how mutations in this protein decrease antibiotic permeability. The combination of genetic, biochemical, biophysical, and structural approaches outlined in this proposal will provide important insight into the mechanisms by which this important human pathogen becomes resistant to antibiotics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEPTIDOMIMETICS ANTIBACTERIALS

OF

D-ALA-D-ALA

AS

NOVEL

Principal Investigator & Institution: Dunlap, Norma K.; Chemistry; Middle Tennessee State University Murfreesboro, Tn 37132 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): Although there are currently numerous antibacterial drugs on the market, many bacteria are becoming resistant to existing drugs, and the emergence of these drug-resistant microorganisms is a significant threat to public health. Virtually all classes of antibacterials in use have been circumvented to some extent by various resistance mechanisms and as a result there is a continual need for new structural classes of antibacterials. Penicillins are bacterial cell wall synthesis inhibitors and act by inhibition of Penicillin Binding Proteins (PBP's), also know as D-

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D-peptidases. The substrate for the D-D-peptidases is the cell wall peptidoglycan strand ending in D-alanine-D-alanine. However, penicillins and other drugs of that class were not designed to inhibit the D-D-peptidases. The objective of this application is to design and synthesize inhibitors of the D-D-peptidases as potential antibacterial drugs. Hydroxyethylene peptidomimetics of peptidic enzyme substrates such as the HIV protease substrate have been previously developed as drugs. A similar design concept should also apply to the D-D-peptidase substrate. The long-term objective of this project is to synthesize a series of peptidomimetics of the dipeptide D-alanine-D-alanine. These compounds will be tested for enzyme binding and for antibacterial activity. Various peptidomimetics have been designed and the syntheses of several have been initiated. Linear analogs of D-ala-D-ala containing a carboxylic acid will be synthesized, as will cyclopropyl analogs. Tetrazoles have been used successfully as bioisosteric replacements for the carboxylic acids in a number of drugs. An example is the angiotensin receptor antagonist Losartan. Along those lines, both linear and cyclopropyl analogs of D-ala-Dala containing a tetrazole as a replacement for the carboxylic acid will be synthesized and tested for enzyme binding and antibacterial activity. The proposed compounds constitute an entirely new structural class of potential antibacterials and as such should possess activity against resistant organisms. This would have a significant impact in the ability to treat bacterial infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHOTOSENSITIZATION MECHANISMS IN HYPOXIC MEDIA Principal Investigator & Institution: Redmond, Robert W.; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2001 Summary: Bacterial endospores derive much of their longevity and resistance properties from therelative dehydration of their protoplasts. This dehydration is maintained by a surrounding peptidoglycan structure, the spore cortex. A structural modification unique to,the spore cortex is removal of all or part of the peptide side chains from the majority of the muramic acid residues andconversion of 50% of the muramic acid to muramic lactam. A mutation in the cwLD gene of Bacillus subtilis, predicted to encode a muramoyl-L-alanine amidase, results in the production of spores containing no muramic lactam. These spores have normally dehydrated protoplasts but are unable to complete the germination/outgrowth process to produce viable cells. Our objective is a detailed understanding of formation and maintenance of a dormant, resistant bacterial (Bacillus subtilis) spore. The aims are: a) analyze the sequence, regulation and function of additional genes encoding penicillin-binding proteins (PBP); b) with strains lacking one or more PBPs, analyze the cortex structure and heat resistance of their spores; and c) identify the enzyme(s) initiating cortex hydrolysis during spore germination. Work being carried out with B. suhtilis should yield knowledge applicable to other Grampositive spore formers. The latter organisms are significant agents of food spoilage and food-borne human disease, largely because of the resistant nature of spores. Thus knowledge gained herein could have significant applications. Muropeptide structures are determined by amino acid/amino sugar analysis and NLAJ-DI-TOF MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PNEUMOCOCCAL INFECTION AND SICKLE CELL DISEASE Principal Investigator & Institution: Briles, d; University of Alabama at Birmingham Uab Station Birmingham, Al 35294

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Timing: Fiscal Year 2001 Summary: Pneumococcal sepsis is a major cause of death among young sickle cell disease (SCD) patients. In recent years prophylactic treatment of SCD patients with antibiotics Primarily penicillin) has been enormously successful at reducing death rates due to pneumoccal disease. The recent rise in the frequency of pneumococci resistant to multiple antibiotics, including penicillin, amy eventually eliminate the value of antibiotic prophylaxis. Our studies will address this problem in three ways. One will be to identify the patterns of antibiotic resistance among pneumococci threatening this population in an effort to alert physicians to necessary changes in the prophylactic antibiotic regimen. Another approach will be to continue to expand efforts to develop a vaccine containing PspA that could be used to prevent colonization and infection in these patients. Because PspA is a protein, it is immunogenic even in infants. PspA shows some serologic variation and a PspA vaccine will probably need to contain PspAs from several different strains to provide the broadest cross- protection. We will examine the diversity of PspA in isolates from SCD patients versus non-SCD patients so a vaccine can be formulated that will cover the PspA types present in strains causing the majority of pneumoccal infections in SCD patients. To permit the examination of large numbers of strains, we will develops new PCR and antibody typing systems based on sequence similarities in the major protection-eliciting region of PspA. We will also examine the clonal structure of pneumococci within capsular types to determine the degree to which different clones, and capsular types, may predominate in infections and/or carriage of SCD versus non-SCD patients. Our data will also permit identification of clones with differences in virulence and the elucidation of the genetic development of new clones with changes in virulence factors or antibiotic resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROLINE PATHOGENESIS

UPTAKE

IN

STAPHYLOCOCCUS

AUREUS

Principal Investigator & Institution: Schwan, William R.; Microbiology; University of Wisconsin La Crosse 1725 State St La Crosse, Wi 54601 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2005 Summary: Staphylococcus aureus is a significant human pathogen, which is the leading cause of surgical-wound infections and the second most frequent cause of nosocomial bloodstream infections in the United States. A significant number of cases of food poisoning are also linked to contamination of foodstuffs with S. aureus. Almost every tissue and organ within the human body is susceptible to infections by this species. Many of the current infections are caused by staphylococcal strains that are resistant to one or more antibiotics. Eighty to ninety percent of all S. aureus strains are resistant to the antibiotic penicillin and up to fifty percent of all strains isolated from patients in hospitals are resistant to methicillin. Recent outbreaks of community-acquired S. aureus possessing methicillin resistance and the emergence of vancomycin-resistant S. aureus strains mean that some strains may be untreatable by any antibiotic. Because S. aureus is able to infect so many different tissues within the human body, this grant proposes to study proline transport in S. aureus as a means to study the role proline transporters play in the pathogenesis of the bacteria. At least two proline transport systems are known for S. aureus. This grant proposes to identify the homolog of the ProP low affinity proline transporter and mutate the prop gene by allelic exchange or transposon mutagenesis with Tn917. With this proP mutant, a proPputP double mutant will then be created. Both the single and double mutants will be tested for proline transport differences in vitro and for their attenuation in animal models of infection. The

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regulation of the high affinity proline transport gene, putP, also will be tested in vitro in proline uptake assays and in vivo in several animal models of infection using a putP transcriptional fusion. The results of this study will help us understand the role of proline transport in S. aureus infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: QSAR CHROMATOGRAPHY

STUDIES

BY

LIPOSOME

ELECTROKINETIC

Principal Investigator & Institution: Khaledi, Morteza G.; Professor; Chemistry; North Carolina State University Raleigh 2230 Stinson Drive Raleigh, Nc 27695 Timing: Fiscal Year 2001; Project Start 01-APR-1989; Project End 31-MAY-2003 Summary: A primary goal of this project is to investigate the usefulness of Micellar Electrokinetic Capillary Chromatography (MECC) and Micellar Liquid Chromatography (MLC) for prediction of bioactivity through Quantitative Retention Activity Relationships (QRAR) and for quantitation of lipophilic character of molecules. The development of quantitative relationships between chemical structural properties and biological activity has had a tremendous impact in the fields of drug design, toxicology, and environmental monitoring. Our aim is to achieve a better understanding of the common underlying molecular interactions that influence retention in MECC and MLC and cause biological activity, partitioning into biomembranes, or binding to proteins. These goals will be realized through parallel studies of correlating MECC / MLC retention, octanol-water partition coefficient, proteins binding, and liposomes partitioning to the Solvatochromic Parameters of solutes through Linear Solvation Energy Relationships (LSER). In order to! fully explore the multidimensional nature of these problems, we will investigate the usefulness of the factor - based, multivariate analysis chemometric techniques such as principal component regression and partial least square in QRAR modeling. This research should lead to the development of unique methodologies for characterization of physicochemical properties of biomolecules. The combination of biomimicry of micellar aggregates due to their amphiphilic and organized nature, the enormous capabilities of MECC and MLC techniques in physicochemical analysis, their flexibility and versatility for incorporation of different types of interactions, and the computional power of the mutivariate analysis techniques for treatment of a large set of data in a multidimensional space should provide exciting opportunities in structure - activity modeling. Another major goal is to explore the enormous capabilities of these two micellar mediated techniques for solving complex bioseparation problems. We will take advantage of the predictive power of the quantitatve models that have been developed in our laboratory, and will extend the range of these models in order to achieve a better understanding of migration behavior of a variety of small biomolecules in MECC and MLC. This will include systematic studies of the chromatographic parameters that influence separation of solutes of general interest in bioanalysis, specifically pharmaceutically important compounds and small peptides. We will investigate the usefulness of computer assisted modeling and, simulation in developing rapid and effective methods for optimization of MECC and MLC separations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RAPID SAMPLING FOR RESISTANT S. PNEUMONAIE IN GUATEMALA Principal Investigator & Institution: Dueger, Erica; International Health; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218

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Penicillin

Timing: Fiscal Year 2003; Project Start 01-JAN-2004; Project End 31-DEC-2007 Summary: (provided by applicant): The purpose of this International Research Scientist Development Award is to provide Erica L. Dueger, DVM, PhD with a period of protected time for training and mentored research that will prepare her to pursue an independent career in international public health. Dr. Dueger is an assistant scientist at the Johns Hopkins Bloomberg School of Public Health (JHSPH) in the Department of International Health and is currently conducting field research on the epidemiology of Streptococcus pneumoniae at the Centro de Estudio y Control de Enfermedades (CECEN) at the Universidad del Valle de Guatemala. The candidate' s long-term goal is to contribute to the improvement of global health through research and policy development in infectious diseases and vaccinology. Following completion of this mentored research project and training period, Dr. Dueger will be positioned to compete successfully for NIH individual investigator funding and effectively and independently conduct collaborative, interdisciplinary research projects in disease surveillance and vaccinology worldwide. Through this grant, the candidate aims to develop a base of skills and knowledge that are critical to conducting large scale, community-based surveillance research and vaccine trials. Her goals are 1) to develop skills necessary to successfully transition from veterinary-focused research to international human public health research; 2) to obtain training in laboratory techniques, quality control assurance, Good Laboratory and Clinical Practices (GLP and GCP), and geographical information systems; 3) to develop grant writing skills; 4) to obtain fluency in Spanish; and 4) to gain practical experience in the conduct of population-based research in the developing world, particularly in the areas of infectious disease surveillance and vaccine trials. She plans to achieve these goals through a combination of coursework, intensive laboratory training, conferences and workshops, conversational Spanish classes, and a mentored research project. The primary objective for this application is to define the community prevalence of penicillin non-susceptible S. pneumoniae (PRSP) and to evaluate the impact of a protein-based vaccine on nasopharyngeal carriage of this organism. We will evaluate the feasibility of using lot quality assurance sampling (LQAS) methods to identify clusters of high PRSP prevalence and we will compare the prevalence and geographic distribution of PRSP in children < 2 years of age from different urban socioeconomic strata with rural areas of Guatemala. This will be accomplished by a series of cross-sectional surveys of nasopharyngeal samples in target socio-economic groups using both stratified random sampling and LQAS. The proposed project will take advantage of the infrastructure created by a large ongoing outpatient surveillance study at CECEN evaluating the incidence of invasive pneumococcal disease in Guatemala City, as well as a CECEN Phase II clinical trial to evaluate a protein based S. pneumoniae vaccine in infants. In the latter part of the award, the proposal will test the feasibility of using LQAS sampling methodologies to determine prevalence of PRSP from selected urban zones and rural departments of Guatemala. The study will provide crucial information for the development of models for community transmission dynamics of drug-resistant S. pneumoniae in Guatemala. These models and study methods will be used to identify intervention points for at risk populations and to evaluate strategies, including vaccines, for the control of PRSP. As such, this proposal addresses an emerging and rapidly increasing public health problem in many developing countries, including Guatemala. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RECOMBINANT/NATIVE GABAA RECEPTORS Principal Investigator & Institution: Macdonald, Robert L.; Professor; Neurology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 01-MAY-1995; Project End 31-JUL-2001 Summary: (from applicant's abstract) GABA is the major inhibitory neurotransmitter in the brain. Fast inhibitory post-synaptic potentials are mediated by GABAA receptors (GABARs), which contain binding sites for many clinically relevant drugs such as benzodiazepines, barbiturates, and general anesthetics. GABAR currents are also modulated by neurosteroids and lanthanum and antagonized by penicillin, picrotoxin, bicuculline, furosemide, and zinc. The GABAR is a hetero-oligomeric protein complex composed of five subunits which together form a transmembrane chloride ion channel. Four different subunit families (alpha, beta, gamma, delta) have been studied extensively and two new subunit families pi and epsilon have been identified recently. Each subunit family is composed of one or more subtypes. Six alpha (alpha1-alpha6), three beta (beta1-beta3), three gamma(gamma1-gamma3), and delta(delta1), one e (e1) and one pi(pi1) subunit subtypes have been identified. Pharmacological studies of recombinant receptors have shown that individual subtypes confer different sensitivities to GABAR modulators such as benzodiazepines, barbiturates, propofol, loreclezole, alcohol, furosemide, zinc, other divalent cations and lanthanum. The hypotheses to be tested are the following: 1) GABAR subunit subtypes contain binding and modulatory sites that are subtype specific. 2) Allosteric modulators bind to N-terminal, extracellular portions of M2 or M2-M2 extracellular domains. 3) Binding of allosteric modulators bind to a restricted number of amino acid residues on these extracellular domains. 4) The kinetic properties of GABARs, including gating and desensitization, are subunit subtype specific. 5) Specific functional domains are present in the transmembrane portion of GABAR subunit subtypes that determine their kinetic properties. The specific aims are to determine: 1) Binding site(s) on GABAR beta and/or alpha subtypes for zinc and other divalent cations. 2) Modulatory sites on alpha, gamma, delta, and epsilon subtypes that regulate sensitivity to zinc and other divalent cations. 3) Binding sites on GABAR subtypes for lanthanum enhancement and inhibitions of GABAR current. 4) Binding sites on GABAR subtypes for furosemide inhibition of GABAR current. 5) Binding sites on GABAR subtypes for barbiturate enhancement of GABAR current and direct activation of current. 6) Biophysical properties of recombinant GABAR isoforms assembled from GABAR subtypes that are expressed in hippocampal dentate granule cells. 7) Structural bases for the biophysical properties of recombinant GABAR isoforms that are assembled from GABAR subtypes expressed in hippocampal dentate granule cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REFINEMENT OF PENICILLIN TARGET ENZYME Principal Investigator & Institution: Kelly, Judith A.; Mellon Pitts Corporation (Mpc Corp) Pittsburgh, Pa 152133890 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF AMPICILLIN RESISTANCE IN E FACEIUM Principal Investigator & Institution: Rice, Louis B.; Professor; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 28-FEB-2005 Summary: (Verbatim from Applicant's Abstract):The dramatic rise in prevalence of multi-resistant enterococci in United States hospitals over the past decade has limited therapeutic options, affected morbidity and mortality and increased the cost of caring for seriously ill hospitalized patients. The expression of resistance to vancomycin has received the most attention during this time. However, it is equally problematic that virtually all vancomycin-resistant enterococci (VRE) are Enterococcus faecium that express resistance to high levels of ampicillin. While it is clear that ampicillin resistance in E. faecium requires expression of low affinity penicillin-binding protein 5 (PBP5), the correlation between the amounts of detectable PBP5 and the level of ampicillin resistance is not exact. Several point mutations in pbp5 have been identified in strains expressing high-level ampicillin resistance, but the specific contributions of these mutations to the levels of resistance have never been assessed. We have identified the first transferable ampicillin resistance described from E. faecium in a VRE strain from Northeast Ohio. The pbp5 gene conferring resistance in this isolate possesses several mutations that have been associated with high-level ampicillin resistance in other E. faecium isolates. Curiously, levels of ampicillin resistance expressed by transconjugant E. faecium strains are not equivalent to those expressed by the donor, despite documentation that equivalent amounts of PBP5 are produced. In the past two years, we have acquired evidence that levels of ampicillin resistance expressed correlate with transcription (but not necessarily translation) of an upstream open reading frame designated ftsWEf. The specific aims of this proposal are to: 1) perform site directed mutagenesis of E. faecium pbp5 to determine the functional (MIC, affinity) and structural importance of specific mutations. With collaborations in France and Switzerland, we now possess the molecular expertise to create the mutants and analyze their functional impact and determine the crystal structure; 2) to investigate the role of the putative upstream repressor psr in regulating expression of ampicillin resistance in E. faecium; 3) to investigate the mechanisms by which transcription of ftsWEf impacts the levels of ampicillin resistance expressed by E. faecium; 4) to assess whether upstream open reading frames designated nanE-Ef and ywrF-Ef affect levels of ampicillin resistance expressed and 5) to determine whether the peptidoglycan precursors differ in sensitive and resistant strains. These investigations will yield new insights into what is arguably the most resistant nosocomial pathogen of our time by providing important structure-function correlations for PBP5, correlations which may be important for the development of newer and better inhibitory compounds. They will also yield important new information on mechanisms of cell wall synthesis in E. faecium and other Gram-positive bacteria as well as on the mechanisms by which ampicillin resistance in E. faecium is regulated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RISK FACTORS FOR DRUG RESISTANT PNEUMOCOCCAL PNEUMONIA Principal Investigator & Institution: Metlay, Joshua P.; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2004

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Summary: Adapted from the Applicant's Abstract): The emergence of antimicrobial drug resistance among isolates of S. pneumoniae threatens to have a major impact on the management of patients with community-acquired pneumonia (CAP). S. pneumoniae is the most common cause of CAP and adequate pneumococcal coverage is at the center of empirical guidelines for the management of this disease. Yet, risk factors for infection with drug-resistant vs. drug-susceptible S. pneumoniae are controversial and the clinical impact of in vitro levels of resistance is poorly understood. This study will focus on resistance to penicillin because penicillin and related ,8-lactam antimicrobials are a major component of current empirical treatment options for patients with CAP. Thus, understanding the risk factors for penicillin resistance can make a major contribution to the empirical management of these patients. The primary aim of this study is to identify risk factors for penicillin drug resistance in patients with bacteremic pneumococcal pneumonia. The primary study hypothesis is that both individual and community risk factors independently predict infection with penicillin resistant S. pneumoniae in patients with bacteremic pneumococcal pneumonia. A secondary hypothesis is that the duration of prior antibiotic use is a strong independent predictor of penicillin resistance in these patients. The secondary aims of this study are (1) to develop a prediction rule for penicillin resistance in patients with bacteremic pneumococcal pneumonia and (2) to measure the impact of different levels of penicillin resistance on medical outcomes in these patients. The hypotheses for these secondary aims are that (1) a prediction rule can be developed which accurately categorizes patients into high and low risk groups in order to improve the empirical selection of antimicrobial therapy for patients with CAP and (2) the in vitro level of penicillin resistance, alone, is a poor predictor of medical outcomes, but categorization of the adequacy of antimicrobial drug coverage, based on drug susceptibility profiles and pharmacodynamic drug considerations, will be a strong predictor of medical outcomes. This study is a population-based, case-control study, enrolling all hospitalized patients diagnosed with bacteremic pneumococcal pneumonia within the Pennsylvania Delaware Valley. Risk factors will be identified through patient interview and outpatient and inpatient medical record review. Pneumococcal drug resistance will be categorized at our microbiology laboratory with standardized susceptibility testing of all pneumococcal blood isolates. Finally, a cohort study will be completed within the study design, by examining outcomes for all patients, stratifying by pneumococcal drug susceptibility and adequacy of antimicrobial drug coverage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF PENICILLIN BINDING PROTEIN 1A IN GBS VIRULENCE Principal Investigator & Institution: Rubens, Craig E.; Professor; Children's Hospital and Reg Medical Ctr Box 5371, 4800 Sand Point Way Ne, Ms 6D-1 Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 15-JUL-2002; Project End 30-APR-2007 Summary: (provided by applicant): Group B streptococci (GBS) remain the most significant bacterial pathogen causing neonatal sepsis, pneumonia and meningitis in the USA despite CDC-recommended chemoprophylaxis strategies for preventing infection due to this organism. Apart from the capsule, the factors required for survival of GBS in the host are not well defined. Recently, signature-tagged transposon mutagenesis (STM) was used to identify genes required for growth and survival of GBS in a neonatal rat sepsis infection model. A significant proportion of the avirulent mutants had transposon insertions in genes involved in cell surface metabolism emphasizing the significance of these functions for in vivo survival of GBS. We characterized the most attenuated mutant from the cell-surface metabolism group, which had a transposon insertion in a

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Penicillin

putative penicillin-binding protein gene (ponA) homologue. Based on sequence homology, the disrupted GBS gene is predicted to code for a class A, high molecular weight penicillin-binding protein (PBP1a), possessing both transglycosylase and transpeptidase activity. These bifunctional enzymes catalyze both the polymerization and cross-linking of bacterial peptidoglycan. The PBP1a gene mutant was significantly attenuated in both competitive index and 50 percent lethal dose assays of GBS virulence in neonatal rats. Additionally, the PBP1a gene mutant displayed a significant defect in resistance to opsonophagocytic killing as measured by in vitro bactericidal assays. Complementation analysis in vivo confirmed that the altered phenotypes observed in the mutant were due to the transposon insertion in ponA. The PBP1a gene mutant had a normal growth rate in vitro, produced wild-type levels of capsular polysaccharide and was otherwise phenotypically identical to the parent strain. We hypothesize that the GBS ponA gene is required for resistance to opsonophagocytic killing in vitro and virulence in vivo. Our investigation seeks to define the role of PBP1a in interactions with the host and virulence of GBS in vivo. Aim 1 will complete analysis of the ponA gene and the prfA gene (penicillin binding protein related factor A), a gene cotranscribed with ponA. A nonpolar prfA deletion mutant will be constructed and subjected to phenotypic analysis. Aim 2 will use genetic and biochemical approaches to define the structure and function of the PBP1a protein. Site-directed mutations that disrupt enzymatic activity of the protein will be introduced into PBP1a. Analysis of these mutants will allow us to evaluate whether enzymatic activity of the protein is required for virulence and resistance to opsonophagocytic killing. Aim 3 will determine the role of the PBP1a protein in resistance of GBS to opsonophagocytic killing by investigating the interaction of aponA mutant with serum opsonins and phagocytic cells. While bacterial cell-wall associated enzymes, including PBPs, have been reported to be required for virulence in numerous animal models of infection, no mechanism has been proposed to explain these observations. These studies will be the first to systematically investigate the role of PBP1a in virulence, will further our understanding of the pathogenesis of GBS infections, and may identify targets for preventative or therapeutic modalities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SAFE ALTERNATIVE SOLVENTS FOR ANTIBIOTICS EXTRACTION Principal Investigator & Institution: Clark, Jennifer F.; Eltron Research, Inc. 4600 Nautilus Ct S Boulder, Co 803013241 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-MAR-2002 Summary: (provided by applicant): This research will result in identification of nonvolatile, non-flammable room temperature ionic liquids (RTIL's) to replace the toxic, flammable, volatile organic compound (VOC) solvents used for extraction of antibiotics from fermentation broths. The solvents used for penicillin extraction include methyl isobutyl ketone, amyl acetate, butyl acetate, and chloroform. These solvents are toxic, irritants, volatile, and extremely flammable. RTIL's have attracted significant attention for green chemistry applications. They are ionic compounds that have very large liquids ranges. Some are air and water stable and immiscible with water. They solubilize aromatics and carbonyls particularly well, so should be effective for antibiotics extraction. RTIL's have been studied for liquid-liquid extraction and other separations. Being non-volatile, they are recyclable, and their large liquids ranges allow efficient separations using temperature control. They are non-flammable. They are "tunable" solvents, as the cations can be substituted and/or paired with different anions to manipulate the properties of the liquids and tailor them for specific applications. The

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use of RTIL's instead of the toxic, flammable, VOC solvents now used would improve the health and safety of pharmaceutical workers, and reduce costs, since they are straightforward to synthesize, and are recyclable. New processes or equipment would not be required. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SPORE PEPTIDOGLYCAN SYNTHESIS IN BACILLUS SUBTILIS Principal Investigator & Institution: Popham, David L.; Assistant Professor; Biology; Virginia Polytechnic Inst and St Univ 460 Turner Street, Suite 306 Blacksburg, Va 24060 Timing: Fiscal Year 2001; Project Start 01-JAN-1998; Project End 31-DEC-2002 Summary: The long-term objectives of the proposed studies are: 1) characterization of the enzymatic activities and gene products involved in synthesis of the peptidoglycan cell wall of bacterial endospores and 2) examination of the role of each type of peptidoglycan structural modification in determining endospore resistance properties. The specific aims are: 1) to determine the structure of the endospore peptidoglycan in the first stages of its synthesis and to track the structure to its final form in the dormant spore; 2) to identify the changes in synthesis of this structure produced by loss of penicillin- binding proteins, autolysins, and sporulation-associated gene products; and 3) to purify and characterize in vitro an enzyme involved in peptidoglycan side chain cleavage and muramic-lactam production. Knowledge of principles of endospore resistance properties, dormancy,and longevity may contribute to better decontamination methods and methods for storage and transport of drugs and vaccines. Peptidoglycan synthesis in general is an attractive target for antibiotic action, further studies of this process will contribute to methods for identification of new antibiotics. Peptidoglycan will be purified from sporulating cultures of Bacillus subtilis by chemical and enzymatic treatments, digested with muramidase, and analyzed by high-pressure liquid chromatography (HPLC) using methods previously developed for analysis of dormant sport peptidoglycan. Novel muropeptides will be identified using amino acid analysis and mass spectrometry. Appearance and loss of peptide side chain alanine and glycine residues, muramic- lactam production, and changes in peptide cross-linking will be quantified throughout the sporulation process. The analysis will be repeated using strains lacking individual penicillin-binding proteins, autolysins, and sporulationassociated gene products. The cwlD gene product will be purified and assayed in vitro for muramoyl-L-alanine activity and for muramic-lactam synthesis. Immature peptidoglycan samples from mutant strains and purified muropeptides will serve as substrates in these assays. Reaction progress will be monitored using the HPLC method and by adaptation of the method to capillary electrophoresis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STAPHYLOCOCCAL METHICILLIN RESISTANCE LOCUS Principal Investigator & Institution: Archer, Gordon L.; Professor of Medicine and Microbiology/i; Internal Medicine; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2001; Project Start 01-APR-1994; Project End 31-DEC-2003 Summary: Staphylococci causing hospital-acquired infections are increasingly resistant to multiple antimicrobial agents. The trait that defines the multidrug-resistant phenotype is resistance to beta-lactam or methicillin resistance (MR). The chromosomal gene responsible for MR, mecA, encodes a penicillin binding protein with low betalactam affinity. MecA is found only in resistant isolates, is common to all resistant

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staphylococcal species and is accompanied by >30 kb of DNA (mec DNA) that is also unique to resistant isolates. Contained within the mec DNA, just 5' to mecA, are two genes, mecRI and mecI, that regulate the transcription of mecA. This proposal will investigate the regulation of mecA by mecRI and mecI; the contribution of regulation to phenotype; and the mutations, insertions, deletions and rearrangements of mecassociated DNA that alter regulatory genes in clinical isolates. In addition, the organization and extent of the entire mec locus will be determined in three staphylococcal isolates. The regulatory loci will be cloned by PCR from wild isolates of defined phenotype and introduced into a MR S. aureus strain with deleted regulatory genes. The contribution of intact and altered regulatory genes to phenotypic resistance and mecA expression will be investigated; induction will be studied by analyzing mRNA transcripts and the PBP2A gene product; the specific role of mutations in determining phenotype will be assessed by making mecR1-mecI fusions; and the failure of reporter gene induction will be used to locate additional inactivated chromosomal regulatory loci. The total extent and composition of mec DNA will also be determined among MR S. aureus and coagulase-negative staphylococci by cloning large, overlapping DNA fragments and DNA sequencing and PCR amplification, generating probes that can be used to compare mec restriction fragment length polymorphisms among a large number of clinical MR isolates. These studies will help to define the role of specific mec-associated DNA in the expression of resistance; identify other regulatory circuits involved in signal transduction; further assess the clonality of MR staphylococci and identify specific DNA sequences that can be used for assessing the molecular epidemiology of hospital-acquired staphylococci. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STREPTOCOCCAL CHEMOATTRACTANTS

INACTIVATOR

IN

HUMAN

Principal Investigator & Institution: Cleary, Paul P.; Professor; Microbiology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 01-SEP-1997; Project End 31-DEC-2006 Summary: (provided by applicant): This project is an attempt to understand the mechanism by which group A streptococcus modulates host defenses. These streptococci have evolved proteins including the C5a peptidase that destroys C5a, an important early signal that attracts protective phagocytes to infected tissue. The recent discovery that the peptidase is also a fibronectin and cell-binding protein has become a significant new focus. Experiments are planned to evaluate the importance of these activities, relative to peptidase activity in virulence using intranasal and subdermal mouse models of infection. Recognition that penicillin often fails to eliminate group A streptococci from throats of ill children and the recent resurgence of serious complications associated with streptococcal infections, has prompted an intense effort to develop preventive vaccines by industry and NIH. The C5a peptidase is a major focus of vaccine development, increasing the need to learn more about its role in virulence, and its impact on host defenses. New data indicates that the C5a peptide required for successful colonization and persistence of streptococci in nasal associated lymphoid tissue. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STREPTOCOCCUS SANGUIS MICROBIAL GENOME PROJECT Principal Investigator & Institution: Macrina, Francis L.; Director and Professor; Oral and Maxillofacial Surgery; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 30-JUN-2003 Summary: (Adapted from the Investigator's Abstract): The investigators propose to determine the nucleotide sequence of the genome of Streptococcus sanguis. This member of the human indigenous oral microflora has long been recognized as a key player in the bacterial colonization of the mouth. It directly binds to oral surfaces and serves as a tether for the attachment of a variety of other oral microorganisms which colonize the tooth surface, form dental plaque, and contribute to the etiology of both caries and periodontal disease. Furthermore, S. sanguis has been long recognized as a leading cause of bacterial endocarditis, a disease of high morbidity which is fatal if untreated. Moreover, S. sanguis and other viridans streptococci of the mouth are emerging as life-threatening bloodstream pathogens in neutropenic patients. And such infections are being compounded by the increasing frequency with which penicillin resistance is being observed in this group of organisms. New knowledge about this organism could be used in controlling oral microbial colonization so as to minimize or eliminate plaque-related oral diseases. Since the mouth is the source of S. sanguis isolates that cause endocarditis and bacteremia, novel controlling strategies also would have an impact on systemic infections. S. sanguis genomic data will provide new insights into this organism's lifestyle and virulence properties that cannot be extrapolated from analyzing the genomic data of even closely related species. The investigators believe that the complete genomic structure of S. sanguis is certain to lead to the discovery of new genes, insights into their regulation, and an appreciation of their interactions at both the genotypic and phenotypic levels. This, in turn, will provide researchers with new targets for vaccines and rationally designed drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRUCTURAL /FUNCTIONAL ANALYSIS OF SFID REGION OF E. COI Principal Investigator & Institution: Mcpartland, Ann A.; California State University Hayward Hayward, Ca 94542 Timing: Fiscal Year 2001; Project Start 01-SEP-1993; Project End 31-MAY-2005 Description (provided by applicant): The overall aim of this project is to probe the mechanisms regulating cell division in Escherichia coli. In virtually all cell types, cell division is strictly controlled; periods of cell growth, DNA duplication and chromosome partitioning always precede cytokinesis. Yet the mechanisms by which these processes are coordinated are poorly understood. E. coli provides a relatively simple model system for studying cell division. An understanding of how division is regulated should eventually lead to an explanation of how DNA replication, chromosome partitioning and cell division are coordinated. This information could prove valuable in the search for ways of blocking uncontrolled growth and division in eukaryotic cells. The sfiD gene appears to play a role in regulating cell division in E. coli. Insertions of the IS1 transposon into an adjacent, upstream site confer mutant phenotypes that can be complemented by the sfiD+ gene. These include normal division in the presence of the inducible division inhibitors SulA and SfiC, cold sensitivity for growth and sensitivity to beta-lactam antibiotics. A number of the proposed experiments are directed toward analysis of the transcription patterns in the sfiD region. These include the use of RT-PCR

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and primer extension to define the sfiD mRNA(s) in normal and mutant cells. The effect of deleting potential regulatory sites on transcription initiated at the sfiD promoter will also be examined. In other experiments the SfiD protein will be purified and its structure, cellular location and stability compared in normal and mutant cells. As a means of understanding how upstream IS1 insertions alter sfiD, the sequence changes in revertants carrying second site mutations linked to sfiD will be determined. Other unlinked second site mutations will be mapped with a view toward identifying proteins that interact with SfiD. Placement of the division complex will be examined in revertants exhibiting altered morphology. Finally, the penicillin binding proteins will be compared in normal and mutant cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURAL GENOMICS OF S. AUREUS PATHOGENICITY ISLANDS Principal Investigator & Institution: Ohlendorf, Douglas H.; Professor; Biochem/Mole Biol/Biophysics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 15-MAR-2002; Project End 28-FEB-2006 Summary: (provided by applicant): Staphylococcus aureus is a primary human pathogen and a leading cause of hospital-acquired infections (over 700,000 annually), food poisoning, sepsis, and toxic shock syndrome. Currently more than 90 percent of community-isolated strains of S. aureus are resistant to penicillin or its derivatives. The ubiquity of S. aureus and its ability to rapidly develop antibiotic resistance have prompted monitoring by the WHO, the CDC and others. Understanding the basis for the pathogenicity of S. aureus opens the door to the development of new therapeutics to combat infectious diseases produced by this organism. S. aureus produces a number of virulence factors. Sequencing of strains of S. aureus has shed light into how the genes for these factors are organized. Recent studies have revealed that the genes for a number of the pyrogenic toxin superantigens are located on mobile genetic elements called pathogenicity islands that are about 16 kb in size and flanked by direct repeats. Recent microarray analysis of S. aureus pathogenicity island 3 (SaPI3) from strain MN NJ has shown that mRNA is produced for 21 of the 23 ORFs examined. In SaPI3 only 6 of these open reading frames (ORFs) encode for proteins whose sequences are homologous to proteins with a known structural fold. The goal of this project is to use the structural genomics paradigm to investigate the SaPI3 ORFs. If soluble protein cannot be isolated or crystallized for a particular ORF, orthologs from other pathogenicity islands (6 S. aureus pathogenicity islands have been identified to date) will be expressed and studied. Functional hypotheses derived from the structures and analyses of ORF null mutants will be tested using assays by the principal investigator and his collaborators. The principal investigator has been working on gram-positive pathogens since 1993. Since then workers in the laboratory have determined the structures of staphylococcal toxic shock syndrome toxin-1 (wild type and 8 mutants), of streptococcal pyrogenic exotoxin A, and of staphylococcal exfoliative toxins A and B. Progress toward the goals to this proposal include cloning 22 ORFs of SaPI3, the production of soluble protein from 7 ORFs and the crystallization of proteins from 3 ORFs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRUCTURAL STUDIES OF BACTERIAL HYALURONATE LYASE ENZYME Principal Investigator & Institution: Jedrzejas, Mark J.; Microbiology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 08-MAY-2001 Summary: The objective of this research proposal is to develop a better understanding of the structural properties and mechanism of action of S. pneumoniae hyaluronate lyase enzyme. The long term objective is to better understand the mechanism of invasion of host tissue and the penetration of host defenses by S. pneumoniae and other Grampositive bacteria. Such understanding may lead to the development of new antibacterial therapeutic agents. S. pneumoniae is the most common cause of fatal pneumonia in the elderly, and it is one of the most common causes of middle ear infections and meningitis in children. The present vaccine consists of a mixture of 23 different capsular polysaccharides. While this vaccine is very effective in young adults, it is only about 60 percent effective in the elderly. In children less than 2 years of age the vaccine is ineffective and is not recommended due to the inability of this age group to mount an antibody response to the penumococcal polysaccharides. Antimicrobial drugs such as penicillin have diminished the risk of pneumococcal disease. However, in most parts of this country, up to 35 percent of pneumococcal strains are now resistant to penicillin and the frequency of multidrug resistant strains is steadily increasing. It has been recently suggested that certain pneumococcal proteins such as hyaluronate lyase, pneumolysin, and pneumococcal surface protein A (PspA) could be used as potential vaccine or drug targets for development of new cure. Hyaluronate lyase is a major surface protein of S. pneumoniae with possibly antigenetically variable properties that might be essential for full pneumococcal virulence. Thus, hyaluronate lyase might represent one of the best alternatives for a pneumococcal vaccine or drug target especially when combined with other pneumococcal virulence factors such as PspA or pneumolysin. We have expressed in E. coli, purified, and crystallized fully active forms of hyaluronate lyase enzyme from S. pneumoniae and Group B Streptococcus. The specific aims of the research proposed in this application are directed towards: a) the determinatin of the crystal structure of the hyaluronate lyase enzyme; b) thoroughly characterizing the properties and mapping the active site of this enzyme utilizing oligonucleotide mediated site directed mutagenesis. The results will enhance our knowledge about mechanisms involved in the action of the enzyme and in the pathogenesis of S. pneumoniae bacteria. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRUCTURE/FUNCTION OF ENGINEERED B LACTAMASES Principal Investigator & Institution: Herzberg, Osnat; Professor; None; University of Md Biotechnology Institute Baltimore, Md 212023101 Timing: Fiscal Year 2001; Project Start 01-JAN-1989; Project End 31-DEC-2002 Summary: The susceptibility of pathogenic bacteria to penicillins and related compounds has been greatly reduced because of the production of beta-lactamases, a group of enzymes that hydrolyze the beta-lactam amide bond characteristic of these antibiotics. The rapid increase in multi-resistant infectious bacteria, together with the prevalence of patients whose immune system has been compromised underscores the urgency of recovering the effectiveness of antibiotics in general, and of beta-lactam therapy in particular. Future design of novel drugs will benefit from the understanding o the mechanism of two enzyme families: the beta- lactamases - the penicillin-degrading

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enzymes; and the peptidases involved in bacterial cell-wall synthesis and repair - the penicillin-binding proteins. The plasmid mediated class A beta-lactamases have emerged in recent years as the group of enzymes that evolve most rapidly when betalactam antibiotics are introduced. The proposed studies will investigate the structural basis for the activity an evolution of these enzymes, using the class A beta-lactamase from Staphylococcus aureus PC1 as a model system. Questions about the catalytic mechanism, substrate specificity, and stability of the enzyme will be addresse by engineering variant molecules and analyzing them by biochemical and X-ray crystallographic methods. The structures of acyl-enzyme complexes with representative substrates will be determined so that insight into the basis fo substrate specificity at the atomic level will be gained. The evolutionary lin between the class A and the class C beta-lactamases, and between these beta-lactamases and the cell-wall peptidases will be investigated by designing specific changes that will convert the protein from a class A enzyme into one of the other related enzyme families. The design is structurally driven, based on analysis of crystal structures of representative members of each family. A mutant beta-lactamase that has lost its ability to hydrolyze beta-lactams and instead is inhibited by these compounds will be further altered to introduce a new deacylation mechanism that resembles that of the class C beta-lactamases. This mutant and the native proteins will serve as the parent molecules for engineering a carboxypeptidase activity toward D-Ala-D-ala peptide, the natura substrate of the bacterial cell wall peptidases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTHRACIS

TARGET

AND

ANTIBIOTIC

DISCOVERY

Principal Investigator & Institution: Youngman, Philip Pharmaceuticals, Inc. 3510 Dunhill St San Diego, Ca 921211212

J.;

IN

BACILLUS

Professor;

Elitra

Timing: Fiscal Year 2002; Project Start 15-JUL-2002; Project End 14-FEB-2004 Summary: (provided by applicant): By simply growing Bacillus anthracis in the presence of sub-inhibitory concentrations of antibiotics it has been made resistant to all commonly used drugs such as penicillin, doxycycline and Ciprofloxacin. If one of these antibiotic resistant strains were used in a future terrorist attack there will be limited or no therapeutic treatments available. Thus there is an urgent need to develop new classes of antibiotics to treat resistant B. anthracis. A shotgun antisense technology is proposed for the rapid identification of B. anthracis essential genes, whose protein products can serve as targets for new classes of antibiotics. This technology conditionally and incrementally reduces the level of an essential gene product, which provides a means to hypersensitize cells to compounds that inhibit that target and thus provides a cell-based assay for drug discovery. Phase I of this proposal will be to develop the molecular biology tools for conditionally delivering random genomic antisense RNA fragments to B. anthracis cells. In Phase II a genome-wide screen in B. anthracis will identify a comprehensive list of essential genes. We have developed a unique microbial relational database, which allows the prioritization of targets based on conservation among bacterial pathogens having no or limited homology to human proteins. Bioinformatics analyses undertaken prior to drug screening should help ensure that new antimicrobial drugs have maximal impact upon the disease and minimal impact on the patient. Cellbased assays will be optimized for these prioritized targets and entered into an established high throughput chemical screening program against the company's chemical library of over 250,000 compounds. This Gene-to-Screen technology platform has been developed to allow miniaturized drug screens to be developed for any

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validated target within 2-3 weeks. Promising hit compounds would then be rapidly developed and advanced into lead-optimization chemistry. New classes of antibiotics would help deter and treat against future bioterrorist attacks and could also be used to treat common drug resistant pathogens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE MOLECULAR CONTROL OF BACTERIAL AUTOLYSIS Principal Investigator & Institution: Bayles, Kenneth W.; Associate Professor; Microbiol/Molec Biol & Biotech; University of Idaho Moscow, Id 838443020 Timing: Fiscal Year 2003; Project Start 01-JUL-1997; Project End 31-DEC-2007 Summary: (provided by applicant): Studies of the Staphylococcus aureus lytSR regulatory locus have led to the identification of a complex regulatory system that controls the activity of peptidoglycan hydrolases produced by the cell. One component of this regulation is the IrgAB operon whose expression has been shown to inhibit murein hydrolase activity and cause tolerance to penicillin. It has been proposed that the products of this operon function in a manner analogous to bacteriophage-encoded antiholins, which are membrane-associated proteins that inhibit peptidoglycan hydrolase activity at the postranslational level. Recently, homologous proteins encoded by the S. aureus cid operon have been identified and studied. Preliminary experiments indicate that this operon encodes the holin component of this system that enhances peptidoglycan hydrolase activity and increases sensitivity to penicillin. The possibility that the Irg and cid operons are involved in a bacterial programmed cell death (PCD) mechanism has been indicated since the cid mutant exhibits tolerance to other bactericidal agents besides penicillin. These include rifampicin and mitomycin C, which have distinct cellular targets suggesting that this system responds to nonspecific cellular stress by inducing cell death. The recent finding that cid expression is dependent on the alternate stress response sigma factor, Sigma B, strengthens this hypothesis. The experiments described in this proposal are based on four specific aims. The first aim utilizes a genetic approach to explore the role the cid and Irg gene products during the bactericidal response to antibiotics and biocides. The second aim includes flow cytometric studies of membrane potential and cell wall pH designed to more clearly define the roles of the cid and Irg gene products in the regulation of murein hydrolase activity. Purification and analysis of the cid and Irg gene products is the third aim of this proposal with the goal of defining the interactions of these proteins prior to and during cell death. Finally, the fourth aim will study the regulation of cid transcription using molecular strategies to examine the kinetics of cid expression, the cis-acting elements necessary for normal regulation, and the role of a putative transcription activator protein. The long-term objectives of this study are to establish the roles that the Irg and cid operons play in the molecular control of bacterial PCD and to explore novel new therapeutic strategies to combat bacterial infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VACCINE EFFICACY IN CHILDREN WITH SICKLE CELL DISEASE Principal Investigator & Institution: Adamkiewicz, Thomas V.; Pediatrics; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2001; Project Start 12-JUL-2000; Project End 30-JUN-2005 Summary: The applicant proposes a comprehensive program for development as a clinical investigator, reflecting his interest and expertise in pediatric infectious diseases and pediatric hematology. Under the mentorship of Dr Jim Eckman, a senior Nationally

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recognized investigator in the area of Sickle Cell Disease, and co- mentorship of two investigator in pediatric infectious disease at Emory University, the applicant will pursue a focused clinical research project and will receive formal and practical instruction in all aspects of clinical investigation. The rich academic environment, including the Emory University School of Medicine and School of Public Health (SPH), the Centers for Disease Control and Prevention (CDC), one of the country's largest comprehensive pediatric SCD clinics and the Emory Vaccine Center, is a remarkable resource for the applicant's optimal development as a pediatric clinical investigator. The applicant is interested in developing more effective prevention strategies of Streptococcus pneumoniae infections in children with sickle cell disease (SCD), inasmuch as these infections remain a major cause of morbidity and mortality in these children. In a recent prospective multicenter survey, the applicant has shown that over 40 percent of S. pneumoniae isolates in children with SCD are now no longer susceptible to penicillin. This rapid increase in penicillin resistance warrants evaluation of more effective prophylaxis of S. pneumoniae infections, to be used in addition to or possibly instead of penicillin prophylaxis. The hypothesis of the applicant project is that protein conjugated vaccines will offer effective protective immunity to children with SCD against S. pneumoniae infections. To test this hypothesis the applicant will conduct a prospective study of the efficacy of this protein conjugate vaccine in pediatric SCD patients. To facilitate this project, the applicant has organized a collaborative network of several major pediatric SCD centers and enlisted the collaboration of senior pediatric clinical investigators who direct those centers. The specific aims of this project are to estimate the conjugate vaccine efficacy in children with SCD by comparing rates of S. pneumoniae infections occurring before and after vaccine introduction in the general population (expected licensure in 2000). In this once in a life time "natural" experiment, the applicant will characterize the specific S. pneumoniae isolates, including serotype distribution and antibiograms. The applicant will also evaluate immunity by laboratory assays (ELISA, functional, and T and B cell memory) following vaccination in children with SCD. This project will be conducted within the framework of a recently formed and CDC funded Emory Consortium (PI: Dr Harry Keyserling). Results from these studies will provide the foundation for future clinical care recommendations to prevent this most lethal complication of childhood SCD. Through the course of this trial, the applicant will enhance and develop clinical research expertise by interactions with colleagues at the CDC and the National Institutes of Health, and with vaccine trial researchers and members of the pharmaceutical industry. To complement his stewardship of a focused clinical research project, he will participate in didactic coursework offered by the Emory University SPH, including biostatistics, epidemiology, clinical trial design, and information systems/database management. Practical instruction in the ethics of informed consent and evaluation of clinical trial design and methods will be obtained through an internship at the Human Investigations Committee of Emory University. A motivated and creative applicant, dedicated mentorship, formal educational opportunities, and an innovative clinical study are factors that indicate the tremendous potential for the applicant's successful career development as a thoughtful, well-trained pediatric clinical investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VARIABLE GENE USE AND PNEUMOCOCCAL IMMUNITY IN AIDS Principal Investigator & Institution: Pirofski, Liise-Anne A.; Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 30-JUN-2005

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Summary: (adapted from abstract of applicant): Human antibodies to capsular polysaccharide of Streptococcus pneumoniae (PPS) express genes from the VH3 gene subgroup. SinceVH3 gene expression is often reduced in the setting of HIV infection and PPS-derived vaccines are poorly immunogenic in HIV-infected individuals, we have hypothesized that decreased expression of the immunoglobulin genes used in antibodies to PPS contributes to PPS vaccine failure in the setting of HIV infection. The structure-function relationship of human antibodies to most pneumococcal serotypes has not been fully investigated. The studies that are proposed in this application are designed to characterize the variable gene use and epitope specificity of human antibodies to two common serotypes of S. pneumoniae, serotypes 8 and 23F, and to use this information to develop probes to determine the specificity of vaccine elicited antibodies to PPS 8 and 23F from individuals with and without HIV infection. The specific aims are: 1) To determine the molecular structure of human Mab to PPS 8 and 23F generated in transgenic mice reconstituted with human immunoglobulin loci; 2) To characterize the Mabs to PPS 8 and 23F produced in aim one as protective, nonprotective or disease enhancing against pneumococcal infection in mice and as opsonic in vitro; 3 ) To use Mabs with functional efficacy as defined in aim two to isolate peptide mimetics of PPS 8 and 23F epitopes, and to use the peptides to determine if PPS-elicited antibodies in patients sera recognize protective, non-protective or disease enhancing epitopes. Studies are proposed to examine the hypothesis that protective antibodies to PPS can be distinguished by their variable gene use and specificity and that the production of antibodies to certain epitopes ,which are derived from VH3 genes, is impaired in the setting of HIV infection. Knowledge gained from these studies will help us to understand the structure-function relationship for antibodies to S. pneumoniae in patients with HIV infection, and to identify possible correlates of PPS vaccine failure and the requirements for more effective anti-pneumococcal vaccines. Significance: Infection with pneumococcus has become a major cause of morbidity and mortality in AIDS. In the past, AIDS-associated infections were easily treated with antibiotics however, penicillin resistant isolates have emerged in the 1990's. This emergence of antibiotic resistant pneumococcus has increased the need for vaccination of high-risk groups such as HIV+ persons. However, available pneumococcal vaccines are poorly immunogenic in HIV+ persons. Thus, the goal of this proposal, which is to identify the molecular and biological basis of human antibody responses to peumococcal vaccination in normal volunteers and HIV+ persons, is very significant. The information gained from the proposed studies could lead to better vaccines for pneumococcus in immunocompromised hosts and importantly, will contribute to the understanding of how antibodies function in resistance to S. pneumoniae. Approach: This is the second revision of this application. Since the last review of this application the author has published 1 manuscript and has two others in press having to do with this application. The first publication describes the generation of a protective human Mab to PPS 8. The second, describes the generation of human antibodies to PPS 3 in XenoMouse mice. The third describes the molecular response of HIV-infected and HIV-uninfected subjects to Pneumovax. Thus, the author has made excellent progress even though she is not funded to do this work. This indicates commitment, enthusiasm and capability of the author to carry out this work. he P.I. has responded to the previous criticisms and has written a strong and significant application. One previous concern was that if HIVinfected individuals can not produce VH3 and only VH3 ab are protective that little of this information will be useful to make patients more resistant to pneumococcus. The PI points out that the goal of this application is not to characterize VH3 expression in HIVinfected individuals, but to determine whether they do or do not produce antibodies to pneumococcal capsular polysaccharides with defined epitope specificity. The PI's response and revisions to other reviewer's comments also strengthen the 1 ZRG-1

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AARR- 4 (01) 3 1 R01 AI45459-01A2 March 2000 Pirofski, Liise-Anne proposal. In addition, because of the subject of this application, the initial applications were difficult to follow. This revised version is clearer and the additions the PI has made are helpful. It is much more apparent what the PI really wants to accomplish. This is important since the reviewers agreed that this was a difficult application to read, mainly because of the subject matter and the specialized nature of the work. Innovation: The overall approach utilized in solving this problem takes advantage of established methods. The author has used these methods in the study of Cryptococcus so that the overall strategy is somewhat proven. Use of the XenoMouse is considered innovative. There are relatively few laboratories interested in antibody-mediated resistance. This makes this work somewhat unique. Investigator: Dr. Pirofski is well qualified to carry out the proposed research. She has published studies utilizing most of the methods in the proposal. Dr. John McKitrick is a consultant and brings expertise in the microbiology of S. pneumoniae. Environment: The P.I. is at Albert Einstein and has several other researchers nearby that have expertise in many of the methods she will utilize. She is in an excellent environment to accomplish this proposal. In summary, the subject of this proposal is timely and significant. The emergence of antibiotic resistant S. pneumoniae infections in AIDS patients requires the development of more efficient means of immunizing these individuals. The PI has made excellent progress on this project despite not being funded in this area. Studies proposed in this application could provide valuable information for developing more immunogenic vaccines for HIV+ persons. Simply put, this work needs to be done. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VIRULENCE GENE EXPRESSION BY BACILLUS ANTHRACIS Principal Investigator & Institution: Koehler, Theresa M.; Associate Professor; Microbiol & Molecular Genetics; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2004; Project Start 01-DEC-1992; Project End 30-NOV-2008 Summary: (provided by applicant): Bacillus anthracis, a Gram-positive spore-forming soil bacterium and member of the Bacillus cereus group species, is distinguished by its ability to cause lethal anthrax disease in mammals, including humans. Well-established virulence factors unique to this organism are the anthrax toxin proteins and a poly-Dglutamic acid capsule. Findings of numerous investigators have established the structure and function of the anthrax toxins and capsule. Work in our laboratory has focused on the genetic basis for expression of the structural genes for the toxin proteins, pagA, lef, and cya, and more recently, the capsule biosynthesis operon, capBCAD. Our model for virulence gene regulation is of increasing complexity and includes numerous trans-acting regulators. The most critical and far-reaching regulator is atxA, a gene that appears to be unique to B. anthracis, atxA is essential for expression of all three toxin genes and contributes to control of the capsule operon. In experiments proposed here, we will continue our investigations of virulence gene expression by testing our current model for regulation of virulence. Our overall approach will be to determine the function of virulence gene regulators in B. anthracis cultured in vitro and to test for significance in a mouse inhalation model for anthrax. We will also assess the physiological roles of newly identified targets of established regulators. Finally, we will probe the molecular basis for differences in 13-1actamase gene expression between prototypical penicillin-susceptible and less common penicillin-resistant B. anthracis stains. Bacillus anthracis is the lead bacterium on the Select Agent List. The intentional release of spores in the fall of 2001 in the U.S. that resulted in eleven confirmed cases of

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anthrax and five deaths dramatically illustrated the public health threat this organism can pose when as a bioweapon. As the recent U.S. cases showed, inhalation of B. anthracis spores can result in a fatal clinical outcome in humans and only timely postexposure intervention can limit the extent of the disease. Our overall objective is to identify and characterize B. anthracis determinants that impact B. anthracis infection in a mouse model for inhalation anthrax. Such determinants are potential targets for therapeutic intervention and/or possible components for new subunit vaccines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: WHOLE GENOME SHOTGUN SEQUENCING OF STREPTOCOCCUS MITIS Principal Investigator & Institution: Tettelin, Herves' S.; Associate Investigator; Institute for Genomic Research Rockville, Md 20850 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-MAR-2003 Summary: (Adapted from the Investigator?s Abstract): The goal is to determine the complete genome sequence of the type strain of Streptococcus mitis, the predominant pioneer colonizer of tooth surfaces, and thus an initiator of dental plaque formation relevant to caries and periodontal disease. These pioneer streptococci facilitate or inhibit the establishment of late colonizers and oral pathogens. The predominance of IgA1 protease producing S. mitis variants in the pharynx is associated with allergic disease. S. mitis is a causative agent of endocarditits. It is an emerging source of septicemia in cancer patients, and the first vancomycin-resistant S. mitis isolate was reported in one such case. Phylogenetically, S. mitis and the overt pathogen S. pneumoniae, the causative agent of otitis, pneumoniae, septicemia and meningitis, are nearest neighbors. There is clear demonstration that the S. mitis type strain constitutes a reservoir of genetic determinants that contribute to penicillin resistance in pathogenic S. pneumoniae. The fear is that resistance to vancomycin will be transferred in a similar manner. The approach is a whole genome random sequencing strategy used successfully at TIGR to sequence twelve prokaryotic genomes. The yearlong project will consists of four phases: 1) Construction of small, medium and large insert size genomic libraries from S. mitis type strain, NCTC 12261. 2) Sequencing both ends of a sufficient number of small insert clones to provide 8-fold sequence coverage of the genome. Medium and large insert clones will be sequenced to 6-fold and 10-fold clone coverage, respectively. This will provide a sequence scaffold that will aid in verifying genome architecture. Further, 10-fold clone coverage from the large (50 kb) insert library will ensure a predicted sequence hit every 5,000 bp of the 2.2 Mb S. mitis genome. 3) Assembling the genome sequence from the collection of sequence reads, and closing remaining gaps. 4) Annotation of the genome sequence to identify all open reading frames, assignment of gene names and functional roles based on database similarity searches. Accomplishing this goal will provide a unique opportunity to compare the repertoire of genes in the commensal S. mitis to that of other streptococci, such as the highly virulent, type-4 S. pneumoniae strain, nearing completion at TIGR, allowing the identification of virulence-associated genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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

[beta]-Lactamase Genes of the Penicillin-Susceptible Bacillus anthracis Sterne Strain. by Chen Y, Succi J, Tenover FC, Koehler TM.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=142833

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Activities of oral and parenteral agents against penicillin-susceptible and -resistant pneumococci. by Pankuch GA, Visalli MA, Jacobs MR, Appelbaum PC.; 1995 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162770

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Activity of Amoxicillin-Clavulanate against Penicillin-Resistant Streptococcus pneumoniae in an Experimental Respiratory Infection Model in Rats. by Smith GM, Slocombe B, Abbott KH, Mizen LW.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105547

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Activity of LY333328 in Experimental Meningitis Caused by a Streptococcus pneumoniae Strain Susceptible to Penicillin. by Gerber J, Smirnov A, Wellmer A, Ragheb J, Prange J, Schutz E, Wettich K, Kalich S, Nau R.; 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90624

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Affinities of [beta]-Lactams for Penicillin Binding Proteins of Chlamydia trachomatis and Their Antichlamydial Activities. by Storey C, Chopra I.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90278

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Alterations in MurM, a Cell Wall Muropeptide Branching Enzyme, Increase HighLevel Penicillin and Cephalosporin Resistance in Streptococcus pneumoniae. by Smith AM, Klugman KP.; 2001 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90664

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Alterations in Penicillin-Binding Protein 1A Confer Resistance to [beta]-Lactam Antibiotics in Helicobacter pylori. by Gerrits MM, Schuijffel D, van Zwet AA, Kuipers EJ, Vandenbroucke-Grauls CM, Kusters JG.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127293

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Amoxicillin dose-effect relationship with Streptococcus pneumoniae in a mouse pneumonia model and roles of in vitro penicillin susceptibilities, autolysis, and tolerance properties of the strains. by Azoulay-Dupuis E, Moine P, Bedos JP, Rieux V, Vallee E.; 1996 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163235

3 4

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

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

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•

AmpC and AmpH, proteins related to the class C beta-lactamases, bind penicillin and contribute to the normal morphology of Escherichia coli. by Henderson TA, Young KD, Denome SA, Elf PK.; 1997 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=179516

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Analysis of Penicillin-Binding Protein Genes of Clinical Isolates of Streptococcus pneumoniae with Reduced Susceptibility to Amoxicillin. by du Plessis M, Bingen E, Klugman KP.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127354

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Antipneumococcal activities of RP 59500 (quinupristin-dalfopristin), penicillin G, erythromycin, and sparfloxacin determined by MIC and rapid time-kill methodologies. by Pankuch GA, Lichtenberger C, Jacobs MR, Appelbaum PC.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163390

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Application of pbp1A PCR in Identification of Penicillin-Resistant Streptococcus pneumoniae. by du Plessis M, Smith AM, Klugman KP.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84499

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Assessment of two penicillins plus beta-lactamase inhibitors versus cefotaxime in treatment of murine Klebsiella pneumoniae infections. by Fournier JL, Ramisse F, Jacolot AC, Szatanik M, Petitjean OJ, Alonso JM, Scavizzi MR.; 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163110

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Association of a Thr-371 Substitution in a Conserved Amino Acid Motif of PenicillinBinding Protein 1A with Penicillin Resistance of Streptococcus pneumoniae. by Asahi Y, Ubukata K.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105808

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Association of Amino Acid Substitutions in Penicillin-Binding Protein 3 with [beta]Lactam Resistance in [beta]-Lactamase-Negative Ampicillin-Resistant Haemophilus influenzae. by Ubukata K, Shibasaki Y, Yamamoto K, Chiba N, Hasegawa K, Takeuchi Y, Sunakawa K, Inoue M, Konno M.; 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90533

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Bacillus subtilis Cells Lacking Penicillin-Binding Protein 1 Require Increased Levels of Divalent Cations for Growth. by Murray T, Popham DL, Setlow P.; 1998 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107467

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Bactericidal activities of cefprozil, penicillin, cefaclor, cefixime, and loracarbef against penicillin-susceptible and -resistant Streptococcus pneumoniae in an in vitro pharmacodynamic infection model. by Cappelletty DM, Rybak MJ.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163281

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Biochemical characterization of penicillin-resistant and -sensitive penicillin-binding protein 2x transpeptidase activities of Streptococcus pneumoniae and mechanistic implications in bacterial resistance to beta-lactam antibiotics. by Zhao G, Yeh WK, Carnahan RH, Flokowitsch J, Meier TI, Alborn WE Jr, Becker GW, Jaskunas SR.; 1997 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=179340

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Biochemistry and Comparative Genomics of SxxK Superfamily Acyltransferases Offer a Clue to the Mycobacterial Paradox: Presence of Penicillin-Susceptible Target

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Proteins versus Lack of Efficiency of Penicillin as Therapeutic Agent. by Goffin C, Ghuysen JM.; 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=134655 •

BOCILLIN FL, a Sensitive and Commercially Available Reagent for Detection of Penicillin-Binding Proteins. by Zhao G, Meier TI, Kahl SD, Gee KR, Blaszczak LC.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89121

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Borderline methicillin-susceptible Staphylococcus aureus strains have more in common than reduced susceptibility to penicillinase-resistant penicillins. by Massidda O, Montanari MP, Mingoia M, Varaldo PE.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163619

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Can penicillins and other beta-lactam antibiotics be used to treat tuberculosis? by Chambers HF, Moreau D, Yajko D, Miick C, Wagner C, Hackbarth C, Kocagoz S, Rosenberg E, Hadley WK, Nikaido H.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163000

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Cloning and Characterization of a Gene, pbpF, Encoding a New Penicillin-Binding Protein, PBP2B, in Staphylococcus aureus. by Komatsuzawa H, Choi GH, Ohta K, Sugai M, Tran MT, Suginaka H.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89327

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Cloning and Characterization of an Aspergillus nidulans Gene Involved in the Regulation of Penicillin Biosynthesis. by Van den Brulle J, Steidl S, Brakhage AA.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=91708

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Cloning and characterization of the ponA gene encoding penicillin-binding protein 1 from Neisseria gonorrhoeae and Neisseria meningitidis. by Ropp PA, Nicholas RA.; 1997 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=179034

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Comparative efficacy and safety of 3-day azithromycin and 10-day penicillin V treatment of group A beta-hemolytic streptococcal pharyngitis in children. by Pacifico L, Scopetti F, Ranucci A, Pataracchia M, Savignoni F, Chiesa C.; 1996 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163247

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Comparative Evaluation of Penicillin, Ampicillin, and Imipenem MICs and Susceptibility Breakpoints for Vancomycin-Susceptible and Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium. by Weinstein MP.; 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88224

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Comparative study of bactericidal activities, postantibiotic effects, and effects of bacterial virulence of penicillin G and six macrolides against Streptococcus pneumoniae. by Fuursted K, Knudsen JD, Petersen MB, Poulsen RL, Rehm D.; 1997 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163794

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Comparison of antimicrobial susceptibility methods for detection of penicillinresistant Streptococcus pneumoniae. by Kiska DL, Kerr A, Jones MC, Chazotte NN, Eskridge B, Miller S, Jordan M, Sheaffer C, Gilligan PH.; 1995 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=227916

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Comparison of dirithromycin and penicillin for treatment of streptococcal pharyngitis. by Watkins VS, Smietana M, Conforti PM, Sides GD, Huck W.; 1997 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163662

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Competition of Various [beta]-Lactam Antibiotics for the Major Penicillin-Binding Proteins of Helicobacter pylori: Antibacterial Activity and Effects on Bacterial Morphology. by DeLoney CR, Schiller NL.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89546

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Complementation of the Essential Peptidoglycan Transpeptidase Function of Penicillin-Binding Protein 2 (PBP2) by the Drug Resistance Protein PBP2A in Staphylococcus aureus. by Pinho MG, Filipe SR, de Lencastre H, Tomasz A.; 2001 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95481

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Concentrations of doxycycline and penicillin G in sera and cerebrospinal fluid of patients treated for neuroborreliosis. by Karlsson M, Hammers S, Nilsson-Ehle I, Malmborg AS, Wretlind B.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163273

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Constitutive Septal Murein Synthesis in Escherichia coli with Impaired Activity of the Morphogenetic Proteins RodA and Penicillin-Binding Protein 2. by de Pedro MA, Donachie WD, Holtje JV, Schwarz H.; 2001 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95299

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Culture-Negative Childhood Empyema Is Usually Due to Penicillin-Sensitive Streptococcus pneumoniae Capsular Serotype 1. by Eltringham G, Kearns A, Freeman R, Clark J.; 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149645

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Detection of Penicillin Susceptibility in Streptococcus pneumoniae by pbp2b PCRRestriction Fragment Length Polymorphism Analysis. by O'Neill AM, Gillespie SH, Whiting GC.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84195

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Determination of Penicillin MICs for Streptococcus pneumoniae by Using a Two- or Three-Disk Diffusion Procedure. by Jacobs MR, Bajaksouzian S, Palavecino-Fasola EL, Holoszyc HM, Appelbaum PC.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124830

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Development of a New Experimental Model of Penicillin-Resistant Streptococcus pneumoniae Pneumonia and Amoxicillin Treatment by Reproducing Human Pharmacokinetics. by Piroth L, Martin L, Coulon A, Lequeu C, Duong M, Buisson M, Portier H, Chavanet P.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89505

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Development of experimental pneumonia by infection with penicillin-insensitive Streptococcus pneumoniae in guinea pigs and their treatment with amoxicillin, cefotaxime, and meropenem. by Ponte C, Parra A, Nieto E, Soriano F.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163606

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Dialysis culture enables more accurate determination of MIC of benzylpenicillin for Borrelia burgdorferi than does conventional procedure. by Stiernstedt SH, Wretlind B.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163640

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Direct Quantitation of the Numbers of Individual Penicillin-Binding Proteins per Cell in Staphylococcus aureus. by Pucci MJ, Dougherty TJ.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139569

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Dissemination of a Chloramphenicol- and Tetracycline-Resistant but PenicillinSusceptible Invasive Clone of Serotype 5 Streptococcus pneumoniae in Colombia. by Tamayo M, Sa-Leao R, Sanches IS, Castaneda E, de Lencastre H.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85154

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Dissemination of High-Level Penicillin-, Extended-Spectrum Cephalosporin-, and Erythromycin-Resistant Streptococcus pneumoniae Clones in Taiwan. by Hsueh PR, Teng LJ, Lee LN, Yang PC, Ho SW, Luh KT.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84215

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Distribution of systemically administered ampicillin, benzylpenicillin, and flucloxacillin in excisional wounds in diabetic and normal rats and effects of local topical vasodilator treatment. by Cross SE, Thompson MJ, Roberts MS.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163399

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Effect of gentamicin dosing interval on efficacy of penicillin or ceftriaxone treatment of experimental endocarditis due to penicillin-susceptible, ceftriaxone-tolerant viridans group streptococci. by Brandt CM, Warner CB, Rouse MS, Steckelberg JM, Wilson WR.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163646

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Effect of gentamicin dosing interval on therapy of viridans streptococcal experimental endocarditis with gentamicin plus penicillin. by Gavalda J, Pahissa A, Almirante B, Laguarda M, Crespo E, Pou L, Fernandez F.; 1995 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162888

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Effects of Amino Acid Alterations in Penicillin-Binding Proteins (PBPs) 1a, 2b, and 2x on PBP Affinities of Penicillin, Ampicillin, Amoxicillin, Cefditoren, Cefuroxime, Cefprozil, and Cefaclor in 18 Clinical Isolates of Penicillin-Susceptible, Intermediate, and -Resistant Pneumococci. by Nagai K, Davies TA, Jacobs MR, Appelbaum PC.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127189

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Effects of Neutrophils on Cefazolin Activity and Penicillin-Binding Proteins in Staphylococcus aureus Abscesses. by Bamberger DM, Herndon BL, Fitch J, Florkowski A, Parkhurst V.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127421

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Efficacies of cefotaxime and ceftriaxone in a mouse model of pneumonia induced by two penicillin- and cephalosporin-resistant strains of Streptococcus pneumoniae. by Sauve C, Azoulay-Dupuis E, Moine P, Darras-Joly C, Rieux V, Carbon C, Bedos JP.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163631

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Efficacy of clarithromycin treatment of acute otitis media caused by infection with penicillin-susceptible, -intermediate, and -resistant Streptococcus pneumoniae in the chinchilla. by Alper CM, Doyle WJ, Seroky JT, Bluestone CD.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163435

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Efficacy of Trovafloxacin against Penicillin-Susceptible and Multiresistant Strains of Streptococcus pneumoniae in a Mouse Pneumonia Model. by Bedos JP, Rieux V, Bauchet J, Muffat-Joly M, Carbon C, Azoulay-Dupuis E.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105556

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Elucidation of conditions allowing conversion of penicillin G and other penicillins to deacetoxycephalosporins by resting cells and extracts of Streptomyces clavuligerus NP1. by Cho H, Adrio JL, Luengo JM, Wolfe S, Ocran S, Hintermann G, Piret JM, Demain AL.; 1998 Sep 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21677

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Emergence of a Pneumococcal Clone with Cephalosporin Resistance and Penicillin Susceptibility. by Smith AM, Botha RF, Koornhof HJ, Klugman KP.; 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90708

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Engineering Streptomyces clavuligerus Deacetoxycephalosporin C Synthase for Optimal Ring Expansion Activity toward Penicillin G. by Wei CL, Yang YB, Wang WC, Liu WC, Hsu JS, Tsai YC.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154807

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Enhanced activity of the combination of penicillin G and gentamicin against penicillin-resistant viridans group streptococci. by Cercenado E, Diaz MD, SanchezCarrillo C, Vicente T, Bernaldo de Quiros JC.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163039

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Experimental Streptococcus pneumoniae infection in mice for studying correlation of in vitro and in vivo activities of penicillin against pneumococci with various susceptibilities to penicillin. by Knudsen JD, Frimodt-Moller N, Espersen F.; 1995 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162722

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Extremely High Prevalence of Nasopharyngeal Carriage of Penicillin-Resistant Streptococcus pneumoniae among Children in Kaohsiung, Taiwan. by Chiou CC, Liu YC, Huang TS, Hwang WK, Wang JH, Lin HH, Yen MY, Hsieh KS.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104955

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Fractional Maximal Effect Method for In Vitro Synergy between Amoxicillin and Ceftriaxone and between Vancomycin and Ceftriaxone against Enterococcus faecalis and Penicillin-Resistant Streptococcus pneumoniae. by Desbiolles N, Piroth L, Lequeu C, Neuwirth C, Portier H, Chavanet P.; 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90833

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Functional Characterization of Penicillin-Binding Protein 1b from Streptococcus pneumoniae. by Di Guilmi AM, Dessen A, Dideberg O, Vernet T.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=148077

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Gene Targeting in Penicillium chrysogenum: Disruption of the lys2 Gene Leads to Penicillin Overproduction. by Casqueiro J, Gutierrez S, Banuelos O, Hijarrubia MJ, Martin JF.; 1999 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93495

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High Rate of Transmission of Penicillin-Resistant Streptococcus pneumoniae between Parents and Children. by Hoshino K, Watanabe H, Sugita R, Asoh N, Ntabaguzi SA, Watanabe K, Oishi K, Nagatake T.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139698

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Identification and characterization of pbpA encoding Bacillus subtilis penicillinbinding protein 2A. by Murray T, Popham DL, Setlow P.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=179068

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Identification of a major cis-acting DNA element controlling the bidirectionally transcribed penicillin biosynthesis genes acvA (pcbAB) and ipnA (pcbC) of Aspergillus nidulans. by Bergh KT, Litzka O, Brakhage AA.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232653

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Identification of a Novel Penicillin-Binding Protein from Helicobacter pylori. by Krishnamurthy P, Parlow MH, Schneider J, Burroughs S, Wickland C, Vakil NB, Dunn BE, Phadnis SH.; 1999 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=94005

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Immunological detection of penicillin-binding protein 2' of methicillin-resistant staphylococci by using monoclonal antibodies prepared from synthetic peptides. by Saito M, Sekiguchi K, Yajima R, Hina M, Doss RC, Kanno H.; 1995 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228456

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Importance of penicillinase production for activity of penicillin alone or in combination with sulbactam in experimental endocarditis due to methicillin-resistant Staphylococcus aureus. by Fantin B, Pierre J, Castela-Papin N, Saint-Julien L, Drugeon H, Farinotti R, Carbon C.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163295

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Importance of the E-46-D-160 polypeptide segment of the non-penicillin-binding module for the folding of the low-affinity, multimodular class B penicillin-binding protein 5 of Enterococus hirae. by Mollerach ME, Partoune P, Coyette J, Ghuysen JM.; 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=177867

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In Vitro Activities of Cethromycin (ABT-773), a New Ketolide, against Streptococcus pneumoniae Strains That Are Not Susceptible to Penicillin or Macrolides. by Mason EO Jr, Lamberth LB, Wald ER, Bradley JS, Barson WJ, Kaplan SL.; 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149018

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In vitro antimicrobial effect against Streptococcus pneumoniae of adding rifampin to penicillin, ceftriaxone, or 1-ofloxacin. by Giron KP, Gross ME, Musher DM, Williams TW Jr, Tharappel RA.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163033

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In Vitro Antimicrobial Effects of Various Combinations of Penicillin and Clindamycin against Four Strains of Streptococcus pyogenes. by Stevens DL, MadarasKelly KJ, Richards DM.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105799

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In vivo activity and pharmacodynamics of amoxicillin in combination with fosfomycin in fibrin clots infected with highly penicillin-resistant Streptococcus pneumoniae. by Chavanet P, Peyrard N, Pechinot A, Buisson M, Duong M, Neuwirth C, Kazmierczak A, Portier H.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163473

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In Vivo Efficacies of Amoxicillin and Cefuroxime against Penicillin-Resistant Streptococcus pneumoniae in a Gerbil Model of Acute Otitis Media. by Cenjor C, Ponte C, Parra A, Nieto E, Garcia-Calvo G, Gimenez MJ, Aguilar L, Soriano F.; 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105604

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In vivo efficacy of azithromycin in treatment of systemic infection and septic arthritis induced by type IV group B Streptococcus strains in mice: comparative study with erythromycin and penicillin G. by Tissi L, von Hunolstein C, Mosci P, Campanelli C, Bistoni F, Orefici G.; 1995 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162860

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In Vivo Penicillin MIC Drift to Extremely High Resistance in Serotype 14 Streptococcus pneumoniae Persistently Colonizing the Nasopharynx of an Infant with Chronic Suppurative Lung Disease: a Case Study. by Leach AJ, Morris PS, SmithVaughan H, Mathews JD.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128758

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Influences of Linezolid, Penicillin, and Clindamycin, Alone and in Combination, on Streptococcal Pyrogenic Exotoxin A Release. by Coyle EA, Cha R, Rybak MJ.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153301

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Inhibition of Penicillinase by Epigallocatechin Gallate Resulting in Restoration of Antibacterial Activity of Penicillin against Penicillinase-Producing Staphylococcus aureus. by Zhao WH, Hu ZQ, Hara Y, Shimamura T.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127279

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Lack of Cell Wall Peptidoglycan versus Penicillin Sensitivity: New Insights into the Chlamydial Anomaly. by Ghuysen JM, Goffin C.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89479

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Lack of Synergy of Erythromycin Combined with Penicillin or Cefotaxime against Streptococcus pneumoniae In Vitro. by Lin E, Stanek RJ, Mufson MA.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149295

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Large-Scale Outbreak of Infection with Mycobacterium chelonae subsp. abscessus after Penicillin Injection. by Zhibang Y, BiXia Z, Qishan L, Lihao C, Xiangquan L, Huaping L.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120593

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Localization of penicillin-binding proteins to the splitting system of Staphylococcus aureus septa by using a mercury-penicillin V derivative. by Paul TR, Venter A, Blaszczak LC, Parr TR Jr, Labischinski H, Beveridge TJ.; 1995 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=177077

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Meningitis Due to Mixed Infection with Penicillin-Resistant and PenicillinSusceptible Strains of Streptococcus pneumoniae. by Chaves F, Campelo C, Sanz F, Otero JR.; 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149642

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MIC and time-kill study of antipneumococcal activities of RPR 106972 (a new oral streptogramin), RP 59500 (quinupristin-dalfopristin), pyostacine (RP 7293), penicillin G, cefotaxime, erythromycin, and clarithromycin against 10 penicillin-susceptible and -resistant pneumococci. by Pankuch GA, Jacobs MR, Appelbaum PC.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163475

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Modification of penicillin-binding protein 5 associated with high-level ampicillin resistance in Enterococcus faecium. by Ligozzi M, Pittaluga F, Fontana R.; 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163115

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Molecular Control of Expression of Penicillin Biosynthesis Genes in Fungi: Regulatory Proteins Interact with a Bidirectional Promoter Region. by Martin JF.; 2000 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111294

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Molecular Epidemiology of Penicillin-Susceptible, Multidrug-Resistant Serotype 6B Pneumococci Isolated from Children in Greece. by Syrogiannopoulos GA, Bogaert D, Grivea IN, Beratis NG, De Groot R, Hermans PW.; 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87779

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Morphological Changes and Lysis Induced by [beta]-Lactams Associated with the Characteristic Profiles of Affinities of Penicillin-Binding Proteins in Actinobacillus pleuropneumoniae. by Inui T, Endo T, Matsushita T.; 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89906

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Multimodular Penicillin-Binding Proteins: An Enigmatic Family of Orthologs and Paralogs. by Goffin C, Ghuysen JM.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98940

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Mutational Analysis of the Streptococcus pneumoniae Bimodular Class A PenicillinBinding Proteins. by Paik J, Kern I, Lurz R, Hakenbeck R.; 1999 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93869

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Mutations in ponA, the Gene Encoding Penicillin-Binding Protein 1, and a Novel Locus, penC, Are Required for High-Level Chromosomally Mediated Penicillin Resistance in Neisseria gonorrhoeae. by Ropp PA, Hu M, Olesky M, Nicholas RA.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127492

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Noncompromised penicillin-resistant pneumococcal pneumonia CBA/J mouse model and comparative efficacies of antibiotics in this model. by Tateda K, Takashima K, Miyazaki H, Matsumoto T, Hatori T, Yamaguchi K.; 1996 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163360

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Nonculture Prediction of Neisseria meningitidis Susceptibility to Penicillin. by Antignac A, Alonso JM, Taha MK.; 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90884

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Novel Penicillin-, Cephalosporin-, and Macrolide-Resistant Clones of Streptococcus pneumoniae Serotypes 23F and 19F in Taiwan Which Differ from International Epidemic Clones. by Chiou CC, McEllistrem MC.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87890

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Once-versus thrice-daily netilmicin combined with amoxicillin, penicillin, or vancomycin against Enterococcus faecalis in a pharmacodynamic in vitro model. by Schwank S, Blaser J.; 1996 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163514

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On-Line Analysis of Penicillin Blood Levels in the Live Rat by Combined Microdialysis/Fast-Atom Bombardment Mass Spectrometry. by Caprioli RM, Lin S.; 1990 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53237

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Opposing Roles of the Staphylococcus aureus Virulence Regulators, Agr and Sar, in Triton X-100- and Penicillin-Induced Autolysis. by Fujimoto DF, Bayles KW.; 1998 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107347

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Optimal Dose of Amoxicillin in Treatment of Otitis Media Caused by a PenicillinResistant Pneumococcus Strain in the Gerbil Model. by Parra A, Ponte C, Cenjor C, Garcia-Calvo G, Gimenez MJ, Aguilar L, Soriano F.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127470

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Oral pristinamycin versus standard penicillin regimen to treat erysipelas in adults: randomised, non-inferiority, open trial. by Bernard P, Chosidow O, Vaillant L.; 2002 Oct 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129632

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Organization of the Gene Cluster for Biosynthesis of Penicillin in Penicillium nalgiovense and Antibiotic Production in Cured Dry Sausages. by Laich F, Fierro F, Cardoza RE, Martin JF.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=91170

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Outbreak of Cefozopran (Penicillin, Oral Cephems, and Aztreonam)-Resistant Neisseria gonorrhoeae in Japan. by Muratani T, Akasaka S, Kobayashi T, Yamada Y, Inatomi H, Takahashi K, Matsumoto T.; 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90878

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Overexpression of the MtrC-MtrD-MtrE Efflux Pump Due to an mtrR Mutation Is Required for Chromosomally Mediated Penicillin Resistance in Neisseria gonorrhoeae. by Veal WL, Nicholas RA, Shafer WM.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139619

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pbpB, a Gene Coding for a Putative Penicillin-Binding Protein, Is Required for Aerobic Nitrogen Fixation in the Cyanobacterium Anabaena sp. Strain PCC7120. by Lazaro S, Fernandez-Pinas F, Fernandez-Valiente E, Blanco-Rivero A, Leganes F.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=94919

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Penicillin for acute sore throat: randomised double blind trial of seven days versus three days treatment or placebo in adults. by Zwart S, Sachs AP, Ruijs GJ, Gubbels JW, Hoes AW, de Melker RA.; 2000 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27262

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Penicillin Pharmacodynamics in Four Experimental Pneumococcal Infection Models. by Erlendsdottir H, Knudsen JD, Odenholt I, Cars O, Espersen F, Frimodt-Moller N, Fuursted K, Kristinsson KG, Gudmundsson S.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90427

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Penicillin resistance in Veillonella. by Reig M, Mir N, Baquero F.; 1997 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=163887

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Penicillin-Binding Protein 1A, 2B, and 2X Alterations in Canadian Isolates of Penicillin-Resistant Streptococcus pneumoniae. by Nichol KA, Zhanel GG, Hoban DJ.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128798

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Penicillin-binding proteins 2b and 2x of Streptococcus pneumoniae are primary resistance determinants for different classes of beta-lactam antibiotics. by Grebe T, Hakenbeck R.; 1996 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163214

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Penicillin-Binding Proteins in Leptospira interrogans. by Brenot A, Trott D, Girons IS, Zuerner R.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90386

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Pharmacodynamic effects of amoxicillin versus cefotaxime against penicillinsusceptible and penicillin-resistant pneumococcal strains: a phase I study. by Aguilar L, Rosendo J, Balcabao IP, Martin M, Gimenez MJ, Frias J, Prieto J.; 1997 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163922

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Pharmacodynamic effects of sub-MICs of benzylpenicillin against Streptococcus pyogenes in a newly developed in vitro kinetic model. by Lowdin E, Odenholt I, Bengtsson S, Cars O.; 1996 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163560

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Pharmacokinetics and Pharmacodynamics of Amoxicillin-Sulbactam, a Novel Aminopenicillin --[beta]-Lactamase Inhibitor Combination, against Escherichia coli. by Bantar C, Nicola F, Arenoso HJ, Galas M, Soria L, Dana D, Rossi A, Bianchini H, Jasovich A.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89308

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Point mutations in Staphylococcus aureus PBP 2 gene affect penicillin-binding kinetics and are associated with resistance. by Hackbarth CJ, Kocagoz T, Kocagoz S, Chambers HF.; 1995 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162493

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Prediction of Enterococcal Imipenem Susceptibility Using Ampicillin or Penicillin MICs: More Evidence for a Class Concept. by Jones RN.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88444

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Production of Penicillin by Fungi Growing on Food Products: Identification of a Complete Penicillin Gene Cluster in Penicillium griseofulvum and a Truncated Cluster in Penicillium verrucosum. by Laich F, Fierro F, Martin JF.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123731

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Rapid Detection of mecA-Positive and mecA-Negative Coagulase-Negative Staphylococci by an Anti-Penicillin Binding Protein 2a Slide Latex Agglutination Test. by Hussain Z, Stoakes L, Garrow S, Longo S, Fitzgerald V, Lannigan R.; 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86725

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Rapid Detection of Methicillin Resistance in Coagulase-Negative Staphylococci by a Penicillin-Binding Protein 2a-Specific Latex Agglutination Test. by Horstkotte MA, Knobloch JK, Rohde H, Mack D.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88411

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Rapid Detection of Penicillin-Resistant Streptococcus pneumoniae in Cerebrospinal Fluid by a Seminested-PCR Strategy. by du Plessis M, Smith AM, Klugman KP.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104558

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Rapid Real-Time PCR for Determination of Penicillin Susceptibility in Pneumococcal Meningitis, Including Culture-Negative Cases. by Kearns AM, Graham C, Burdess D, Heatherington J, Freeman R.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153399

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Rapid Screening for Penicillin Susceptibility of Systemic Pneumococcal Isolates by Restriction Enzyme Profiling of the pbp2B Gene. by Beall B, Facklam RR, Jackson DM, Starling HH.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105050

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Rationale behind high-dose amoxicillin therapy for acute otitis media due to penicillin-nonsusceptible pneumococci: support from in vitro pharmacodynamic studies. by Lister PD, Pong A, Chartrand SA, Sanders CC.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=164037

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Reduced Function of a Phenylacetate-Oxidizing Cytochrome P450 Caused Strong Genetic Improvement in Early Phylogeny of Penicillin-Producing Strains. by Rodriguez-Saiz M, Barredo JL, Moreno MA, Fernandez-Canon JM, Penalva MA, Diez B.; 2001 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95435

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Regulation of the Aspergillus nidulans Penicillin Biosynthesis Gene acvA (pcbAB) by Amino Acids: Implication for Involvement of Transcription Factor PACC. by Bergh KT, Brakhage AA.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=106336

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Relative Sensitivities of Streptococcus pneumoniae Strains to Penicillin and Ceftriaxone. by Hodes DS, Sudol TE.; 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88601

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Role of Penicillin-Binding Protein 4 in Expression of Vancomycin Resistance among Clinical Isolates of Oxacillin-Resistant Staphylococcus aureus. by Finan JE, Archer GL, Pucci MJ, Climo MW.; 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90784

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Roles of Low-Molecular-Weight Penicillin-Binding Proteins in Bacillus subtilis Spore Peptidoglycan Synthesis and Spore Properties. by Popham DL, Gilmore ME, Setlow P.; 1999 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103540

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Sensitivity of Amoxicillin-Resistant Helicobacter pylori to Other Penicillins. by Dore MP, Graham DY, Sepulveda AR, Realdi G, Osato MS.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89370

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Septal Localization of Penicillin-Binding Protein 1 in Bacillus subtilis. by Pedersen LB, Angert ER, Setlow P.; 1999 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93777

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Specific interaction between beta-lactams and soluble penicillin-binding protein 2a from methicillin-resistant Staphylococcus aureus: development of a chromogenic assay. by Roychoudhury S, Kaiser RE, Brems DN, Yeh WK.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163476

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Staphylococcal Cell Wall: Morphogenesis and Fatal Variations in the Presence of Penicillin. by Giesbrecht P, Kersten T, Maidhof H, Wecke J.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98950

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Structure of the low-affinity penicillin-binding protein 5 PBP5fm in wild-type and highly penicillin-resistant strains of Enterococcus faecium. by Zorzi W, Zhou XY, Dardenne O, Lamotte J, Raze D, Pierre J, Gutmann L, Coyette J.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=178279

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Studies of the killing kinetics of benzylpenicillin, cefuroxime, azithromycin, and sparfloxacin on bacteria in the postantibiotic phase. by Odenholt I, Lowdin E, Cars O.; 1997 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=164155

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Suboptimal Antibiotic Dosage as a Risk Factor for Selection of Penicillin-Resistant Streptococcus pneumoniae: In Vitro Kinetic Model. by Odenholt I, Gustafsson I, Lowdin E, Cars O.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151721

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Susceptibilities of 228 penicillin- and erythromycin-susceptible and -resistant pneumococci to RU 64004, a new ketolide, compared with susceptibilities to 16 other agents. by Ednie LM, Spangler SK, Jacobs MR, Appelbaum PC.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163845

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Synergy between amoxicillin and gentamicin in combination against a highly penicillin-resistant and -tolerant strain of Streptococcus pneumoniae in a mouse

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pneumonia model. by Darras-Joly C, Bedos JP, Sauve C, Moine P, Vallee E, Carbon C, Azoulay-Dupuis E.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163489 •

The Staphylococcus aureus lrgAB Operon Modulates Murein Hydrolase Activity and Penicillin Tolerance. by Groicher KH, Firek BA, Fujimoto DF, Bayles KW.; 2000 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101860

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Timing of penicillin treatment influences the course of Streptococcus pneumoniaeinduced middle ear inflammation. by Sato K, Quartey MK, Liebeler CL, Giebink GS.; 1995 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162851

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Transcriptional Analysis of the Staphylococcus aureus Penicillin Binding Protein 2 Gene. by Pinho MG, de Lencastre H, Tomasz A.; 1998 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107690

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Transcriptional Induction of the Penicillin-Binding Protein 2 Gene in Staphylococcus aureus by Cell Wall-Active Antibiotics Oxacillin and Vancomycin. by Boyle-Vavra S, Yin S, Challapalli M, Daum RS.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149319

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Treatment of experimental pneumonia due to penicillin-resistant Streptococcus pneumoniae in immunocompetent rats. by Gavalda J, Capdevila JA, Almirante B, Otero J, Ruiz I, Laguarda M, Allende H, Crespo E, Pigrau C, Pahissa A.; 1997 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163797

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Trovafloxacin in treatment of rabbits with experimental meningitis caused by highlevel penicillin-resistant Streptococcus pneumoniae. by Kim YS, Liu Q, Chow LL, Tauber MG.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163879

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Unreliability of Disc Diffusion Test for Screening for Reduced Penicillin Susceptibility in Neisseria meningitidis. by Block C, Davidson Y, Keller N.; 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105127

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Use of Penicillin MICs To Predict In Vitro Activity of Other [beta]-Lactam Antimicrobial Agents against Streptococcus pneumoniae. by Brueggemann AB, Pfaller MA, Doern GV.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87734

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Use of reporter genes to identify recessive trans-acting mutations specifically involved in the regulation of Aspergillus nidulans penicillin biosynthesis genes. by Brakhage AA, Van den Brulle J.; 1995 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=176949

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Visualization of Penicillin-Binding Proteins during Sporulation of Streptomyces griseus. by Hao J, Kendrick KE.; 1998 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107139

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

A case of retropharyngeal abscess caused by penicillin-resistant Streptococcus pneumoniae. Author(s): Kobayashi KI, Haruta T, Kubota M, Nishio T. Source: The Journal of Infection. 2002 May; 44(4): 267-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12099737&dopt=Abstract

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A novel epimerization system in fungal secondary metabolism involved in the conversion of isopenicillin N into penicillin N in Acremonium chrysogenum. Author(s): Ullan RV, Casqueiro J, Banuelos O, Fernandez FJ, Gutierrez S, Martin JF. Source: The Journal of Biological Chemistry. 2002 November 29; 277(48): 46216-25. Epub 2002 September 11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12228250&dopt=Abstract

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A prospective observational study of the effect of penicillin skin testing on antibiotic use in the intensive care unit. Author(s): Arroliga ME, Radojicic C, Gordon SM, Popovich MJ, Bashour CA, Melton AL, Arroliga AC. Source: Infection Control and Hospital Epidemiology : the Official Journal of the Society of Hospital Epidemiologists of America. 2003 May; 24(5): 347-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12785408&dopt=Abstract

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A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis. Author(s): Hook EW 3rd, Martin DH, Stephens J, Smith BS, Smith K. Source: Sexually Transmitted Diseases. 2002 August; 29(8): 486-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12172535&dopt=Abstract

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

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Activity of telithromycin against penicillin-resistant Streptococcus pneumoniae isolates recovered from French children with invasive and noninvasive infections. Author(s): Bingen E, Doit C, Loukil C, Brahimi N, Bidet P, Deforche D, Geslin P. Source: Antimicrobial Agents and Chemotherapy. 2003 July; 47(7): 2345-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821495&dopt=Abstract

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Age-related frequency of penicillin resistance of oral Veillonella. Author(s): Nyfors S, Kononen E, Bryk A, Syrjanen R, Jousimies-Somer H. Source: Diagnostic Microbiology and Infectious Disease. 2003 August; 46(4): 279-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12944020&dopt=Abstract

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Alarming increase in ciprofloxacin- and penicillin-resistant Neisseria gonorrhoeae isolates in New Delhi, India. Author(s): Bala M, Ray K, Kumari S. Source: Sexually Transmitted Diseases. 2003 June; 30(6): 523-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12782955&dopt=Abstract

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Anaphylactic shock after traditional Russian beauty-treatment-unpleasant surprise in a strongly penicillin-sensitized patient. Author(s): Rogalski C, Kleine-Tebbe J, Rytter M, Haustein UF, Paasch U. Source: Asian Pac J Allergy Immunol. 2002 September; 20(3): 197-202. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12587844&dopt=Abstract

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Anaphylactic shock due to cefuroxime in a patient taking penicillin prophylaxis. Author(s): Prosser DP, Gompels M. Source: Paediatric Anaesthesia. 2002 January; 12(1): 73-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11849580&dopt=Abstract

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Anaphylaxis during negative penicillin skin prick testing confirmed by elevated serum tryptase. Author(s): Alonso Diaz de Durana MD, Fernandez-Rivas M, Casas ML, Esteban E, Cuevas M, Tejedor MA. Source: Allergy. 2003 February; 58(2): 159. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12622750&dopt=Abstract

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Antibiotic prescribing and penicillin-resistant pneumococci in a Merseyside Health District. Author(s): Vardhan MS, Allen KD, Bennett E. Source: The Journal of Infection. 2003 January; 46(1): 30-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12504606&dopt=Abstract

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Apparent failure of endocarditis prophylaxis caused by penicillin-resistant Streptococcus mitis. Author(s): Hall GE, Baddour LM. Source: The American Journal of the Medical Sciences. 2002 July; 324(1): 51-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12120826&dopt=Abstract

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Azithromycin versus penicillin V for treatment of acute group A streptococcal pharyngitis. Author(s): Schaad UB, Kellerhals P, Altwegg M; Swiss Pharyngitis Study Group. Source: The Pediatric Infectious Disease Journal. 2002 April; 21(4): 304-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12075761&dopt=Abstract

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Bactericidal activity of levofloxacin, gatifloxacin, penicillin, meropenem and rokitamycin against Bacillus anthracis clinical isolates. Author(s): Drago L, De Vecchi E, Lombardi A, Nicola L, Valli M, Gismondo MR. Source: The Journal of Antimicrobial Chemotherapy. 2002 December; 50(6): 1059-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12461034&dopt=Abstract

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Benzylpenicillin differentially conjugates to IFN-gamma, TNF-alpha, IL-1beta, IL-4 and IL-13 but selectively reduces IFN-gamma activity. Author(s): Brooks BM, Thomas AL, Coleman JW. Source: Clinical and Experimental Immunology. 2003 February; 131(2): 268-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562387&dopt=Abstract

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beta-Lactam allergenic determinants: fine structural recognition of a cross-reacting determinant on benzylpenicillin and cephalothin. Author(s): Zhao Z, Baldo BA, Rimmer J. Source: Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology. 2002 November; 32(11): 1644-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12569987&dopt=Abstract

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beta-Lactamase-producing Moraxella catarrhalis may prevent the emergence of penicillin-resistant Streptococcus pneumoniae in children with recurrent acute otitis media. Author(s): Joki-Erkkila VP, Aittoniemi J, Vuento R, Puhakka H. Source: International Journal of Pediatric Otorhinolaryngology. 2002 May 15; 63(3): 21922. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11997157&dopt=Abstract

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Bifunctional penicillin-binding proteins: focus on the glycosyltransferase domain and its specific inhibitor moenomycin. Author(s): Di Guilmi AM, Dessen A, Dideberg O, Vernet T. Source: Current Pharmaceutical Biotechnology. 2002 June; 3(2): 63-75. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12022260&dopt=Abstract

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Birth outcome of 1886 pregnancies after exposure to phenoxymethylpenicillin in utero. Author(s): Dencker BB, Larsen H, Jensen ES, Schonheyder HC, Nielsen GL, Sorensen HT. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2002 April; 8(4): 196-201. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12047410&dopt=Abstract

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Ceftriaxone compared with sodium penicillin g for treatment of severe leptospirosis. Author(s): Panaphut T, Domrongkitchaiporn S, Vibhagool A, Thinkamrop B, Susaengrat W. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 June 15; 36(12): 1507-13. Epub 2003 Jun 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12802748&dopt=Abstract

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Cerebral blood flow changes in general paresis following penicillin treatment: a longitudinal single photon emission computed tomography study. Author(s): Kitabayashi Y, Ueda H, Narumoto J, Nakamura K, Kita H, Tsuchida H, Iizumi H, Fukui K. Source: Psychiatry and Clinical Neurosciences. 2002 February; 56(1): 65-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11929572&dopt=Abstract

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Changes in antibiotic-prescribing practices and carriage of penicillin-resistant Streptococcus pneumoniae: A controlled intervention trial in rural Alaska. Author(s): Hennessy TW, Petersen KM, Bruden D, Parkinson AJ, Hurlburt D, Getty M, Schwartz B, Butler JC. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 June 15; 34(12): 1543-50. Epub 2002 May 21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12032887&dopt=Abstract

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Chloramphenicol versus benzylpenicillin and gentamicin for the treatment of severe pneumonia in children in Papua New Guinea: a randomised trial. Author(s): Duke T, Poka H, Dale F, Michael A, Mgone J, Wal T. Source: Lancet. 2002 February 9; 359(9305): 474-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11853793&dopt=Abstract

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Clarithromycin mediated the expression of polymorphonuclear granulocyte response against streptococcus pneumoniae strains with different patterns of susceptibility and resistance to penicillin and clarithromycin. Author(s): Cuffini AM, Tullio V, Mandras N, Roana J, Scalas D, Banche G, Carlone NA. Source: Int J Tissue React. 2002; 24(1): 37-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12013153&dopt=Abstract

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Clinical outcome of erythema migrans after treatment with phenoxymethyl penicillin. Author(s): Bennet L, Danell S, Berglund J. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(2): 129-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12693565&dopt=Abstract

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Clinical relevance of penicillin-resistant Streptococcus pneumoniae. Author(s): Cunha BA. Source: Seminars in Respiratory Infections. 2002 September; 17(3): 204-14. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12226800&dopt=Abstract

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Clinical significance of inhibition kinetics for Streptococcus pyogenes in response to penicillin. Author(s): Steininger C, Allerberger F, Gnaiger E. Source: The Journal of Antimicrobial Chemotherapy. 2002 October; 50(4): 517-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12356796&dopt=Abstract

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Combined effects of in vitro penicillin and sickle cell disease sera on normal lymphocyte functions. Author(s): Taylor SC, Shacks SJ, Qu Z, Bryant P. Source: Journal of the National Medical Association. 2002 August; 94(8): 678-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12152923&dopt=Abstract

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Comparison of two dosages of azithromycin for three days versus penicillin V for ten days in acute group A streptococcal tonsillopharyngitis. Author(s): Cohen R, Reinert P, De La Rocque F, Levy C, Boucherat M, Robert M, Navel M, Brahimi N, Deforche D, Palestro B, Bingen E. Source: The Pediatric Infectious Disease Journal. 2002 April; 21(4): 297-303. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12075760&dopt=Abstract

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Controlled administration of penicillin to patients with a positive history but negative skin and specific serum IgE tests. Author(s): Torres MJ, Mayorga C, Leyva L, Guzman AE, Cornejo-Garcia JA, Juarez C, Blanca M. Source: Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology. 2002 February; 32(2): 270-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11929493&dopt=Abstract

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Cross-reactivity of cefotetan and ceftriaxone antibodies, associated with hemolytic anemia, with other: cephalosporins and penicillin. Author(s): Arndt PA, Garratty G. Source: American Journal of Clinical Pathology. 2002 August; 118(2): 256-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12162687&dopt=Abstract

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Culture-negative childhood empyema is usually due to penicillin-sensitive Streptococcus pneumoniae capsular serotype 1. Author(s): Eltringham G, Kearns A, Freeman R, Clark J, Spencer D, Eastham K, Harwood J, Leeming J. Source: Journal of Clinical Microbiology. 2003 January; 41(1): 521-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12517914&dopt=Abstract

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Determination of the incidence of sensitization after penicillin skin testing. Author(s): Nugent JS, Quinn JM, McGrath CM, Hrncir DE, Boleman WT, Freeman TM. Source: Annals of Allergy, Asthma & Immunology : Official Publication of the American College of Allergy, Asthma, & Immunology. 2003 April; 90(4): 398-403. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12722961&dopt=Abstract

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Diagnosing nonimmediate reactions to penicillins by in vivo tests. Author(s): Romano A, Viola M, Mondino C, Pettinato R, Di Fonso M, Papa G, Venuti A, Montuschi P. Source: International Archives of Allergy and Immunology. 2002 October; 129(2): 169-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12403935&dopt=Abstract

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Distinct delayed T-cell response to beta-methasone and penicillin-G in the same patient. Author(s): Scala E, Giani M, Pastore S, Pallotta S, Guerra EC, Pirrotta L, Locanto ML, Frezzolini A, De Pita O, Puddu P. Source: Allergy. 2003 May; 58(5): 439-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12752333&dopt=Abstract

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Diversity among clinical isolates of penicillin-resistant Streptococcus mitis: indication for a PBP1-dependent way to reach high levels of penicillin resistance. Author(s): Sanchez M, Vicente MF, Cercenado E, de Pedro MA, Gomez P, Moreno R, Moron R, Berenguer J. Source: International Microbiology : the Official Journal of the Spanish Society for Microbiology. 2001 December; 4(4): 217-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12051565&dopt=Abstract

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Diversity of beta-lactam resistance-conferring amino acid substitutions in penicillinbinding protein 3 of Haemophilus influenzae. Author(s): Dabernat H, Delmas C, Seguy M, Pelissier R, Faucon G, Bennamani S, Pasquier C. Source: Antimicrobial Agents and Chemotherapy. 2002 July; 46(7): 2208-18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12069976&dopt=Abstract

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Diversity of penicillin-nonsusceptible Streptococcus pneumoniae circulating in Iceland after the introduction of penicillin-resistant clone Spain(6B)-2. Author(s): Sa-Leao R, Vilhelmsson SE, de Lencastre H, Kristinsson KG, Tomasz A. Source: The Journal of Infectious Diseases. 2002 October 1; 186(7): 966-75. Epub 2002 September 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12232837&dopt=Abstract

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Effect of high-dose amoxicillin on the prevalence of penicillin-resistant Streptococcus pneumoniae in rural Alaska. Author(s): Hennessy TW, Bruden D, Petersen KM, Parkinson AJ, Hurlburt D, Getty M, Butler JC, Schwartz B. Source: Jama : the Journal of the American Medical Association. 2002 April 24; 287(16): 2078-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11966381&dopt=Abstract

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Effect of penicillin resistance of Streptococcus pneumoniae on the presentation, prognosis, and treatment of pneumococcal endocarditis in adults. Author(s): Martinez E, Miro JM, Almirante B, Aguado JM, Fernandez-Viladrich P, Fernandez-Guerrero ML, Villanueva JL, Dronda F, Moreno-Torrico A, Montejo M, Llinares P, Gatell JM; Spanish Pneumococcal Endocarditis Study Group. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 July 15; 35(2): 130-9. Epub 2002 June 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12087518&dopt=Abstract

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Effect of subminimal inhibitory concentrations of gentamicin, penicillin, trimethoprim-sulfamethoxazole on adherence of uropathogenic Escherichia coli strains. Author(s): Baskin H, Dogan Y, Hakki BI, Yulug N. Source: Journal of Chemotherapy (Florence, Italy). 2002 April; 14(2): 161-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12017371&dopt=Abstract

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Effects of amino acid alterations in penicillin-binding proteins (PBPs) 1a, 2b, and 2x on PBP affinities of penicillin, ampicillin, amoxicillin, cefditoren, cefuroxime, cefprozil, and cefaclor in 18 clinical isolates of penicillin-susceptible, -intermediate, and -resistant pneumococci. Author(s): Nagai K, Davies TA, Jacobs MR, Appelbaum PC. Source: Antimicrobial Agents and Chemotherapy. 2002 May; 46(5): 1273-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11959556&dopt=Abstract

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Efficacy and pharmacodynamics of simulated human-like treatment with levofloxacin on experimental pneumonia induced with penicillin-resistant pneumococci with various susceptibilities to fluoroquinolones. Author(s): Croisier D, Chavanet P, Lequeu C, Ahanou A, Nierlich A, Neuwirth C, Piroth L, Duong M, Buisson M, Portier H. Source: The Journal of Antimicrobial Chemotherapy. 2002 September; 50(3): 349-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12205059&dopt=Abstract

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Efficacy of a targeted, oral penicillin-based yaws control program among children living in rural South America. Author(s): Scolnik D, Aronson L, Lovinsky R, Toledano K, Glazier R, Eisenstadt J, Eisenberg P, Wilcox L, Rowsell R, Silverman M. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 May 15; 36(10): 1232-8. Epub 2003 May 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746767&dopt=Abstract

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Efficacy of penicillin G benzathine as antimicrobial treatment of cutaneous secondary syphilis in patients with HIV infection. Author(s): Calza L, Manfredi R, Marinacci G, Tadolini M, Fortunato L, Chiodo F. Source: Journal of Chemotherapy (Florence, Italy). 2002 October; 14(5): 533-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12462435&dopt=Abstract

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Efficacy of penicillin vs. amoxicillin in children with group A beta hemolytic streptococcal tonsillopharyngitis. Author(s): Curtin-Wirt C, Casey JR, Murray PC, Cleary CT, Hoeger WJ, Marsocci SM, Murphy ML, Francis AB, Pichichero ME. Source: Clinical Pediatrics. 2003 April; 42(3): 219-25. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12739920&dopt=Abstract

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Efficacy of short-course therapy with the ketolide telithromycin compared with 10 days of penicillin V for the treatment of pharyngitis/tonsillitis. Author(s): Norrby SR, Rabie WJ, Bacart P, Mueller O, Leroy B, Rangaraju M, ButticazIroudayassamy E. Source: Scandinavian Journal of Infectious Diseases. 2001; 33(12): 883-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11868759&dopt=Abstract

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Emergence of a novel penicillin-nonsusceptible, invasive serotype 35B clone of Streptococcus pneumoniae within the United States. Author(s): Beall B, McEllistrem MC, Gertz RE Jr, Boxrud DJ, Besser JM, Harrison LH, Jorgensen JH, Whitney CG; Active Bacterial Core Surveillance/Emerging Infections Program Network. Source: The Journal of Infectious Diseases. 2002 July 1; 186(1): 118-22. Epub 2002 June 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12089672&dopt=Abstract

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Emergence of penicillin resistance among Fusobacterium nucleatum populations of commensal oral flora during early childhood. Author(s): Nyfors S, Kononen E, Syrjanen R, Komulainen E, Jousimies-Somer H. Source: The Journal of Antimicrobial Chemotherapy. 2003 January; 51(1): 107-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12493794&dopt=Abstract

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Endocarditis caused by penicillin-resistant Streptococcus mitis in a 12-year-old boy. Author(s): Huang IF, Chiou CC, Liu YC, Hsieh KS. Source: J Microbiol Immunol Infect. 2002 June; 35(2): 129-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12099335&dopt=Abstract

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Epidemiology of penicillin-resistant pneumococci in a Merseyside Health District over a 14-year period. Author(s): Vardhan MS, Allen KD. Source: The Journal of Infection. 2003 January; 46(1): 23-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12504605&dopt=Abstract

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Fatal outcome from meningococcal disease--an association with meningococcal phenotype but not with reduced susceptibility to benzylpenicillin. Author(s): Trotter CL, Fox AJ, Ramsay ME, Sadler F, Gray SJ, Mallard R, Kaczmarski EB. Source: Journal of Medical Microbiology. 2002 October; 51(10): 855-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12435065&dopt=Abstract

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Gemifloxacin is efficacious against penicillin-resistant and quinolone-resistant pneumococci in experimental meningitis. Author(s): Cottagnoud P, Acosta F, Cottagnoud M, Tauber MG. Source: Antimicrobial Agents and Chemotherapy. 2002 May; 46(5): 1607-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11959614&dopt=Abstract

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Health care resource utilization associated with treatment of penicillin-susceptible and -nonsusceptible isolates of Streptococcus pneumoniae. Author(s): Klepser ME, Klepser DG, Ernst EJ, Brooks J, Diekema DJ, Mozaffari E, Hendrickson J, Doern GV. Source: Pharmacotherapy. 2003 March; 23(3): 349-59. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627934&dopt=Abstract

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High percentages of resistance to tetracycline and penicillin and reduced susceptibility to azithromycin characterize the majority of strain types of Neisseria gonorrhoeae isolates in Cuba, 1995-1998. Author(s): Sosa J, Ramirez-Arcos S, Ruben M, Li H, Llanes R, Llop A, Dillon JA. Source: Sexually Transmitted Diseases. 2003 May; 30(5): 443-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916137&dopt=Abstract

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High prevalence of cfxA beta-lactamase in aminopenicillin-resistant Prevotella strains isolated from periodontal pockets. Author(s): Fosse T, Madinier I, Hannoun L, Giraud-Morin C, Hitzig C, Charbit Y, Ourang S. Source: Oral Microbiology and Immunology. 2002 April; 17(2): 85-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11929554&dopt=Abstract

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High rate of transmission of penicillin-resistant Streptococcus pneumoniae between parents and children. Author(s): Hoshino K, Watanabe H, Sugita R, Asoh N, Ntabaguzi SA, Watanabe K, Oishi K, Nagatake T. Source: Journal of Clinical Microbiology. 2002 November; 40(11): 4357-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409431&dopt=Abstract

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History of penicillin allergy and referral for skin testing: evaluation of a pediatric penicillin allergy testing program. Author(s): Langley JM, Halperin SA, Bortolussi R. Source: Clinical and Investigative Medicine. Medecine Clinique Et Experimentale. 2002 October; 25(5): 181-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12375719&dopt=Abstract

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Howard Florey, Alexander Fleming and the fairy tale of penicillin. Author(s): Vellar ID. Source: The Medical Journal of Australia. 2002 July 1; 177(1): 52; Author Reply 53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12088484&dopt=Abstract

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IgE antibodies to penicillin in skin test negative patients. Author(s): Torres MJ, Mayorga C, Cornejo-Garcia JA, Romano A, Blanca M. Source: Allergy. 2002 October; 57(10): 965. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12269955&dopt=Abstract

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In vitro activity of extended-spectrum cephalosporins against Streptococcus pneumoniae strains with reduced susceptibility to penicillin isolated from patients in Portugal between 1995 and 2000. Author(s): Canica M, Dias R, Louro D, Carvalho C; Multicentre Study Group. Source: The Journal of Antimicrobial Chemotherapy. 2002 October; 50(4): 611-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12356811&dopt=Abstract

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In vitro susceptibility of Staphylococcus aureus towards amoxycillin-clavulanic acid, penicillin-clavulanic acid, dicloxacillin and cefuroxime. Author(s): Skov R, Frimodt-Moller N, Espersen F. Source: Apmis : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica. 2002 August; 110(7-8): 559-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12390414&dopt=Abstract

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In vivo penicillin MIC drift to extremely high resistance in Serotype 14 Streptococcus pneumoniae persistently colonizing the nasopharynx of an infant with chronic suppurative lung disease: a case study. Author(s): Leach AJ, Morris PS, Smith-Vaughan H, Mathews JD. Source: Antimicrobial Agents and Chemotherapy. 2002 November; 46(11): 3648-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12384383&dopt=Abstract

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Independent risk factors for carriage of penicillin-non-susceptible Streptococcus pneumoniae. Author(s): Regev-Yochay G, Raz M, Shainberg B, Dagan R, Varon M, Dushenat M, Rubinstein E. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(4): 219-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839146&dopt=Abstract

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Influences of linezolid, penicillin, and clindamycin, alone and in combination, on streptococcal pyrogenic exotoxin a release. Author(s): Coyle EA, Cha R, Rybak MJ. Source: Antimicrobial Agents and Chemotherapy. 2003 May; 47(5): 1752-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12709354&dopt=Abstract

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Intramuscular penicillin is more effective than oral penicillin in secondary prevention of rheumatic fever--a systematic review. Author(s): Manyemba J, Mayosi BM. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 2003 March; 93(3): 212-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12768947&dopt=Abstract

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Introduction of new clones of penicillin-nonsusceptible Streptococcus pneumoniae in Hong Kong. Author(s): Ip M, Lyon DJ, Yung RW, Tsang L, Cheng AF. Source: Journal of Clinical Microbiology. 2002 April; 40(4): 1522-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11923387&dopt=Abstract

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Is penicillin and/or erythromycin resistance present in clinical isolates of group B streptococcus in our community? Author(s): Stylianopoulos A, Kelly N, Garland S. Source: The Australian & New Zealand Journal of Obstetrics & Gynaecology. 2002 November; 42(5): 543-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495105&dopt=Abstract

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Lack of penicillin resensitization in patients with a history of penicillin allergy after receiving repeated penicillin courses. Author(s): Solensky R, Earl HS, Gruchalla RS. Source: Archives of Internal Medicine. 2002 April 8; 162(7): 822-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11926858&dopt=Abstract

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Large-scale outbreak of infection with Mycobacterium chelonae subsp. abscessus after penicillin injection. Author(s): Zhibang Y, BiXia Z, Qishan L, Lihao C, Xiangquan L, Huaping L. Source: Journal of Clinical Microbiology. 2002 July; 40(7): 2626-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12089291&dopt=Abstract

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Listerial endocarditis in a penicillin-allergic woman successfully treated with a combination of 4 drugs. Author(s): Benes J, Viechova J, Kabelkova M, Horova B. Source: Scandinavian Journal of Infectious Diseases. 2002; 34(5): 383-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12069025&dopt=Abstract

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Meningitis due to mixed infection with penicillin-resistant and penicillin-susceptible strains of Streptococcus pneumoniae. Author(s): Chaves F, Campelo C, Sanz F, Otero JR. Source: Journal of Clinical Microbiology. 2003 January; 41(1): 512-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12517910&dopt=Abstract

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Mosaic-like structure of penicillin-binding protein 2 Gene (penA) in clinical isolates of Neisseria gonorrhoeae with reduced susceptibility to cefixime. Author(s): Ameyama S, Onodera S, Takahata M, Minami S, Maki N, Endo K, Goto H, Suzuki H, Oishi Y. Source: Antimicrobial Agents and Chemotherapy. 2002 December; 46(12): 3744-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12435671&dopt=Abstract

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Nasopharyngeal carriage of drug-resistant Streptococcus pneumoniae in children with acute otitis media evaluated by polymerase chain reaction-based genotyping of penicillin-binding proteins. Author(s): Hotomi M, Yamanaka N, Faden H, Shimada J, Suzumoto M, Sakai A, Saito T, Kuki K. Source: Acta Oto-Laryngologica. 2002 January; 122(1): 72-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11876602&dopt=Abstract

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Nasopharyngeal penicillin-resistant Streptococcus pneumoniae strains among young children in Japan. Author(s): Ito M, Ito K, Yoshizaki T, Nishimura T, Miwa T, Furukawa M. Source: Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 2002 May; 23(3): 349-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11981394&dopt=Abstract

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Neisseria meningitidis with decreased susceptibility to penicillin in Istanbul, Turkey. Author(s): Punar M, Eraksoy H, Cagatay AA, Ozsut H, Kaygusuz A, Calangu S, Dilmener M. Source: Scandinavian Journal of Infectious Diseases. 2002; 34(1): 11-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11874158&dopt=Abstract

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Non-penicillinase producing Neisseria gonnorhoeae: are they still in existence in Ibadan, Nigeria? Author(s): Bakare RA, Oni AA, Umar US, Kehinde AO, Fayemiwo SA, Alli OO. Source: Afr J Med Med Sci. 2001 December; 30(4): 281-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14510104&dopt=Abstract

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Obstacles to penicillin use in treating pneumococcal infection. Author(s): Nord JA, LaBombardi VJ. Source: International Journal of Infectious Diseases : Ijid : Official Publication of the International Society for Infectious Diseases. 2001; 5(4): 199-201. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11953216&dopt=Abstract

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Oral antibiotic adverse reactions after penicillin skin testing: multi-year follow-up. Author(s): Macy E, Burchette RJ. Source: Allergy. 2002 December; 57(12): 1151-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12464043&dopt=Abstract

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Oral pristinamycin versus standard penicillin regimen to treat erysipelas in adults: randomised, non-inferiority, open trial. Author(s): Bernard P, Chosidow O, Vaillant L; French Erysipelas Study Group. Source: Bmj (Clinical Research Ed.). 2002 October 19; 325(7369): 864. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12386036&dopt=Abstract

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Outcome of penicillin-nonsusceptible Streptococcus pneumoniae meningitis: a nested case-control study. Author(s): Kellner JD, Scheifele DW, Halperin SA, Lebel MH, Moore D, Le Saux N, Ford-Jones EL, Law B, Vaudry W; Canadian Paediatric Society/Centre for Infectious Disease Prevention and Control Immunization Monitoring Program. Source: The Pediatric Infectious Disease Journal. 2002 October; 21(10): 903-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12394810&dopt=Abstract

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Outcome of penicillin-susceptible streptococcal prosthetic joint infection treated with debridement and retention of the prosthesis. Author(s): Meehan AM, Osmon DR, Duffy MC, Hanssen AD, Keating MR. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 April 1; 36(7): 845-9. Epub 2003 March 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12652384&dopt=Abstract

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Overexpression of the MtrC-MtrD-MtrE efflux pump due to an mtrR mutation is required for chromosomally mediated penicillin resistance in Neisseria gonorrhoeae. Author(s): Veal WL, Nicholas RA, Shafer WM. Source: Journal of Bacteriology. 2002 October; 184(20): 5619-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12270819&dopt=Abstract

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Pathogens in acute otitis media--impact of intermittent penicillin V prophylaxis on infant nasopharyngeal flora. Author(s): Fogle-Hansson M, White P, Hermansson A. Source: International Journal of Pediatric Otorhinolaryngology. 2003 May; 67(5): 511-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12697353&dopt=Abstract

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Penicillin allergy. Author(s): Torres MJ, Blanca M. Source: Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology. 2003 May; 33(5): 714. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12752603&dopt=Abstract

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Penicillin allergy. Author(s): Torres MJ, Blanca M. Source: Allergy. 2003 May; 58(5): 452. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12752336&dopt=Abstract

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Penicillin allergy: consider trying penicillin again. Author(s): Arroliga ME, Pien L. Source: Cleve Clin J Med. 2003 April; 70(4): 313-4, 317-8, 320-1 Passim. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701985&dopt=Abstract

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Penicillin and semisynthetic penicillins in dermatology. Author(s): Kadurina M, Bocheva G, Tonev S. Source: Clinics in Dermatology. 2003 January-February; 21(1): 12-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12609584&dopt=Abstract

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Penicillin at the late stage of leptospirosis: a randomized controlled trial. Author(s): Costa E, Lopes AA, Sacramento E, Costa YA, Matos ED, Lopes MB, Bina JC. Source: Revista Do Instituto De Medicina Tropical De Sao Paulo. 2003 May-June; 45(3): 141-5. Epub 2003 July 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870063&dopt=Abstract

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Penicillin enhances the toll-like receptor 2-mediated proinflammatory activity of Streptococcus pneumoniae. Author(s): Moore LJ, Pridmore AC, Dower SK, Read RC. Source: The Journal of Infectious Diseases. 2003 October 1; 188(7): 1040-8. Epub 2003 September 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14513425&dopt=Abstract

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Penicillin failures?! Author(s): Stollerman GH. Source: Pediatrics. 2002 June; 109(6): 1190-2; Author Reply 1190-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12042574&dopt=Abstract

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Penicillin failures?! Author(s): Pichichero ME. Source: Pediatrics. 2002 June; 109(6): 1189-90; Author Reply 1190-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12042573&dopt=Abstract

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Penicillin failures?! Author(s): Burke BL Jr. Source: Pediatrics. 2002 June; 109(6): 1189; Author Reply 1190-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12042572&dopt=Abstract

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Penicillin failures?! Author(s): Rowe DS. Source: Pediatrics. 2002 June; 109(6): 1188-9; Author Reply 1190-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12042571&dopt=Abstract

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Penicillin for secondary prevention of rheumatic fever. Author(s): Manyemba J, Mayosi BM. Source: Cochrane Database Syst Rev. 2002; (3): Cd002227. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12137650&dopt=Abstract

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Penicillin kills. Author(s): Baumgartner P. Source: Anaesthesia. 2002 September; 57(9): 942-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12240619&dopt=Abstract

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Penicillin resistance in pneumococcal pneumonia. Antibiotics with low resistance potential are effective and pose less risk. Author(s): Cunha BA. Source: Postgraduate Medicine. 2003 January; 113(1): 42-4, 47-8, 52-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12545592&dopt=Abstract

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Penicillin resistance is not equal to virulence: rational choice of antibiotics in pneumococcal infections. Author(s): Lin TY. Source: Acta Paediatr Taiwan. 2003 March-April; 44(2): 65-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12845844&dopt=Abstract

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Penicillin resistant Streptococcus pneumoniae isolated from infected children in Athens, Greece: resistance patterns, serotypes and penicillin-binding protein 2B mutation characterization by PCR. Author(s): Chatzipanagiotou S, Papavasileiou E, Panagea T, Makri A, Paraskaki I, Nicolaou C, Ioannidis A, Legakis NJ. Source: International Journal of Antimicrobial Agents. 2002 August; 20(2): 147-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12297366&dopt=Abstract

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Penicillin resistant Streptococcus pneumoniae. Author(s): Shenoy S, K E V. Source: Indian Pediatrics. 2003 June; 40(6): 587-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824677&dopt=Abstract

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Penicillin sensitivity. Author(s): Palomeque FE, Fulton J, Derbes VJ. Source: Archives of Dermatology. 1965 September; 92(3): 271-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11851248&dopt=Abstract

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Penicillin skin testing in advance of need: multiyear follow-up in 568 test resultnegative subjects exposed to oral penicillins. Author(s): Macy E, Mangat R, Burchette RJ. Source: The Journal of Allergy and Clinical Immunology. 2003 May; 111(5): 1111-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12743578&dopt=Abstract

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Penicillin susceptibility and epidemiological typing of invasive pneumococcal isolates in the Republic of Ireland. Author(s): Bennett D, Lennon B, Humphreys H, Cafferkey M. Source: Journal of Clinical Microbiology. 2003 August; 41(8): 3641-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904369&dopt=Abstract

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Penicillin tolerance amongst non-toxigenic Corynebacterium diphtheriae isolated from cases of pharyngitis. Author(s): von Hunolstein C, Scopetti F, Efstratiou A, Engler K. Source: The Journal of Antimicrobial Chemotherapy. 2002 July; 50(1): 125-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12096018&dopt=Abstract

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Penicillinase producing Neisseria gonnorhoeae: the review of the present situation in Ibadan, Nigeria. Author(s): Bakare RA, Oni AA, Arowojolu AO, Umar US, Kehinde AO, Fayemiwo SA, Fasina NA. Source: Niger Postgrad Med J. 2002 June; 9(2): 59-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12163874&dopt=Abstract

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Penicillin-binding protein 1A, 2B, and 2X alterations in Canadian isolates of penicillin-resistant Streptococcus pneumoniae. Author(s): Nichol KA, Zhanel GG, Hoban DJ. Source: Antimicrobial Agents and Chemotherapy. 2002 October; 46(10): 3261-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12234855&dopt=Abstract

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Penicillin-resistant Aerococcus viridans bacteremia associated with granulocytopenia. Author(s): Uh Y, Son JS, Jang IH, Yoon KJ, Hong SK. Source: Journal of Korean Medical Science. 2002 February; 17(1): 113-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11850599&dopt=Abstract

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Penicillin-resistant pneumococci-implications for management of communityacquired pneumonia and meningitis. Author(s): Ziglam HM, Finch RG. Source: International Journal of Infectious Diseases : Ijid : Official Publication of the International Society for Infectious Diseases. 2002 March; 6 Suppl 1: S14-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12044285&dopt=Abstract

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Penicillin-resistant Streptococcus pneumoniae septic shock and meningitis complicating chronic graft versus host disease: a case report and review of the literature. Author(s): Haddad PA, Repka TL, Weisdorf DJ. Source: The American Journal of Medicine. 2002 August 1; 113(2): 152-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12133754&dopt=Abstract

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Peripartum transmission of penicillin-resistant Streptococcus pneumoniae. Author(s): McDonald LC, Bryant K, Snyder J. Source: Journal of Clinical Microbiology. 2003 May; 41(5): 2258-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12734296&dopt=Abstract

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Phenotypic and genotypic characterization of two penicillin-susceptible serotype 6B Streptococcus pneumoniae clones circulating in Italy. Author(s): Gherardi G, Del Grosso M, Scotto D'Abusco A, D'Ambrosio F, Dicuonzo G, Pantosti A. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 2855-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843012&dopt=Abstract

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Possible overestimation of penicillin resistant Streptococcus pneumoniae colonization rates due to misidentification of oropharyngeal streptococci. Author(s): Wester CW, Ariga D, Nathan C, Rice TW, Pulvirenti J, Patel R, Kocka F, Ortiz J, Weinstein RA. Source: Diagnostic Microbiology and Infectious Disease. 2002 April; 42(4): 263-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12007444&dopt=Abstract

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Prevalence of moderate penicillin resistant invasive Neisseria meningitidis infection in Scotland, 1994-9. Author(s): Kyaw MH, Bramley JC, Clark S, Christie P, Jones IG, Campbell H. Source: Epidemiology and Infection. 2002 April; 128(2): 149-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12002531&dopt=Abstract

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Prevalence of penicillin non-susceptible invasive pneumococcal disease in the elderly in Scotland, 1992-99. Author(s): Kyaw MH, Jones IG, Campbell H. Source: Scandinavian Journal of Infectious Diseases. 2002; 34(8): 559-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12238568&dopt=Abstract

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Rapid emergence of resistance to penicillin and trimethoprim-sulphamethoxazole in invasive Streptococcus pneumoniae in Zimbabwe. Author(s): Gwanzura L, Pasi C, Nathoo KJ, Hakim J, Gangaidzo I, Mielke J, Robertson VJ, Heyderman RS, Mason PR. Source: International Journal of Antimicrobial Agents. 2003 June; 21(6): 557-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791469&dopt=Abstract

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Rapid increase in macrolide resistance among penicillin non-susceptible pneumococci in Finland, 1996-2000. Author(s): Pihlajamaki M, Kaijalainen T, Huovinen P, Jalava J; Finnish Study Group for Antimicrobial Resistance. Source: The Journal of Antimicrobial Chemotherapy. 2002 May; 49(5): 785-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12003972&dopt=Abstract

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Rapid spread of penicillin-resistant Streptococcus pneumoniae among high-risk hospital inpatients and the role of molecular typing in outbreak confirmation. Author(s): Subramanian D, Sandoe JA, Keer V, Wilcox MH. Source: The Journal of Hospital Infection. 2003 June; 54(2): 99-103. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818581&dopt=Abstract

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Recent advances in the understanding of the penicillin urticarias. Author(s): Jillson OF, Porter PS. Source: Archives of Dermatology. 1965 August; 92(2): 200-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11850931&dopt=Abstract

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Ref.: Penicillin at the late stage of leptospirosis: a randomized controlled trial. Author(s): Leblebicioglu H. Source: Revista Do Instituto De Medicina Tropical De Sao Paulo. 2003 July-August; 45(4): 237; Author Reply 238. Epub 2003 September 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14502355&dopt=Abstract

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Relationship between beta-lactamase production, outer membrane protein and penicillin-binding protein profiles on the activity of carbapenems against clinical isolates of Acinetobacter baumannii. Author(s): Fernandez-Cuenca F, Martinez-Martinez L, Conejo MC, Ayala JA, Perea EJ, Pascual A. Source: The Journal of Antimicrobial Chemotherapy. 2003 March; 51(3): 565-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615856&dopt=Abstract

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Relief of symptoms in patients with group A beta-hemolytic streptococcus tonsillopharyngitis: comparison between telithromycin and penicillin V. Author(s): Norrby SR, Chang J, Stewart JA, Brumpt I, Conway DP. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(4): 223-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839147&dopt=Abstract

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Risk factors for penicillin resistance and mortality in Korean adults with Streptococcus pneumoniae bacteremia. Author(s): Kim BN, Bae LG, Kim MN, Park SJ, Woo JH, Ryu J, Kim YS. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2002 January; 21(1): 35-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11913499&dopt=Abstract

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Separating fact from fiction: the data behind allergies and side effects caused by penicillins, cephalosporins, and carbapenem antibiotics. Author(s): Leviton I. Source: Current Pharmaceutical Design. 2003; 9(12): 983-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12678864&dopt=Abstract

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Shortage of penicillin G: impact on antibiotic prescribing at a US tertiary care centre. Author(s): Harbarth S, Gundlapalli AV, Stockdale W, Samore MH. Source: International Journal of Antimicrobial Agents. 2003 May; 21(5): 484-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12727084&dopt=Abstract

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Short-course penicillin therapy for meningococcal disease: accumulating evidence and persistent uncertainty. Author(s): Quagliarello V. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 September 1; 37(5): 663-4. Epub 2003 August 11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12942397&dopt=Abstract

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Solitary erythema migrans in children: comparison of treatment with azithromycin and phenoxymethylpenicillin. Author(s): Arnez M, Pleterski-Rigler D, Luznik-Bufon T, Ruzic-Sabljic E, Strle F. Source: Wiener Klinische Wochenschrift. 2002 July 31; 114(13-14): 498-504. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12422590&dopt=Abstract

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Stabilization of penicillin resistance among Streptococcus pneumoniae isolated in Eastern Tennessee. Author(s): Baddour LM, Cole ME. Source: International Journal of Antimicrobial Agents. 2002 August; 20(2): 141-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12297364&dopt=Abstract

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Streptococcus pneumoniae bacteremia: duration of previous antibiotic use and association with penicillin resistance. Author(s): Ruhe JJ, Hasbun R. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 May 1; 36(9): 1132-8. Epub 2003 April 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12715307&dopt=Abstract

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Streptococcus pneumoniae resistance to penicillin and ceftriaxone in a tertiary care center in Saudi Arabia. Author(s): Al-Aqeeli AA, Guy ML, Al-Jumaah SA. Source: Saudi Med J. 2002 April; 23(4): 400-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11953764&dopt=Abstract

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Streptococcus pneumoniae sepsis and meningitis during the penicillin prophylaxis era in children with sickle cell disease. Author(s): Hord J, Byrd R, Stowe L, Windsor B, Smith-Whitley K. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2002 August-September; 24(6): 470-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12218595&dopt=Abstract

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Successful desensitization to penicillin after diagnostic reassessment. Author(s): Soriano V, Niveiro E, Fernandez J, Castello JV, Gonzalez P. Source: Allergologia Et Immunopathologia. 2003 March-April; 31(2): 94-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12646126&dopt=Abstract

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Successful treatment of meningitis caused by highly-penicillin-resistant Streptococcus mitis in a leukemic child. Author(s): Jaing TH, Chiu CH, Hung IJ. Source: Chang Gung Med J. 2002 March; 25(3): 190-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12022740&dopt=Abstract

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Syphilis in pregnancy in Tanzania. II. The effectiveness of antenatal syphilis screening and single-dose benzathine penicillin treatment for the prevention of adverse pregnancy outcomes. Author(s): Watson-Jones D, Gumodoka B, Weiss H, Changalucha J, Todd J, Mugeye K, Buve A, Kanga Z, Ndeki L, Rusizoka M, Ross D, Marealle J, Balira R, Mabey D, Hayes R. Source: The Journal of Infectious Diseases. 2002 October 1; 186(7): 948-57. Epub 2002 September 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12232835&dopt=Abstract

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Tendency toward increase in the frequency of isolation of beta-lactamasenonproducing Neisseria gonorrhoeae exhibiting penicillin resistance, and recent emergence of multidrug-resistant isolates in Japan. Author(s): Kobayashi I, Kanayama A, Saika T, Nishida M, Nakayama H, Tanaka M, Naito S. Source: Journal of Infection and Chemotherapy : Official Journal of the Japan Society of Chemotherapy. 2003 June; 9(2): 126-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12825110&dopt=Abstract

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The economic burden of antibiotic treatment of penicillin-allergic patients in internal medicine wards of a general tertiary care hospital. Author(s): Sade K, Holtzer I, Levo Y, Kivity S. Source: Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology. 2003 April; 33(4): 501-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12680867&dopt=Abstract

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The glycosyltransferase domain of penicillin-binding protein 2a from Streptococcus pneumoniae catalyzes the polymerization of murein glycan chains. Author(s): Di Guilmi AM, Dessen A, Dideberg O, Vernet T. Source: Journal of Bacteriology. 2003 August; 185(15): 4418-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12867450&dopt=Abstract

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The influence of caprate on rectal absorption of phenoxymethylpenicillin: experience from an in-vivo perfusion in humans. Author(s): Lennernas H, Gjellan K, Hallgren R, Graffner C. Source: The Journal of Pharmacy and Pharmacology. 2002 April; 54(4): 499-508. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11999127&dopt=Abstract

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The penicillins: a review and update. Author(s): Miller EL. Source: Journal of Midwifery & Women's Health. 2002 November-December; 47(6): 42634. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12484664&dopt=Abstract

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The value of routine penicillin allergy skin testing in an outpatient population. Author(s): Warrington RJ, Burton R, Tsai E. Source: Allergy and Asthma Proceedings : the Official Journal of Regional and State Allergy Societies. 2003 May-June; 24(3): 199-202. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12866324&dopt=Abstract

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Three days of intravenous benzyl penicillin treatment of meningococcal disease in adults. Author(s): Ellis-Pegler R, Galler L, Roberts S, Thomas M, Woodhouse A. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 September 1; 37(5): 658-62. Epub 2003 August 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12942396&dopt=Abstract

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Tolerance to penicillin in Staphylococcus pyogenes isolated from skin infections. Author(s): Panzaru C, Gotia D, Taranu T, Ungureanu V, Coman G. Source: Rev Med Chir Soc Med Nat Iasi. 2002 April-June; 107(2): 356-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12638291&dopt=Abstract

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Treatment of latent syphilis in HIV-infected patients with 10 d of benzylpenicillin G benethamine: a prospective study in Maputo, Mozambique. Author(s): Tattevin P, Renault P, Joly V, Bastos R, Coelho E, Adda C, Ebel A, Yeni P. Source: Scandinavian Journal of Infectious Diseases. 2002; 34(4): 257-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12064687&dopt=Abstract

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Two years of penicillin prophylaxis is sufficient to prevent clinically evident carditis in poststreptococcal reactive arthritis. Author(s): Kamphuisen PW, Jansen TL, De Gendt C, de Jong AJ, Janssen M. Source: Journal of Internal Medicine. 2001 November; 250(5): 449-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11887981&dopt=Abstract

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Value of Etest penicillin V and penicillin G strips for penicillin susceptibility testing of Neisseria meningitidis. Author(s): Daher O, Lopardo HA, Rubeglio EA. Source: Diagnostic Microbiology and Infectious Disease. 2002 June; 43(2): 119-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12088618&dopt=Abstract

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Variables influencing bacteriological outcome in patients with streptococcal tonsillopharyngitis treated with penicillin V. Author(s): Ovetchkine P, Levy C, de la Rocque F, Boucherat M, Bingen E, Cohen R. Source: European Journal of Pediatrics. 2002 July; 161(7): 365-7. Epub 2002 May 29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12111186&dopt=Abstract

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Varidans streptococci in the oral flora of the patients at risk for infective endocarditis: species and penicillin susceptibilities. Author(s): Chayakul P, Hortiwakul R, Yipintsoi T, Ingviya N. Source: J Med Assoc Thai. 2002 July; 85(7): 825-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12296416&dopt=Abstract

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

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

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

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

A case of retropharyngeal abscess caused by penicillin-resistant Streptococcus pneumoniae. Author(s): Department of Pediatrics, Kobe City General Hospital, Japan. [email protected] Source: Kobayashi, K I Haruta, T Kubota, M Nishio, T J-Infect. 2002 May; 44(4): 267-9 0163-4453

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A morphologically structured model for penicillin production. Author(s): Department of Chemical and Environmental Engineering, Illinois Institute of Technology, Chicago, Illinois 60616, USA. [email protected] Source: Birol, Gulnur Undey, Cenk Parulekar, Satish J Cinar, Ali Biotechnol-Bioeng. 2002 March 5; 77(5): 538-52 0006-3592

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A study of the effect of benzylpenicillin on isolated human gallbladder. Author(s): Department of Pharmacology, Medical Faculty, University Svetozar Marcovic, Kragujevac, Serbia FR Ugoslavia. Source: Jankovic, S M Papaioannidou, P P Kouvelas, D Mirtsou Fidani, V Methods-FindExp-Clin-Pharmacol. 1999 May; 21(4): 265-7 0379-0355

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Clarithromycin versus penicillin in the treatment of streptococcal pharyngitis. Author(s): South Africa Academy of Family Practice, Medical House, Pinelands, Capetown. Source: Levenstein, J H J-Antimicrob-Chemother. 1991 February; 27 Suppl A67-74 03057453

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Combined effects of in vitro penicillin and sickle cell disease sera on normal lymphocyte functions. Author(s): Department of Pediatrics, Charles R. Drew University of Medicine and Science, King/Drew Medical Center, Los Angeles, California 90059, USA. Source: Taylor, Stephen C Shacks, Samuel J Qu, Zengwei Bryant, Psyhra J-Natl-MedAssoc. 2002 August; 94(8): 678-85 0027-9684

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Comparative neurotoxicity of benzylpenicillin, imipenem/cilastatin and FCE 22101, a new injectible penem. Author(s): Department of Infectious Diseases, University of Umea, Sweden. Source: Schliamser, S E Broholm, K A Liljedahl, A L Norrby, S R J-AntimicrobChemother. 1988 November; 22(5): 687-95 0305-7453

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Computerized EEG analysis of penicillin induced seizure threshold in developing rats. Source: Sharma, S K Selvamurthy, W Behari, M Maheshwari, M C Singh, T P Indian-JMed-Res. 1987 December; 86775-82 0971-5916

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Cultivation of recombinant Escherichia coli to achieve high cell density with a high level of penicillin G acylase activity. Author(s): Department of Chemical Engineering, National Chung Hsing University, Taichung, Taiwan, ROC. Source: Liu, Y C Liao, L C Wu, W T Proc-Natl-Sci-Counc-Repub-China-B. 2000 October; 24(4): 156-60 0255-6596

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Effect of lactoferrin in combination with penicillin on the morphology and the physiology of Staphylococcus aureus isolated from bovine mastitis. Author(s): Dairy and Swine Research and Development Centre, Agriculture and AgriFood Canada, Lennoxville, QC.

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Source: Diarra, M S Petitclerc, D Lacasse, P J-Dairy-Sci. 2002 May; 85(5): 1141-9 00220302 •

Effect of penicillin on postoperative endodontic pain and swelling in symptomatic necrotic teeth. Author(s): Department of Health Services Research, College of Dentistry, The Ohio State University, Columbus 43210, USA. Source: Henry, M Reader, A Beck, M J-Endod. 2001 February; 27(2): 117-23 0099-2399

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Enhanced in-vitro activity of liposome-trapped penicillin-G against Pseudomonas aeruginosa. Author(s): Department of Experimental Physiology, School of Health Sciences, Athens, Greece. Source: Kotsifaki, H Tzouvelekis, L S Panagiotidou, G Vatopoulos, A C Economopoulou, C Legakis, N J J-Chemother. 1990 April; 2(2): 82-6 1120-009X

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Enhancement by epinephrine of benzylpenicillin transport in rat small intestine. Author(s): Department of Pharmacology, Tokushima University School of Dentistry, Tokushima, Japan. Source: Skowronski, M T Ishikawa, Y Ishida, H J-Pharmacol-Exp-Ther. 2000 April; 293(1): 128-35 0022-3565

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Equilibrium modeling of extractive enzymatic hydrolysis of penicillin G with concomitant 6-aminopenicillanic acid crystallization. Author(s): Delft University of Technology, Kluyver Laboratory for Biotechnology, Julianalaan 67, NL-2628 BC Delft, The Netherlands. Source: Diender, M B Straathof, A J J van der Does, T Ras, C Heijnen, J J BiotechnolBioeng. 2002 May 20; 78(4): 395-402 0006-3592

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Folate-targeted enzyme prodrug cancer therapy utilizing penicillin-V amidase and a doxorubicin prodrug. Author(s): Department of Chemistry, Purdue University, West Lafayette, IN 47907-1393, USA. Source: Lu, J Y Lowe, D A Kennedy, M D Low, P S J-Drug-Target. 1999; 7(1): 43-53 1061186X

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Highly antibacterial active aminoacyl penicillin conjugates with acylated biscatecholate siderophores based on secondary diamino acids and related compounds. Author(s): Hans Knoll-Institute for Natural Products Research, Jena, Germany. [email protected] Source: Heinisch, Lothar Wittmann, Steffen Stoiber, Thomas Berg, Albrecht Ankel Fuchs, Dorothe Mollmann, Ute J-Med-Chem. 2002 July 4; 45(14): 3032-40 0022-2623

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Influence of hydroxypropyl beta-cyclodextrin on the stability of benzylpenicillin in chloroacetate buffer. Author(s): School of Pharmacy, Curtin University of Technology, Bentley, Australia. Source: Ong, J K Sunderland, V B McDonald, C J-Pharm-Pharmacol. 1997 June; 49(6): 617-21 0022-3573

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Inhibition of penicillinase by epigallocatechin gallate resulting in restoration of antibacterial activity of penicillin against penicillinase-producing Staphylococcus aureus. Author(s): Department of Microbiology and Immunology, Showa University School of Medicine, Tokyo, Japan. [email protected] Source: Zhao, W H Hu, Z Q Hara, Y Shimamura, T Antimicrob-Agents-Chemother. 2002 July; 46(7): 2266-8 0066-4804

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Inulin formation of penicillin producing industrial Penicillium chrysogenum strains. Author(s): Biological Research Department, BIOGAL Pharmaceutical Co., Debrecen, Hungary. Source: Olah, A Papp, Z Szentirmai, A Acta-Microbiol-Hung. 1993; 40(4): 379-86 02314622

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Optimization of bagasse, nutrients and initial moisture ratios on the yield of penicillin in solid-state fermentation. Source: Dominguez, M. Mejia, A. Revah, S. Barrios Gonzalez, J. World-j-microbiolbiotechnol. Dordrecht, The Netherlands: Kluwer Academic Publishers. October 2001. volume 17 (7) page 751-756. 0959-3993

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Penicillin acylase-catalyzed ampicillin synthesis using a pH gradient: a new approach to optimization. Author(s): Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia. Source: Youshko, M I van Langen, L M de Vroom, E van Rantwijk, F Sheldon, R A Svedas, V K Biotechnol-Bioeng. 2002 June 5; 78(5): 589-93 0006-3592

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Penicillin therapy of spontaneous streptococcal meningitis in pigs. Author(s): Department of Veterinary Pharmacology, University of Glasgow Veterinary School, Bearsden. Source: McKellar, Q A Baxter, P Taylor, D Bogan, J A Vet-Rec. 1987 October 10; 121(15): 347-50 0042-4900

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Penicillin tolerance genes of Streptococcus pneumoniae: the ABC-type manganese permease complex PSA. Author(s): Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN 38105, USA. Source: Novak, R Braun, J S Charpentier, E Tuomanen, E Mol-Microbiol. 1998 September; 29(5): 1285-96 0950-382X

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Phenoxymethyl penicillin potassium as an in-feed medication for pigs with streptococcal meningitis. Source: Johnston, P.I. Henry, N. Boer, R. de Braidwood, J.C. Vet-Rec-J-Br-Vet-Assoc. London : The Association. February 15, 1992. Volume 130 (7) page 138-139. 0042-4900

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Possible overestimation of penicillin resistant Streptococcus pneumoniae colonization rates due to misidentification of oropharyngeal streptococci. Author(s): Division of Infectious Diseases and Division of Microbiology, Cook County Hospital, Rush Medical College, Chicago, IL, USA. Source: Wester, C William Ariga, Deepak Nathan, Catherine Rice, Thomas W Pulvirenti, Joseph Patel, Robin Kocka, Frank Ortiz, Joanna Weinstein, Robert A Diagn-MicrobiolInfect-Dis. 2002 April; 42(4): 263-8 0732-8893

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Potentially allergenic airborne particles in the vicinity of a yeast and penicillin production plant. Author(s): Agricultural University Wageningen, Wageningen, The Netherlands Source: Preller, L. Hollander, A. Heederik, D. Brunekreef, B. JAPCA (USA). (August 1989). volume 39(8) page 1094-1097.

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Randomized evaluation of benzathine penicillin V twice daily versus potassium penicillin V three times daily in the treatment of group A streptococcal pharyngitis. Pharyngitis Study Group. Author(s): Institute of Medical Microbiology, Technical University (RWTH), Aachen, Germany.

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Source: Kaufhold, A Eur-J-Clin-Microbiol-Infect-Dis. 1995 February; 14(2): 92-8 09349723 •

Recurrent penicillin-resistant pneumococcal sepsis after matched unrelated donor (MUD) transplantation for refractory T cell lymphoma. Author(s): Bone Marrow Transplant Unit, University Hospital Birmingham NHS Trust, UK. Source: Tauro, S Dobie, D Richardson, G Hastings, M Mahendra, P Bone-MarrowTransplant. 2000 November; 26(9): 1017-9 0268-3369

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Reversion of L-lysine inhibition of penicillin G biosynthesis by 6-oxopiperidine-2carboxylic acid in Penicillium chrysogenum PQ-96. Author(s): State Institute of Hygiene, Warsaw, Poland. Source: Kurzatkowski, W Kurzatkowski, J D Filipek, J Solecka, J Kurylowicz, W ApplMicrobiol-Biotechnol. 1990 December; 34(3): 397-8 0175-7598

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Risk/benefit in the treatment of children with imipenem-cilastatin for meningitis caused by penicillin-resistant pneumococcus. Author(s): Section of Pediatric Infectious Diseases, University Hospital La Fe, Valencia, Spain. Source: Asensi, F Otero, M C Perez Tamarit, D Rodriguez Escribano, I Cabedo, J L Gresa, S Canton, E J-Chemother. 1993 April; 5(2): 133-4 1120-009X

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Role of alphaArg145 and betaArg263 in the active site of penicillin acylase of Escherichia coli. Author(s): Department of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands. Source: Alkema, Wynand B L Prins, Antoon K de Vries, Erik Janssen, Dick B Biochem-J. 2002 July 1; 365(Pt 1): 303-9 0264-6021

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Studies of isopenicillin N synthase enzymatic properties using a continuous spectrophotometric assay. Author(s): Laboratoire d'Enzymologie, CIP, Institut di Chimie B6, University of Liege, Belgium. [email protected] Source: Dubus, A Sami, M Brown, T J Schofield, C J Baldwin, J E Frere, J M FEBS-Lett. 2000 November 24; 485(2-3): 142-6 0014-5793

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The effect of streptomycin and penicillin on trace metal ions level in biological system. Author(s): Balochistan Univ., Quetta (Pakistan). Inst. of Biotechnology Source: Rehmani, F.S. Noor, H. Khawaja, E. Pakistan-Journal-of-Biological-Sciences (Pakistan). (February 2000). volume 3(2) page 354-355.

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The influence of caprate on rectal absorption of phenoxymethylpenicillin: experience from an in-vivo perfusion in humans. Author(s): Department of Pharmacy, Uppsala University, Sweden. [email protected] Source: Lennernas, H Gjellan, K Hallgren, R Graffner, C J-Pharm-Pharmacol. 2002 April; 54(4): 499-508 0022-3573

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The role of hydrophobic active-site residues in substrate specificity and acyl transfer activity of penicillin acylase. Author(s): Department of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, the Netherlands.

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Source: Alkema, Wynand B L Dijkhuis, Anne January De Vries, Erik Janssen, Dick B Eur-J-Biochem. 2002 April; 269(8): 2093-100 0014-2956 •

Toxicity studies of amphetamine sulfate, ampicillin trihydrate, codeine, 8methoxypsoralen, alpha-methyldopa, penicillin VK and propantheline bromide in rats and mice. Author(s): National Toxicology Program, National Institutes of Environmental Health Sciences, Research Triangle Park, NC 27709. Source: Dunnick, J K Elwell, M R Toxicology. 1989 June 1; 56(2): 123-36 0300-483X

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Vitamins Vitamin K Source: Healthnotes, Inc.; www.healthnotes.com

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Food and Diet Garlic Source: Prima Communications, Inc.www.personalhealthzone.com

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CHAPTER 3. ALTERNATIVE MEDICINE AND PENICILLIN Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to penicillin. At the conclusion of this chapter, we will provide additional sources.

National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to penicillin and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “penicillin” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to penicillin: •

Activities of trovafloxacin, gatifloxacin, clinafloxacin, sparfloxacin, levofloxacin, and ciprofloxacin against penicillin-resistant Streptococcus pneumoniae in an in vitro infection model. Author(s): Hershberger E, Rybak MJ. Source: Antimicrobial Agents and Chemotherapy. 2000 March; 44(3): 598-601. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10681324&dopt=Abstract

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beta-Lactam antibiotic-induced release of free endotoxin: in vitro comparison of penicillin-binding protein (PBP) 2-specific imipenem and PBP 3-specific ceftazidime. Author(s): Jackson JJ, Kropp H. Source: The Journal of Infectious Diseases. 1992 June; 165(6): 1033-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1583320&dopt=Abstract

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beta-Lactam resistance in Serratia marcescens: comparison of action of benzylpenicillin, Apalcillin, Cefazolin, and ceftizoxime. Author(s): Takata N, Suginaka H, Kotani S, Ogawa M, Kosaki G. Source: Antimicrobial Agents and Chemotherapy. 1981 March; 19(3): 397-401. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7018390&dopt=Abstract

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Cerebral blood flow changes in general paresis following penicillin treatment: a longitudinal single photon emission computed tomography study. Author(s): Kitabayashi Y, Ueda H, Narumoto J, Nakamura K, Kita H, Tsuchida H, Iizumi H, Fukui K. Source: Psychiatry and Clinical Neurosciences. 2002 February; 56(1): 65-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11929572&dopt=Abstract

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Changes of the electrical activity in cortical auditory areas produced by penicillin [proceedings] Author(s): Zahlava J, Sobotka P. Source: Act Nerv Super (Praha). 1978 June; 20(2): 106-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=726826&dopt=Abstract

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Characterization of extracellular beta-lactamases from penicillin G-resistant cells of Streptococcus thermophilus. Author(s): Chirica LC, Guray T, Gurakan GC, Bozoglu TF. Source: J Food Prot. 1998 July; 61(7): 896-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9678176&dopt=Abstract

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Effect of electroacupuncture on the level of preproenkephalin mRNA in rat during penicillin-induced epilepsy. Author(s): Wang BE, Yang R, Cheng JS. Source: Acupuncture & Electro-Therapeutics Research. 1994 June-September; 19(2-3): 129-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7863837&dopt=Abstract

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Effect of gamma irradiation, fractionation, and penicillin supplementation on the rachitogenic activity of rye for chicks. Author(s): Mac-Auliffe T, Zaviezo D, McGinnis J. Source: Poultry Science. 1979 March; 58(2): 329-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=231258&dopt=Abstract

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Effect of hyperbaric oxygen and penicillin in a murine model of streptococcal myositis. Author(s): Oztas E, Kilic A, Ozyurt M, Korkmaz A, Basustaoglu A.

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Source: Undersea & Hyperbaric Medicine : Journal of the Undersea and Hyperbaric Medical Society, Inc. 2001 Fall; 28(4): 181-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12153145&dopt=Abstract •

Effects of acute and chronic paleocerebellar stimulation on experimental models of epilepsy in the cat: studies with enflurane, pentylenetetrazol, penicillin, and chloralose. Author(s): Myers RR, Burchiel KJ, Stockard JJ, Bickford RG. Source: Epilepsia. 1975 June; 16(2): 257-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1149712&dopt=Abstract

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Effects of penicillin and silymarin on liver enzymes and blood clotting factors in dogs given a boiled preparation of Amanita phalloides. Author(s): Floersheim GL, Eberhard M, Tschumi P, Duckert F. Source: Toxicology and Applied Pharmacology. 1978 November; 46(2): 455-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=569913&dopt=Abstract

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Evaluation of penicillin and hyperbaric oxygen in the treatment of streptococcal myositis. Author(s): Zamboni WA, Mazolewski PJ, Erdmann D, Bergman BA, Hussman J, Cooper MD, Smoot EC, Russell RC. Source: Annals of Plastic Surgery. 1997 August; 39(2): 131-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9262765&dopt=Abstract

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From mercury to malaria to penicillin: the history of the treatment of syphilis at the Mayo Clinic--1916-1955. Author(s): Sartin JS, Perry HO. Source: Journal of the American Academy of Dermatology. 1995 February; 32(2 Pt 1): 255-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7829712&dopt=Abstract

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Inhibition of penicillinase by epigallocatechin gallate resulting in restoration of antibacterial activity of penicillin against penicillinase-producing Staphylococcus aureus. Author(s): Zhao WH, Hu ZQ, Hara Y, Shimamura T. Source: Antimicrobial Agents and Chemotherapy. 2002 July; 46(7): 2266-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12069986&dopt=Abstract

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Inhibition of penicillinase by plant metabolites. Author(s): Lakshmi VV, Sridhar P, Polasa H. Source: Indian J Exp Biol. 1987 November; 25(11): 778-80. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3330726&dopt=Abstract

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Inhibitory effect of jujuboside A on penicillin sodium induced hyperactivity in rat hippocampal CA1 area in vitro. Author(s): Shou CH, Wang J, Zheng XX, Guo DW. Source: Acta Pharmacologica Sinica. 2001 November; 22(11): 986-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11749788&dopt=Abstract

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Mechanisms of acquired penicillin-resistance in Streptomyces cacaoi. Role of penicillin-binding proteins in penicillin resistant mutants. Author(s): Nakazawa H, Ogawara H. Source: J Antibiot (Tokyo). 1982 December; 35(12): 1683-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6820018&dopt=Abstract

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Membrane-bound DD-carboxypeptidases from Bacillus megaterium KM general properties, substrate specificity and sensitivity to penicillins, cephalosporins and peptide inhibitors of the activity at pH5. Author(s): Maurino T, Nieto M, Perkins HR. Source: The Biochemical Journal. 1974 November; 143(2): 391-402. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4218954&dopt=Abstract

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Modified fluorimetric assay for estimating ampicilloate concentrations and its use for detecting beta-lactamase and penicillin acylase activity in bacteria. Author(s): Baker WL. Source: The Analyst. 1997 May; 122(5): 447-53. Erratum In: Analyst 1997 August; 122(8): 867. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9246811&dopt=Abstract

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Overexpression, solubilization and refolding of a genetically engineered derivative of the penicillin-binding protein 3 of Escherichia coli K12. Author(s): Belder JB, Nguyen-Disteche M, Houba-Herin N, Ghuysen JM, Maruyama IN, Hara H, Hirota Y, Inouye M. Source: Molecular Microbiology. 1988 July; 2(4): 519-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3050360&dopt=Abstract

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Partial purification and characterization of isopenicillin N epimerase activity from Streptomyces clavuligerus. Author(s): Jensen SE, Westlake DW, Wolfe S. Source: Canadian Journal of Microbiology. 1983 November; 29(11): 1526-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6671166&dopt=Abstract

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Penetrability of the outer membrane of Neisseria gonorrhoeae in relation to acquired resistance to penicillin and other antibiotics. Author(s): Scudamore RA, Beveridge TJ, Goldner M.

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Source: Antimicrobial Agents and Chemotherapy. 1979 June; 15(6): 820-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=112915&dopt=Abstract •

Penicillin and essential fatty acid supplementation in schizophrenia. Author(s): Vaddadi KS. Source: Prostaglandins Med. 1979 January; 2(1): 77-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=121601&dopt=Abstract

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Penicillin resistant Neisseria gonorrhoeae in low prevalence areas: implications for cost-effective management. Author(s): Nettleman MD, Smith V, Moyer NP. Source: Sexually Transmitted Diseases. 1990 October-December; 17(4): 175-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2124730&dopt=Abstract

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Penicillin, battery acid and sacrifice. Cures and causes in Nyole medicine. Author(s): Whyte SR. Source: Social Science & Medicine (1982). 1982; 16(23): 2055-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7157036&dopt=Abstract

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Penicillin-induced epileptiform activity does not prevent ocular dominance shifts in monocularly deprived kittens. Author(s): Videen TO, Daw NW, Collins RC. Source: Brain Research. 1986 April 16; 371(1): 1-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3708337&dopt=Abstract

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Peptidoglycan synthetic activities in membranes of Escherichia coli caused by overproduction of penicillin-binding protein 2 and rodA protein. Author(s): Ishino F, Park W, Tomioka S, Tamaki S, Takase I, Kunugita K, Matsuzawa H, Asoh S, Ohta T, Spratt BG, et al. Source: The Journal of Biological Chemistry. 1986 May 25; 261(15): 7024-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3009484&dopt=Abstract

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Purification and light-scattering analysis of penicillin-binding protein 4 from Escherichia coli. Author(s): Fusetti F, Dijkstra BW. Source: Microbial Drug Resistance (Larchmont, N.Y.). 1996 Spring; 2(1): 73-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9158725&dopt=Abstract

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Purification and properties of inducible penicillin beta-lactamase isolated from Alcaligenes faecalis. Author(s): Fujii T, Sato K, Inoue M, Mitsuhashi S.

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Source: Antimicrobial Agents and Chemotherapy. 1985 April; 27(4): 608-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3873902&dopt=Abstract •

Purification and properties of inducible penicillin beta-lactamase isolated from Pseudomonas maltophilia. Author(s): Saino Y, Kobayashi F, Inoue M, Mitsuhashi S. Source: Antimicrobial Agents and Chemotherapy. 1982 October; 22(4): 564-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6983856&dopt=Abstract

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Purification and properties of penicillin acylase of Bovista plumbea. Author(s): Schneider WJ, Roehr M. Source: Biochimica Et Biophysica Acta. 1976 November 8; 452(1): 177-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=990310&dopt=Abstract

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Purification of penicillin G acylase using immobilized metal affinity membranes. Author(s): Liu YC, ChangChien CC, Suen SY. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 August 25; 794(1): 67-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12888199&dopt=Abstract

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Recurrent penicillin-resistant pneumococcal sepsis after matched unrelated donor (MUD) transplantation for refractory T cell lymphoma. Author(s): Tauro S, Dobie D, Richardson G, Hastings M, Mahendra P. Source: Bone Marrow Transplantation. 2000 November; 26(9): 1017-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11100283&dopt=Abstract

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Relations between beta-lactamases and penicillin-binding proteins: beta-lactamase activity of penicillin-binding protein 5 from Escherichia coli. Author(s): Nicholas RA, Strominger JL. Source: Reviews of Infectious Diseases. 1988 July-August; 10(4): 733-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3055172&dopt=Abstract

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Release of periplasmic enzymes from Escherichia coli by penicillinethylenediaminetetraacetate treatment. Author(s): Ananthaswamy HN. Source: Journal of Bacteriology. 1977 August; 131(2): 710-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=195932&dopt=Abstract

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Renal function in patients treated with tobramycin-cefuroxime or tobramycinpenicillin G. Author(s): Trollfors B, Alestig K, Rodjer S, Sandberg T, Westin J.

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Source: The Journal of Antimicrobial Chemotherapy. 1983 December; 12(6): 641-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6363382&dopt=Abstract •

Resistance of Staphylococcus aureus to penicillins and cephalosporins: reversal of intrinsic resistance with some chelating agents. Author(s): Sabath LD, Wallace SJ, Byers K, Toftegaard I. Source: Annals of the New York Academy of Sciences. 1974 July 31; 236(0): 435-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4214383&dopt=Abstract

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Simple assay and extraction of periplasmic penicillinase in Escherichia coli. Author(s): Choma CT, Yamazaki H. Source: Canadian Journal of Microbiology. 1981 May; 27(5): 547-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6166361&dopt=Abstract

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Site-directed mutants of a soluble form of penicillin-binding protein 5 from Escherichia coli and their catalytic properties. Author(s): Nicholas RA, Strominger JL. Source: The Journal of Biological Chemistry. 1988 February 5; 263(4): 2034-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3276680&dopt=Abstract

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Sorcery and penicillin: treating illness on a Papua New Guinea island. Author(s): Lepowsky M. Source: Social Science & Medicine (1982). 1990; 30(10): 1049-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2363057&dopt=Abstract

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Synergy between penicillin and gentamicin against enterococci. Author(s): Winstanley TG, Hastings JG. Source: The Journal of Antimicrobial Chemotherapy. 1990 April; 25(4): 551-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2112537&dopt=Abstract

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Systemic penicillin as an experimental model of epilepsy. Author(s): Chen RC, Huang YH, How SW. Source: Experimental Neurology. 1986 June; 92(3): 533-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3709733&dopt=Abstract

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The influence of hexachlorophene scrubs on the response to placebo or penicillin therapy in impetigo. Author(s): Ruby RJ, Nelson JD. Source: Pediatrics. 1973 December; 52(6): 854-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4203555&dopt=Abstract

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

General Overview Cutaneous Drug Reactions Source: Integrative Medicine Communications; www.drkoop.com Ear Infection Source: Integrative Medicine Communications; www.drkoop.com Erythema Source: Integrative Medicine Communications; www.drkoop.com Infection Source: Healthnotes, Inc.; www.healthnotes.com Lupus Source: Integrative Medicine Communications; www.drkoop.com Lyme Disease Source: Integrative Medicine Communications; www.drkoop.com

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Otitis Media Source: Integrative Medicine Communications; www.drkoop.com Pharyngitis Source: Integrative Medicine Communications; www.drkoop.com Serum Sickness Source: Integrative Medicine Communications; www.drkoop.com Sore Throat Source: Integrative Medicine Communications; www.drkoop.com Systemic Lupus Erythematosus Source: Integrative Medicine Communications; www.drkoop.com •

Herbs and Supplements Amoxicillin Source: Healthnotes, Inc.; www.healthnotes.com Ampicillin Source: Healthnotes, Inc.; www.healthnotes.com Antibiotics Source: Healthnotes, Inc.; www.healthnotes.com Brewer's Yeast Source: Healthnotes, Inc.; www.healthnotes.com Bromelain Source: Healthnotes, Inc.; www.healthnotes.com Dicloxacillin Source: Healthnotes, Inc.; www.healthnotes.com Echinacea Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Erythromycin Source: Healthnotes, Inc.; www.healthnotes.com Fiber Source: Integrative Medicine Communications; www.drkoop.com Penicillamine Source: Healthnotes, Inc.; www.healthnotes.com Penicillin Derivatives Source: Integrative Medicine Communications; www.drkoop.com

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Penicillin V Source: Healthnotes, Inc.; www.healthnotes.com Penicillins Source: Healthnotes, Inc.; www.healthnotes.com Probiotics Source: Healthnotes, Inc.; www.healthnotes.com Silybum Alternative names: Milk Thistle; Silybum marianum (L.) Gaertn. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org

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

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

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

A Role for Penicillin-Binding Protein 2 (pbp2) in Conferring the Borderline Oxacillinresistant Phenotype of Staphylococcus Aureus by Nadarajah, Jeya Thirumagal; MSC from University of Toronto (Canada), 2002, 130 pages http://wwwlib.umi.com/dissertations/fullcit/MQ74042

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Action of Penicillin G on Neisseria Meningitidis by Neirinck, Leonard G; PhD from McGill University (Canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK58073

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Pathophysiology of Generalized Penicillin Epilepsy in the Cat : the Role of Cortical and Subcortical Structures by Quensney, Luis Felipe; PhD from McGill University (Canada), 1977 http://wwwlib.umi.com/dissertations/fullcit/NK33360

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Penicillin Allocation on the American Home Front: the Committee on Chemotherapeutic and Other Agents, 1940-1945 by Adams, David Parrish, Jr., PhD from University of Florida, 1987, 248 pages http://wwwlib.umi.com/dissertations/fullcit/8809611

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Some Aspects of the Pummerer Reaction and Their Relationship to Penicillin Biosynthesis by Kazmaier, Peter Michael; PhD from Queen's University at Kingston (Canada), 1978 http://wwwlib.umi.com/dissertations/fullcit/NK39503

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Some Synthetic and Mechanistic Studies Related to Penicillin by Hasan, Syed Khaqan; AdvDeg from Queen's University at Kingston (Canada), 1969 http://wwwlib.umi.com/dissertations/fullcit/NK04426

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Studies on the Genetic Determinant Responsible for Penicillin Resistance in Staphylococcus Aureus by Weling, Shashikant V; PhD from University of Toronto (Canada), 1971 http://wwwlib.umi.com/dissertations/fullcit/NK10834

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Studies on the Molecular Basis of Penicillin-binding Protein-mediated Beta-lactam Resistance in Haemophilus Influenzae by Malouin, Francois; PhD from University of Calgary (Canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL46631

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Substrate and Inhibitor Specificity Studies on Low Molecular Weight Penicillinbinding Proteins by Peddi, Sridhar; Ms from University of Missouri - Kansas City, 2002, 79 pages http://wwwlib.umi.com/dissertations/fullcit/1411566

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Synthesis and Biological Evaluation of Potential Intermediates in the Biosynthesis of Penicillin by Bowers, Raymond John; PhD from Queen's University at Kingston (Canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK52869

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The Respective Roles of the Thalamus and Cortex in Feline Penicillin-induced Generalized Epilepsy by Avoli, Massimo; PhD from McGill University (Canada), 1982 http://wwwlib.umi.com/dissertations/fullcit/NK60909

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

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CHAPTER 5. CLINICAL TRIALS AND PENICILLIN Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning penicillin.

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

A Pilot Study Evaluating Penicillin G and Ceftriaxone as Therapies for Presumed Neurosyphilis in HIV Seropositive Individuals Condition(s): HIV Infections; Neurosyphilis Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID); Hoffmann-La Roche Purpose - Excerpt: To provide information on the response of HIV infected, neurosyphilis patients to the currently recommended treatment for neurosyphilis; to determine whether possible co-infection with both HIV and syphilis makes more difficult the diagnosis of syphilis; to explore the usefulness of an alternative treatment which, if effective, would permit outpatient treatment for neurosyphilis that until now required prolonged hospitalization. Studies suggest that syphilis treatment failures may be more common in HIV infected patients than in patients without HIV infection and that treatment failures occur due to and/or are displayed as central nervous system (CNS) involvement. Very little is known about the best treatment course for neurosyphilis in patients who are also infected with HIV. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000648

8

These are listed at www.ClinicalTrials.gov.

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Penicillin Prophylaxis in Sickle Cell Disease (PROPS) Condition(s): Anemia, Sickle Cell; Hematologic Diseases; Hemoglobinopathies; Infection (S. pneumoniae); Pneumonia Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine whether the regular daily administration of oral penicillin would reduce the incidence of documented infection due to Streptococcus pneumoniae in children with sickle cell anemia. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000585

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “penicillin” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

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

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

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

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

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

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

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

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•

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

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

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

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

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

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

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

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

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

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

9Adapted

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

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

7-vinylidene cephalosporins and methods of using the same Inventor(s): Bachmann; Brian (Dallas, TX), Buynak; John D. (Dallas, TX) Assignee(s): Southern Methodist University (Dallas, TX) Patent Number: 5,597,817 Date filed: December 9, 1994 Abstract: Cephalosporins with an exocyclic allene in the 7-position and their pharmaceutically active salts are potent inhibitors of.beta.-lactamases and are therefore useful in the treatment of penicillin resistant infections. Excerpt(s): The present invention relates to a new class of chemical compounds, specifically 7-vinylidene cephalosporins, pharmaceutically acceptable salts thereof and a method of inhibiting.beta.-lactamases. The most important mechanism of microbial resistance to.beta.-lactam antibiotics is the bacterial production of.beta.-lactamases, enzymes which hydrolytically destroy.beta.-lactam antibiotics, such as penicillins and cephalosporins. This type of resistance can be transferred horizontally by plasmids that are capable of rapidly spreading the resistance, not only to other members of the same strain, but even to other species. Due to such rapid gene transfer, a patient can become infected with different organisms, each possessing the same.beta.-lactamase.beta.lactamase enzymes have been organized into four molecular classes: A, B, C, and D based on amino acid sequence. Class A, which includes RTEM and the.beta.-lactamase of Staphylococcus aureus, class C, which includes the lactamase derived from P99 Enterobacter cloacae, and class D are serine hydrolases. Class A enzymes have a molecular weight of about 29 kDa and preferentially hydrolyze penicillins. The class B lactamases are metalloenzymes and have a broader substrate profile than the proteins in the other classes. Class C enzymes include the chromosomal cephalosporinases of gramnegative bacteria and have molecular weights of approximately 39 kDa. The recently recognized class D enzymes exhibit a unique substrate profile which differs significantly from both class A and class C. Web site: http://www.delphion.com/details?pn=US05597817__

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Administration of an injectable antibiotic in the ear of an animal Inventor(s): Brown; Scott A. (Galesburg, MI) Assignee(s): Pharmacia & Upjohn Company () Patent Number: 6,074,657 Date filed: March 20, 1997 Excerpt(s): The present invention provides for a method of injecting an antibiotic in the ear of an animal, such as cattle, swine, sheep and goats. These injectable antibiotics include the following: injectable suspensions of sparingly water-soluble antimicrobial agents, such as procaine penicillin, benzathine penicillin, ceftiofur crystalline free acid, ampicillin trihydrate and amoxicillin trihydrate; sustained-release non-aqueous solutions of sparingly water-soluble antimicrobial agents, such as oxytetracycline, erythromycin, tylosin, tilmicosin and florfenicol; and injectable solutions of zwitterionic antimicrobial agents, such as enrofloxacin, danofloxacin and premafloxacin. Specifically,

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the present invention provides for a method of injecting a relatively large volume (1 to 15 mL) of a sterile oil suspension of an antibiotic, such as ceftiofur crystalline free acid of formula I, in the posterior of the ear of cattle and swine. The injection of many antibiotics produces irritation and, potentially, illegal drug residues at the injection site of food-producing animals. Current cattle practice is oriented toward changing from an intramuscular injection of drugs and vaccines, which then leaves both irritation and possibly drug residues in edible meat, to subcutaneous injection, which places those unwanted occurrences at the surface of the carcass in cattle. Because the hide of cattle is removed at slaughter, the injection sites are potentially visible and will be trimmed from the carcass. Even if that is not done, the edible meat is not damaged because the injection is not into muscle. Nevertheless, even with subcutaneous administration, injection site irritation and potentially violative drug residues still remain on an edible portion of the carcass, namely the surface of the carcass itself. Furthermore, any violative drug residues at the injection site cannot be monitored by current United States Department of Agriculture (USDA) inspectors, who require a "target tissue" for residue monitoring to homogeneously contain drug residues and always be readily identifiable to the layman. These target tissues are now defined as the kidney, liver, muscle and fat; and an injection site in any edible tissue, regardless of whether the injection is intramuscular or subcutaneous, fails the criteria for a target tissue because it is not always readily identifiable, circumscript or homogenous with respect to drug residues. Web site: http://www.delphion.com/details?pn=US06074657__ •

Antibacterial agents Inventor(s): Harimoto; Takashi (Kobe, JP), Matsumoto; Yoshimi (Souraku-gun, JP), Nishio; Hitoshi (Toyonaka, JP), Sekiyama; Ryoji (Ikeda, JP), Tawara; Shuichi (Kawanishi, JP) Assignee(s): Fujisawa Pharmaceutical Co., Ltd. (Osaka, JP) Patent Number: 6,369,050 Date filed: November 17, 2000 Abstract: The invention provides an antimicrobial agent capable of producing an excellent effect in the prevention or treatment of bacteria of two or more genera selected from among Streptococcus, Moraxella, Haemophilus, Klebsiella and the like. The agent comprises a penicillin antibiotic, in particular amoxicillin, and a cephem antibiotic, in particular cefixime or cefdinir. The antimicrobial agent of the invention is administered in the form of a mixed preparation containing both or in the form of individual preparations respectively containing them for combined administration. Excerpt(s): This is a 371 of PCT/JP 99/01924 filed Apr. 9, 1999. This invention relates to an antimicrobial agent which comprises a penicillin antibiotic, in particular amoxicillin, and a cephem antibiotic, in particular cefixime or cefdinir, and which is suited for use in the prevention or treatment of respiratory infections and mixed respiratory infections. The invention is utilized in the field of medicine. Cefixime (hereinafter sometimes referred to as "CFIX") and cefdinir (hereinafter sometimes referred to as "CFDN") are oral cephem antibiotics, show a broad antibacterial spectrum against gram-positive and gram-negataive bacteria, and are in wide use. However, they are not very effective against the penicillin G-resistant pneumococcus belonging to the genus Streptococcus (Streptococcus pneumoniae). Web site: http://www.delphion.com/details?pn=US06369050__

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Antibiotic formulation and a method of making this formulation Inventor(s): Carpenter; John R. (Savannah, MO), Faris; Heidi M. P. (Webster City, IA), Mihalik; Richard (St. Joseph, MO) Assignee(s): Phoenix Scientific, Inc. (St. Joseph, MO) Patent Number: 6,537,985 Date filed: November 30, 2001 Abstract: An antibiotic formulation in a true solution is provided. This formulation includes an antibiotic and N-methyl-2-pyrrolidone. It also may include a preservative, an antioxidant, and/or an additive. The antibiotic is a beta lactam, such as a penicillin, a cephalosporin, other beta lactams, or combinations thereof. The formulation is made by dissolving the antibiotic in the N-methyl-2-pyrrolidone. The antibiotic formulation is suitable for use at temperatures below about 0.degree. C. and without agitation. Further, the antibiotic formulation in true solution can be made with non-sterile ingredients and can be filtered to remove impurities. Excerpt(s): Not Applicable. The present invention relates to an antibiotic formulation. More specifically, the present invention relates to an antibiotic formulation that includes beta lactams in a true solution. Web site: http://www.delphion.com/details?pn=US06537985__

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Chromosomal DNA fragments encoding enzymes for encoding.beta.-lactam biosynthetic enzymes, and vectors and transformants for their expression Inventor(s): Burnham; Martin Karl Russel (Betchworth, GB), Hodgson; John Edward (Betchworth, GB), Normansell; Ian David (Worthing, GB) Assignee(s): Beecham Group plc (Brentford, GB) Patent Number: 6,066,468 Date filed: June 7, 1995 Abstract: DNA sequences obtained from S. clavuligerus ATCC 27064, recombinant vectors incorporating such sequences and hosts transformed with such vectors are disclosed. The DNA comprises one or more genes coding for one or more enzymes involved in the biosynthesis of penicillin and cephalosporin.beta.-lactams and such enzymes are expressed by hosts into which the recombinant vectors are transformed. The DNA and the enzymes encoded thereby have utility in the preparation of penicillins and cephalosporins, both known and novel, possessing pharmacological, especially antimicrobial, activity. Excerpt(s): The present invention relates to recombinant DNA molecules, and in particular to recombinant vectors for use in the transformation of a microbial host which contain inserted DNA fragments carrying one or more genes coding for one or more enzymes involved in the biosynthesis of.beta.-lactam antibiotics, especially penicillins and cephalosporins. Progress in understanding the biosynthesis of.beta.-lactam antibiotics produced by micro-organisms such as Streptomyces clavuligerus has been slow. Nevertheless it has been established that the biosynthetic pathways of certain penicillins and cephalosporins (including cephamycins) are closely related. Isopenicillin N is an intermediate in the biosynthesis of both groups of compounds and is formed by the action of a `cyclase` enzyme on the tripeptide.delta.(L-.alpha.-aminoadipyl)-Lcysteinyl-D-valine (sometimes referred to as LLD-ACV or, more simply, ACV as used

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hereinbelow). The intermediate isopenicillin N may be converted either into penicillin G or, by the action of an `epimerase` enzyme, into penicillin N and it is from the latter that various cephalosporins and cephamycins may be derived by a multi-step pathway following an initial ring-expansion with an `expandase` enzyme. A recent summary of the state of the art is given by J. F. Martin and P. Liras in Trends in Biotechnology, 1985, 3, 39-44. Thus, in the biosynthesis of Cephamycin C, penicillin N is converted into deacetoxycephalosporin C which is then converted by a dioxygenase enzyme into desacetylcephalosporin C. Web site: http://www.delphion.com/details?pn=US06066468__ •

Combined supported liquid membrane/strip dispersion process for the removal and recovery of penicillin and organic acids Inventor(s): Ho; W. S. Winston (Lexington, KY) Assignee(s): Commodore Separation Technoligies, Inc. (New York, NY) Patent Number: 6,433,163 Date filed: April 3, 2000 Abstract: The present invention provides a novel process for the removal and recovery of penicillin and organic acids from process streams and waste waters. The process of the present invention utilizes a combination of a supported liquid membrane (SLM) and a strip dispersion to improve extraction of the penicillin and organic acids while increasing membrane stability and reducing processing costs. Excerpt(s): The present invention relates to the removal and recovery of penicillin and organic acids from feed solutions, such as process streams and waste waters, using supported liquid membrane technology. Liquid membranes combine extraction and stripping into one step, rather than the two separate steps required in conventional processes such as solvent extractions. A one-step liquid membrane process provides the maximum driving force for the separation of a targeted species, leading to the best clean-up and recovery of the species (W. S. Winston Ho and Kamalesh K. Sirkar, eds., Membrane Handbook, Chapman & Hall, New York, 1992). There are two types of liquid membranes: (1) supported liquid membranes (SLMs) and (2) emulsion liquid membranes (ELMs). In SLMs, the liquid membrane phase is the organic liquid imbedded in pores of a microporous support, e.g., microporous polypropylene hollow fibers (W. S. Winston Ho and Kamalesh K. Sirkar, eds., Membrane Handbook, Chapman & Hall, New York, 1992). When the organic liquid contacts the microporous support, it readily wets the pores of the support, and the SLM is formed. Web site: http://www.delphion.com/details?pn=US06433163__

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Discharge apparatus with organic component active against microorganisms Inventor(s): Bommer; Rene (Radolfzell, DE) Assignee(s): Ing. Erich Pfeiffer GmbH (Radolfzell, DE) Patent Number: 6,227,413 Date filed: October 10, 1997 Abstract: A discharge apparatus for media with a medium reservoir and a discharge opening for the medium is at least partly made from a plastic containing at least one

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substance active against microorganisms. This substance can be an antibiotic, e.g. an antibiotic with bactericidal action from the penicillin group. It is appropriate for the parts of the discharge apparatus coming into contact with the medium to be made from the plastic with additive. Preferably the discharge apparatus is substantially completely made from the plastic with additive. The discharge apparatus according to the invention is preferably used for dosing, feeding, atomizing and/or dispensing pharmaceuticals or cosmetics. Excerpt(s): The invention relates to a discharge apparatus for media having a medium reservoir and a discharge opening for the medium. Numerous designs of such discharge apparatuses for numerous applications are known. They are able to discharge, e.g. dose, feed or dispense gaseous, liquid, creamy, gelatinous, pulverulent and/or solid media. The medium can optionally additionally be discharged in atomized form. A generally known application of such discharge apparatuses is e.g. in the cosmetic or pharmaceutical sector, but they are also widely used in other fields of technology. Independently thereof, when using the most varied products and goods, a control of microorganisms is necessary or desired. This is normally achieved by the use of disinfectants, preservatives or chemotherapeuticals. It is also possible in this connection to maintain sterile correspondingly endangered surfaces by the addition of germicidal agents to the base material. Web site: http://www.delphion.com/details?pn=US06227413__ •

DNA encoding a novel penicillin binding protein from streptococcus pneumoniae Inventor(s): Hoskins; Jo Ann (Indianapolis, IN), Jaskunas, Jr.; S. Richard (Indianapolis, IN), Norris; Franklin H. (Indianapolis, IN), Rockey; Pamela K. (Indianapolis, IN), Rosteck, Jr.; Paul R. (Indianapolis, IN) Assignee(s): Eli Lilly and Company (Indianapolis, IN) Patent Number: 5,789,202 Date filed: October 17, 1996 Abstract: The invention provides isolated nucleic acid compounds encoding a novel high molecular weight PBP of Streptococcus pneumoniae. Also provided are vectors and transformed heterologous host cells for expressing the PBP and a method for identifying compounds that bind and/or inhibit the enzymatic activity of the PBP. Excerpt(s): This invention relates to recombinant DNA technology. In particular the invention pertains to the cloning of a gene, pbp-nv, encoding a novel high molecular weight penicillin binding protein (PBP), PBP-Nv, from Streptococcus pneumoniae and the use of said gene and its encoded protein in a screen for new inhibitors of bacterial cell wall biosynthesis. The emergence of antibiotic resistance in common pathogenic bacterial species has justifiably alarmed the medical and research communities. The emergence and rapid spread of beta-lactam resistance in Streptococcus pneumoniae has been particularly problematic. This organism is responsible for many respiratory tract infections, and resistance to beta-lactam drugs has been attributed to a modification of one or more of the penicillin-binding proteins (PBPs). Furthermore, penicillin-resistant Streptococcus pneumoniae are frequently resistant to other commonly used antibiotics, such as erythromycin. These multi-drug resistant (MDR) organisms are a real threat to humans, particularly children and the elderly. Increasingly, the only drug that can be used to treat infections with MDR organisms is vancomycin, and there is considerable concern that the bacteria could also develop resistance to vancomycin.

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Web site: http://www.delphion.com/details?pn=US05789202__ •

DNA encoding ACV synthetase Inventor(s): Bull; John Henry (Cheshire, GB), Burnham; Martin Karl Russell (Collegeville, PA), Earl; Alison Jane (Steyning, GB), Smith; David John (Turku, FI), Turner; Geoffrey (Sheffield, GB) Assignee(s): Beecham Group p.l.c. (GB) Patent Number: 6,258,555 Date filed: August 11, 1997 Abstract: DNA encoding the gene for the synthetase enzyme capable of generating.delta. (L-a-aminoadipyl)-L-crysteinyl-D-valine (ACV) from its constituent amino acids was obtained from several penicillin and cephalosporin producing organisms, e.g. Penicillium chrysogenum, cephalosporium and a Flavobacterium species. The DNA was used to prepare recombinant vectors comprising the ACV synthetase gene and hosts transformed with such vectors. The ACV synthetase gene can form part of a gene cluster comprising other genes involved in -.beta.-lactam biosynthesis and the production of penicillin by expression of the entire biosynthetic gene cluster for the synthesis of penicillin from primary amino acids is described. Suitable hosts in which expression can take place include heterologous hosts which are naturally non-producers of penicillin. Excerpt(s): The present invention relates to DNA molecules, and to recombinant vectors for use in the transformation of a microbial host. In particular, the invention relates to biosynthetic genes for enzymes involved in penicillin biosynthesis, vectors comprising such genes, host cells transformed with the vectors, and the use of such host cells in penicillin production. It has been established that the biosynthetic pathways of penicillins and cephalosporins (including cephamycins) are closely related. Isopenicillin N is an intermediate in the biosynthesis of both groups of compounds and is formed by the action of a `cyclase` enzyme on the tripeptide.delta. (L-.alpha.-aminoadipyl)-Lcysteinyl-D-valine (sometimes referred to as LLD-ACV or, more simply, ACV as used hereinbelow). The intermediate isopenicillin N may be converted either to penicillin G or, by the action of an `epimerase` enzyme, to penicillin N and it is from the latter that various cephalosporins and cephamycins may be derived by a multi-step pathway following an initial ring-expansion with an `expandase`enzyme. A recent summary of the state of the art is given by J. F. Martin and P. Liras in Trends in Biotechnology, 1985, 3, 39-44. The generation of the intermediate tripeptide ACV from its constituent amino acids is the least well understood and most difficult step to study of the entire pathway as reported by Adlington et al (Biochem. J., 1983, 213, 573-576) and reviewed by S. E. Jensen in CRC Critical Reviews in Biotechnology, 1986, Vol. 3, Part 3, pages 277-310, and Nuesch et al (Ann. Rev. Microbiol, 1987, 41, 54). Web site: http://www.delphion.com/details?pn=US06258555__

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Enzymatic conversion in a solvent mixture containing water and flourinated, nonchlorinated solvent Inventor(s): Nicola; Mazin (Worthing, GB) Assignee(s): Advanced Phytonic Limited (West Yorkshire, GB) Patent Number: 6,383,772 Date filed: March 2, 2000 Abstract: A first compound is converted to a second compound enzymatically in a solvent mixture containing water and a fluorinated, non-chlorinated alkane, alkene, or alkyne having up to 4 carbon atoms. Lactams, for example 6-aminopenicillanic acid (6APA), may be prepared by enzymatic conversion of a first compound, for example penicillin-G, in a solvent mixture comprising water and a non-aqueous organic solvent, for example 1,1,1, 2-tetrafluoroethane. The 6-APA can be caused to precipitate, isolated by filtration and optionally derivatized to produce a desired compound. A by-product of the enzymatic conversion, for example phenylacetic acid, can be isolated by solvent extraction, suitably using a solvent which also comprises 1, 1, 1, 2-tetrafluoroethane. Excerpt(s): This invention relates to the preparation of a compound, especially an active pharmaceutical compound. Particularly, although not exclusively, the invention relates to the preparation of lactams, for example penicillins and cephalosporins and/or derivatives thereof. 6-Aminopenicillanic acid (6-APA) and 7aminodesacetoxycephalosporanic acid (7-ADCA) are intermediates used for the manufacture of most semi-synthetic.beta.-lactam antibiotics. The commercially preferred method for the manufacture of 6-APA is by means of biochemical de-acylation of benzyl penicillin, commonly known as Pen-G or equivalent enzymatic deacylation of phenoxymethyl penicillin, commonly known as Pen-V. This is achieved using an enzyme such as penicillin acylase, which has been immobilised on an insoluble matrix such as polystyrene or polyacrylate polymers or co-polymers. The immobilised enzymes used in the above described process may be sensitive to product inhibition. Hence, the reaction is normally carried out on relatively dilute solutions. A drawback of this is that the solubility of 6-APA in water is around 2% which means that a concentration step is necessary in order to minimise product losses in the mother liquors. A costly concentration step is therefore often applied to increase 6-APA content to 12-16%. Web site: http://www.delphion.com/details?pn=US06383772__

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Immobilization of penicillin G amidase, glutaryl-7-ACA acylase or D-aminoacid oxidase on an aminofunctional organosiloxane polymer carrier Inventor(s): Daser; Adelheid (Schlehdorf, DE), Tischer; Wilhelm (Peissenberg, DE), Wedekind; Frank (Penzberg, DE) Assignee(s): Boehringer Mannheim GmbH (Mannheim-Waldhof, DE) Patent Number: 5,780,260 Date filed: May 30, 1996 Abstract: An enzyme selected from penicillin-G amidase, glutaryl-7-ACA acylase and Damino acid oxidase is immobilized by covalent bonding on an aminofunctional organosiloxane polymer carrier to provide an immobilized enzyme having a specific volume activity of at least 100 U/g wet carrier. Preferably, the carrier has an average diameter or 0.01 to 3 mm and is essentially spherical. Covalent bonding is accomplished

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by activating amino groups on the carrier with a dialdehyde and reacting the activated groups with reactive groups on the enzyme. An amount of enzyme is immobilized to provide a weight ratio of enzyme to carrier of 1 to 300 mg protein per g wet carrier. Excerpt(s): The application is a 371 of PCT/EP94/04132, filed Dec. 13, 1994. The present invention concerns enzymes immobilized on carriers selected from the group comprising penicillin-G amidase, glutaryl-7-ACA acylase and D-amino acid oxidase, the use of these enzymes in an enzymatic synthesis reaction as well as a process for improving the volume activity and stability of these enzymes immobilized on carriers. The immobilization of biologically active substances, e.g. enzymes, on solid carrier materials can be carried out by numerous methods and is described in many monographs and publications (see e.g. Characterization of Immobilized Biocatalysts, Buchholz, K., (publisher), DECHEMA Monographs No. 1724-1731, vol. 84 (1979), Protein Immobilization - Fundamentals and Applications, Taylor R. F. (publisher), Marcel Dekker, Inc. (1991)). Apart from non-covalent immobilization techniques such as adsorption, entrapment, microencapsulation, chelation and aggregation, covalent immobilization methods have gained prominence for industrial applications. Web site: http://www.delphion.com/details?pn=US05780260__ •

Inhibition of expression of beta-lactamase using esters of fatty acid alcohols Inventor(s): Brown-Skrobot; Susan (Hamilton, NJ), Novick; Richard P. (New York, NY), Projan; Steven J. (New York, NY) Assignee(s): Public Health Research Institute (New York, NY) Patent Number: 5,633,245 Date filed: June 6, 1995 Abstract: A class of chemical compounds comprising fatty acid ester derivatives used to inhibit beta-lactamase production by infectious bacteria. These inhibitors have been found to retard the resistance of certain strains of bacteria to beta-lactam antibiotics, such as penicillin, by interfering with the transcription of the beta-lactamase gene and precluding expression of beta-lactamase. In accordance therewith, these inhibitors permit effective treatment of infections of otherwise resistive bacteria with antibiotics. Excerpt(s): This invention relates to the chemotherapy of bacterial infections whereby a class of fatty acid ester derivatives can be utilized as inhibitors of beta-lactamase production. Beta-lactam antibiotics, such as penicillin, methicillin, amoxicillin and the like, have been used for many years in battling bacterial infections in humans. After repeated exposure to this type of antibiotic, however, many bacterial strains have become resistant to these antibiotics and now render them ineffective in treating infections. The medical and scientific community believes that bacterial resistance to beta-lactam antibiotics can usually be attributed to the ability of these bacteria to produce beta-lactamase, an enzyme that cleaves the chemical structure of the betalactam antibiotics. Researchers have, therefore, approached this problem by searching for beta-lactamase inhibitors that will prevent the action of beta-lactamase and permit this class of antibiotics to remain active in treating bacterial infections. Some of these beta-lactamase inhibitors are antibacterial; some act synergistically with beta-lactam antibiotics to increase their effectiveness. Web site: http://www.delphion.com/details?pn=US05633245__

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Medium for preserving tissue without tissue culturing occurring Inventor(s): Goldstein; Marc (New York, NY), Li; Philip S. (Flushing, NY), Schulsinger; David A. (New York, NY) Assignee(s): Cornell Research Foundation, Inc. (Ithaca, NY) Patent Number: 5,925,510 Date filed: October 8, 1997 Abstract: A method for autotransplantation, is provided including the steps of (a) obtaining a piece of tissue from one part of a body, (b) preserving the tissue by contacting it with a tissue preserving medium, without tissue culturing occurring, and (c) grafting the tissue in another part of the body. The method is especially advantageous for the repair of hypospadias using buccal mucosa tissue. The tissue preserving medium preferably is a solution of (a) 80-120 mM NaCl, (b) 3-6 mM KCl, (c) 0.1-0.3 mM MgSO.sub.4.7H.sub.2 O, (d) 1-3 mM CaCl.sub.2.2H.sub.2 O, (e) 0.2-0.6 mM NaH.sub.2 PO.sub.4, (f) 1.5-4 mM glucose, (g) 15-25 mM Na lactate, (h) 0.2-0.6 mM Na pyruvate, (i) 0.01-0.05 mM phenol red, (j) 0.1-0.4 mM L-glutamine, (k) 2-35 mM sodium bicarbonate, (l) 125-200 units/ml penicillin-G, (m) 40-60.mu.g/ml streptomycin sulfate, (n) vehicle consistent with tissue preservation; said medium having a pH ranging from 7.0-7.8. Excerpt(s): The present invention relates to a medium for preserving tissue and to a method for autotransplantation utilizing medium for preserving tissue between the time of removal from the donor location and transplantation. Autotransplantation, i.e., the transfer of one's own tissue from one location to another, is used, for example, for replacement or repair in the urinary tract or in the vascular system or in other body sites. In autotransplantations, one problem is preserving the tissue between the time of removal from the donor location and the transplantation so as to improve chances of effective transplantation. Web site: http://www.delphion.com/details?pn=US05925510__

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Method and apparatus for preparation of chiral beta amino acids using penicilln G acylase Inventor(s): Landis; Bryan H. (Manchester, MO), Ng; John S. (Chicago, IL), Topgi; Ravindra S. (Palatine, IL), Wang; Ping T. (Manchester, MO), Yonan; Edward E. (Carol Stream, IL) Assignee(s): Monsanto Company (Skokie, IL) Patent Number: 6,214,609 Date filed: May 1, 1998 Abstract: A method for preparing a chiral beta amino acid or its corresponding esters which comprises contacting a racemic beta amino acid, an acyl donor and Penicillin G acylase enzyme under conditions appropriate to stereoselectively acylate one enantiomer of the racemic beta amino acid to its corresponding N-acylated derivative whereby the opposite enantiomer of the beta amino acid is retained in enantiomerically enriched form. Excerpt(s): This invention generally relates to enzyme catalyzed processes for producing chiral.beta.-amino acids. In particular, this invention relates to processes for producing chiral.beta.-amino acids employing Penicillin G acylase. The current evolving

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regulatory climate in the development of chiral drugs has created the necessity of preparing highly optically active compounds in pharmaceutical, agricultural and chemical industries. This development has presented many opportunities to synthetic chemists who are interested in the development of new chirotechnology. In recent years there have been explosive advances in the development of new synthetic methods, including asymmetric syntheses, stereoselective crystallization, chiral chromatography, racemate resolution and catalytic kinetic resolution, to prepare optically pure compounds. Despite these new developments, there are still relatively few efficient scalable chirotechnologies capable of producing multikilogram to ton quantities of optically active compounds economically. Enzyme-catalyzed syntheses have been used in the commercial production of chiral pharmaceuticals. We have developed a new process for the preparation of chiral.beta.-amino acids or their corresponding esters using enzyme-catalyzed acylations or enzyme-catalyzed deacylations. Web site: http://www.delphion.com/details?pn=US06214609__ •

Method for influencing.beta.-lactam antibiotic production and for isolation of large quantities of ACV synthetase Inventor(s): Barredo; Jose Luis (Burgos, ES), Garcia; Bruno Diez (San Sebastian, ES), Gutierez; Santiago (Leon, ES), Martin; Juan Francisco (Leon, ES), Montenegro Prieto; Eduardo (Leon, ES), Palissa; Harriet (Berlin, DE), Van Liempt; Henk (Berlin, DE), Veenstra; Annemarie (Nieuw Vennep, NL), Von Doehren; Hans (Berlin, DE) Assignee(s): Gist-Brocades, N.V. (Delft, NL) Patent Number: 5,882,879 Date filed: April 4, 1994 Abstract: Novel methods and compositions are provided for the enhanced production of.beta.-lactam antibiotics. The process is exemplified by the production of penicillin. In addition, the P. chrysogenum and A. chrysogenum.delta.-(L-.alpha.-aminoadipyl)-Lcysteinyl-D-valine synthetase genes have been isolated and sequenced. Also methods are provided for the production of.delta.-(L-.alpha.-aminoadipyl)-L-cysteinyl-D-valine synthetase using recombined DNA techniques. Excerpt(s): This invention relates to methods and compositions to enhance the in vivo and in vitro production of fermentable or known and new secondary metabolites, particularly.beta.-lactams and their biosynthetic intermediates using recombinant DNA techniques.beta.-Lactam antibiotics are the largest family of secondary metabolites produced in nature by microorganisms. The most important classes of the.beta.-lactam antibiotics both clinically and economically are the penicillins (penam) and cephalosporins (cephem). Their biosynthesis occurs via a complex pathway of enzymatic steps; the unravelling of this pathway has been the subject of many studies during the last few decades. The first two steps are the key steps in the biosynthetic pathways of the penam and cephem classes of.beta.-lactam antibiotics. After these two steps the biosynthetic pathways to the penicillins and cephalosporins diverge. The first step in the biosynthesis of the penicillin, cephalosporin and cephamycin antibiotics is the condensation of the L-isomers of three amino acids, L-.alpha.-amino adipic acid (A), L-cysteine (C) and L-valine (V) into a tripeptide,.delta.-(L-.alpha.-aminoadipyl)-Lcysteinyl-D-valine or ACV. This step is catalyzed by 67 -(L-.alpha.-aminoadipyl)Lcysteinyl-D-valine synthetase or ACVS. In the second step, the tripeptide ACV is oxidatively cyclised by the action of the Isopenicillin N synthase (hereinafter referred to as IPNS) or cyclase. The product of this reaction is Isopenicillin N; this compound

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contains the typical.beta.-lactam and thiazolidine ring structures and possesses antibacterial activity. From Isopenicillin N the penicillins G or V are formed by exchange of the hydrophilic A side chain by a hydrophobic side chain. The side chains commonly used in industrial processes are either phenylacetic acid (PA), yielding penicillin G, or phenoxyacetic acid (POA), yielding penicillin V; this exchange reaction is catalyzed by the enzyme acyltransferase (hereinafter referred to as AT). Web site: http://www.delphion.com/details?pn=US05882879__ •

Method for the acylation of the 7-amino group of the cephalosporanic ring Inventor(s): Fuganti; Claudio (Milan, IT), Zenoni; Maurizio (Leffe, IT) Assignee(s): Finpael S.p.A. (Milan, IT) Patent Number: 5,654,425 Date filed: May 1, 1995 Abstract: A method for the acylation of the 7-amino group of the cephalosporanic ring, according to which a 7-ACA amino thiazolyl protected adduct is prepared by acylating said amino group by an aminothiazolyl acetic acid whose amino group has been protected by a phenyl acetyl or a phenoxy acetyl group, the amino group being then deprotected by aqueous hydrolysis in the presence of penicillin G amidase or respectively penicillin V amidase. Excerpt(s): The present invention relates to a method for the acylation of the 7 -amino group of the cephalosporanic ring. c) optionally substituting the 3-acetoxymethyl group of the cephalosporinic ring by a nucleophilic agent. The sequencing of the above reported steps can be varied at will. For instance, the step sequencing can be a), b), c); or a), c), b); or c), a), b), too, as it is described in the journal of Antibiotics, December 1978: 1262-1271 and in the BE-A-823861 by Takeda (concerning the antibiotic CEFOTIAM). Web site: http://www.delphion.com/details?pn=US05654425__

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Method for treating mastitis and other staphylococcal infections Inventor(s): Blackburn; Peter (New York, NY), Polak; June (Brooklyn, NY) Assignee(s): Ambi Inc. (Tarrytown, NY) Patent Number: 5,760,026 Date filed: September 9, 1994 Abstract: Lysostaphin is used to eliminate and cure staphylococcal infections including the cure of mastitis by intramammary infusion. Administration of from 2 mg to 400 mg of lysostaphin to an infected bovine mammary gland eliminates staphylococci, and the reoccurrence common with antibiotic therapy is not observed. Teat-dips containing lysostaphin, mutanolysin and lysozyme can be used as a prophylactic. Synergistic enhancement of the killing effect of lysostaphin is observed when a mild surfactant or penicillin or both is included in the formulation. Excerpt(s): This application relates to the use of lysostaphin in the treatment and prevention of staphylococcal infection and, in particular, to the treatment and prevention of staphylococcal bovine mastitis. Lysostaphin is a bacteriocin secreted by a single known strain of Staphylococcus simulans originally isolated and named

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Staphylococcus staphylolyticus by Schindler and Schuhardt. The production of lysostaphin by S. staphylolyticus has been described previously in U.S. Pat. No. 3,278,378 issued Oct. 11, 1966 and in Proceedings of the National Academy or Sciences, Vol. 51, pp. 414-421 (1964). The single organism S. staphylolyticus (NRRL B-2628) which produced lysostaphin was recently identified as a biovar of S. simulans by Sloan et al., Int. J. System. Bacteriol., Vol. 32, pp. 170-174 (1982). Since the name S. staphylolyticus, is not on the Approved List of Bacterial Names, the organism producing lysostaphin has been redesignated as S. simulans. Bacteriocins are proteins secreted by bacteria that kill and sometimes lyse related bacteria. For example, lysostaphin lyses and kills practically all known staphylococcal species but is inactive against bacteria of all other genera. Lysostaphin, isolated from culture filtrates of S. simulans (NRRL B-2628) grown according to published references, is an endopeptidase which cleaves the polyglycine cross-links of the peptidoglycan found in the cell walls of staphylococci. In addition, cultures that produce lysostaphin appear to be resistant to its activities while cultures grown under non-lysostaphin producing conditions are sensitive. Web site: http://www.delphion.com/details?pn=US05760026__ •

Mutant penicillin G acylases Inventor(s): Novotny; Jiri (Princeton, NJ), Usher; John James (East Syracuse, NY), White; Brenda Joyce (Jamesville, NY), You; Li (Jamesville, NY) Assignee(s): Bristol-Myers Squibb Co. (Princeton, NJ) Patent Number: 6,403,356 Date filed: October 31, 1997 Abstract: New mutant penicillin G acylases preferably from E. coli are provided, exhibiting altered enzymatic activity. These penicillin G acylases are obtained by expression of a gene encoding said penicillin G acylase having an amino acid sequence which differs at least in one amino acid from the wild-type penicillin G acylase. Excerpt(s): The present invention relates to mutated genes encoding Type II penicillin G acylases, to penicillin G acylases encoded by these genes resulting in altered properties, and to methods for the synthesis of.beta.-lactam antibiotics using these penicillin G acylases. Today, semisynthetic.beta.-lactam derivatives such as ampicillin, amoxicillin, cephalexin, cefadroxil, and cefprozil are, on an industrial scale, prepared by chemical methods. The synthesis of these antibiotics catalyzed by enzymes constitutes a clear example of an enzymatic reaction of possible industrial importance. The enzymatic approach has several advantages as compared to conventional chemical methods: (1) avoidance of toxic reagents and solvents; (2) enzyme specificity renders protection of carboxyl groups in the antibiotic nucleus unnecessary; (3) avoidance of side reactions, including racemization. The preferred acyl group is phenylacetyl, although other aromatic and aliphatic (hydrophobic, or charged/polar) acyl groups can also be hydrolyzed to varying degrees (generally less). The preference for different acyl groups are not necessarily true for the reverse reaction, namely the formation of amide bonds between the acyl groups and 6-APA and 7-ACA (III and IV). For instance, the chloroacetyl group can be put on to 7-ACA much faster than most aromatic acyl groups (patent JP08000284-A). For many currently marketed.beta.-lactam antibiotics, the acyl groups are aromatic functions with varying degrees of hydrophobicity. The wild type penicillin G amidase can catalyze the semisyntheses (amide bond formation) of these antibiotics, but the reactions rarely go to completion under suitable or economical

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conditions for the production of these antibiotics. Improvements in the production yield and efficiency of these reactions are highly desired. Web site: http://www.delphion.com/details?pn=US06403356__ •

Mutated penicillin G acylase genes Inventor(s): Quax; Wilhelmus J. (Voorschoten, NL), Riemens; Adriana M. (Delft, NL), Van Der Laan; Jan M. (Breda, NL) Assignee(s): Gist-Hrocades (Delft, NL) Patent Number: 5,891,703 Date filed: April 23, 1997 Abstract: New mutant.beta.-lactam Penicillin G acylases are provided, exhibiting altered substrate specificities. These Penicillin G acylases are obtained by expression of a gene encoding for said Penicillin G acylase and having an amino acid sequence which differs at least in one amino acid from the wild-type Penicillin G acylase. Excerpt(s): The present invention relates to mutations of prokaryotic Penicillin G acylase or its preenzyme or preproenzyme, resulting in altered properties of the mutant penicillin G acylase. The basic antibiotics of the.beta.-lactam type are principally obtained by fermentation. Fungi of the genus Penicillium and Cephalosporium (Acremonium) are used for the production of raw material for.beta.-lactam antibiotics as penicillin G, penicillin V and cephalosporin C. These fermentation products, also referred to as PenG, PenV and CefC, respectively, are the starting materials for nearly all currently marketed penicillins and cephalosporins. In general the acyl group at the 6amino of the penicillin nucleus or at the 7-amino position of the cephalosporin nucleus is referred to as `side chain`, the corresponding acid as `side chain acid`. The side chains of PenG, PenV and CefC are phenylacetyl, phenoxyacetyl and aminoadipyl, respectively. The side chains are removed by cleavage of an amide linkage (deacylation), resulting in 6-aminopenicillanic acid (6-APA) in case of the penicillin molecules and 7aminocephalosporanic acid (7-ACA) in case of the cephalosporin molecule. In this respect also phenylacetyl-7-aminodesacetoxycephalosporanic acid (CefG) should be mentioned as a precursor of 7-ADCA, although CefG is not a fermentation product. CefG is usually produced chemically from Penicillin G. In order to obtain.beta.-lactam compounds with an altered activity spectrum, an increased resistance against.beta.lactamases or improved clinical performance of.beta.-lactam compounds, 6-APA, 7-ACA and 7-ADCA are used as starting points for synthetic manipulation to produce the various penicillins and cephalosporins of choice. At present these semisynthetic penicillins and cephalosporins form by far the most important market of.beta.-lactam antibiotics. Web site: http://www.delphion.com/details?pn=US05891703__

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Nucleosides, nucleotides and oligonucleotides containing enzymatically cleavable protecting groups Inventor(s): Birkner; Christian (Uffing, DE), Heuser; Axel (Karlsruhe, DE), Muehlegger; Klaus (Polling, DE), Reidel; Armin (Bingen, DE), Von Der Eltz; Herbert (Weilheim, DE), Waldman; Herbert (Rheinzabern, DE) Assignee(s): Boehringer Mannheim GmbH (Mannheim, DE) Patent Number: 5,677,441 Date filed: October 20, 1994 Abstract: Process for the production of oligonucleotides of formula II, in which the exocyclic amino groups of the bases adenine, guanine, cytosine, 7-deazaadenine and 7deazaguanine carry N-phenylacetyl groups, are used for oligonucleotide synthesis, wherein in a first step a starting nucleotide is bound to a solid carrier, subsequently the desired oligonucleotide is synthesized by stepwise coupling with appropriately activated further monomeric nucleotide building blocks of the general formula I with the above-mentioned meanings, if desired, trivalent phosphorus is oxidized to pentavalent phosphorus during and after the synthesis, the oligonucleotide is cleaved from the carrier and the 5' protecting groups are cleaved off. The phenylacetyl functional groups that protect exocyclic NH.sub.2 groups of the bases can be cleaved off in a mild way with penicillin amidohydrolase (EC 3.5.1.11). Excerpt(s): This invention relates to nucleotides and nucleosides derivatives in which the exocyclic amino groups thereof are protected by phenyl acetate groups, as well as the use for the production of oligonucleotides. Nucleic acid derivatives such as nucleosides and their phosphoric acid esters, the nucleotides, play an important role in nature. There they are of central importance as carriers or transmitters of genetic information. As knowledge has increased of the molecular biological mechanisms that form the basis for these processes, it has become possible in recent years to work on new combinations of genes see, for example E.-L. Winnacker in "Gene und Klone, eine Einfuhrung in die Gentechnologie, VCH Verlagsgesellschaft Weinheim (1985)". This technology opens new possibilities in many areas e.g. medicine and plant breeding. Web site: http://www.delphion.com/details?pn=US05677441__

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Oxidation of organosulphur compounds Inventor(s): Brown; Scott W. (Standish, GB), Lee; Angela M. (West Derby, GB), Oakes; Stephen C. (Widnes, GB) Assignee(s): Solvay Interox Limited (Barrington, GB2) Patent Number: 5,621,097 Date filed: November 3, 1995 Abstract: A process for the oxidation of organosulphur compounds with hydrogen peroxide is provided. The process employs solid supported polyacids comprising tungsten, molybdenum and/or vanadium as catalysts. The supports are selected from compounds, preferably oxides, of Group IIa, IIb, IIIb, IVa and IVb elements, and strong base ion exchange resins. Certain embodiments of the process provide for the oxidation of sulphides to sulphoxides or sulphones, particularly for the oxidation of penicillins to penicillin sulphoxides. Other embodiments of the process provide for the selective oxidation of thiols to sulphoxides.

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Excerpt(s): This invention concerns the oxidation of organosulphur compounds. In the agrochemical and pharmaceutical industries, it is often desired to oxidise sulphur compounds. One particular sulphur oxidation that it is desirable to perform is the oxidation of the sulphide group in penicillins to the corresponding sulphoxide. This is of particular commercial importance as the sulphoxide is often employed as an intermediate in the production of cephalosporins. A further important sulphur oxidation is the oxidation of thiols to sulphonic acids. The oxidation of thiols is not only important in the agrochemical and pharmaceutical industries, but is also of importance in the field of waste treatment, where it is often desirable to oxidise malodorous thiols to relatively odour free compounds. An aqueous solution of hydrogen peroxide would be a desirable oxidant to employ in the oxidation of sulphur compounds because it is relatively cheap, easy to handle and is environmentally acceptable in that its decomposition products are water and oxygen. Although hydrogen peroxide can oxidise some sulphur compounds to a certain extent in the absence of a catalyst, it has often been found that the use of a catalyst is preferred, in order, for example, to increase the rate of reaction or to favour the production of a particular, desired product. Some catalysts, particularly transition metal-based catalysts such as copper (II), iron (II), tungstate and vanadate, are well known in the sulphur oxidation art. However, many such catalysts are employed as homogeneous catalysts i.e. they are employed in the same phase and/or physical state as the reagents. Additionally, Spanish Patent No. 8301909 describes the use of soluble heteropolyacids as homogeneous catalysts for the oxidation of sulphides to sulphones. Web site: http://www.delphion.com/details?pn=US05621097__ •

Penicillin binding protein derivatives and uses thereof Inventor(s): Balganesh; Tanjore Soundararajan (Bangalore, IN), Town; Christine Mary (Sodertalje, SE) Assignee(s): Astra Aktiebolag (Sodertalje, SE) Patent Number: 6,027,906 Date filed: July 10, 1995 Abstract: The present invention relates to variants of Penicillin Binding Proteins (PBP), which proteins are involved in bacterial peptidoglycan biosynthesis. Disclosed are also DNA molecules coding for the said PBP variants, as well as vectors and cells harbouring such DNA molecules. The invention is also related to processes for assaying and designing therapeutically useful compounds which have high affinity to PBP, which processes utilize the said PBP variants. Excerpt(s): Bacteria and most other unicellular organisms possess a cell wall, which comprises a cross-linked polysaccharide-peptide complex called peptidoglycan. Peptidoglycan biosynthesis consists of three stages: (1) synthesis of precursors (sugar nucleotides) in the cytosol, (2) precursor transfer across the membrane and formation of the polysaccharide chain, and (3) cross-linking of individual peptidoglycan strands in the cell wall. In the latter stage of peptidoglycan biosynthesis, new bonds must be made between nascent glycan strands and existing peptidoglycan. The newly synthesized chains are about 10 disaccharides long and are extended by transglycosylase enzymes to a final glycan strand of between 100 and 150 disaccharide units. The peptidoglycan is crosslinked by the action of transpeptidases which link the terminal D-ala of one glycan strand to a free.epsilon.-amino group on a diaminopimelic acid residue on an adjacent region.

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Web site: http://www.delphion.com/details?pn=US06027906__ •

Penicillin G acylase immobilized with a crosslinked mixture of gelled gelatin and amino polymer Inventor(s): De Vroom; Erik (Leiden, NL) Assignee(s): Gist-Brocades B.V. (NL) Patent Number: 6,060,268 Date filed: January 15, 1998 Abstract: Penicillin G acylase is immobilized by covalent bonding to a crosslinked mixture of a gelled gelling agent such as gelatin and a polymer containing free amino groups such as alginate amine, chitosan or polyethylene imine. The immobilized penicillin G acylase provides a higher synthesis/hydrolysis ratio as compared to immobilizing with other carriers when producing.beta.-lactam derivatives by a condensing reaction of an amino.beta.-lactam with an acylating agent. The acylating agent may be a derivative of D-phenylglycine, a derivative of D-phydroxyphenylglycine or a derivative of D-2,5-dihydro-phenylglycine. Examples of.beta.-lactam derivatives that can be produced are amoxycillin, ampicillin, cephaclor, cephadroxil, cephprozil, cephalexin and cephradine. Excerpt(s): The present invention relates to an improved immobilized Penicillin G acylase. Furthermore, the invention relates to the preparation of.beta.-lactam-antibiotics by enzymatic acylation of the parent amino.beta.-lactam nucleus with the corresponding acylating agent using said immobilized enzyme. Enzymatic production of semisynthetic.beta.-lactam antibiotics by acylation of the parent amino.beta.-lactam moiety with an activated side chain acid derivative, such as an amide or an ester, is known from Dutch patent 158847, European patent applications 339751 and 473008, international patent applications WO 92/01061 and WO 93/12250, U.S. Pat. No. 3,816,253, and West German patent documents 2163792 and 2621618. The enzymes used in the art are in most cases penicillin acylases obtained from Escherichia coli and are immobilized on various types of water-insoluble materials. A drawback of the known enzymatic methods for the production of amoxycillin, ampicillin, cephadroxil, cephalexin, and cephradine is the high cost due to the selectivity of the immobilized enzyme. Said immobilized enzymes are capable of condensing activated side chain derivatives such as D(-)-phenylglycine amide (PGA), D(-)-phenylglycine methyl ester (PGM), D(-)-4-hydroxyphenylglycine amide (HPGA), D(-)-4-hydroxyphenylglycine methyl ester (HPGM), D(-)-2,5-dihydro-phenylglycine amide (DPGA), and D(-)-2,5dihydrophenylglycine methyl ester (DPGM) with amino.beta.-lactams such as 6-aminopenicillanic acid (6-APA), 7-aminocephalosporanic acid (7-ACA), 7-amino-3-chloro-3cephem-4-carboxylic acid (7-ACCA), 7-aminodesacetoxycephalosporanic acid (7-ADCA) and 7-amino-3-[(Z)-1-propenyl]-3-cephem-4-carboxylic acid. On the other hand, said immobilized enzymes will also hydrolyse the activated side chain derivatives to worthless side chain acids. Also, the desired product hydrolyses to form side chain acid and the parent amino.beta.-lactam. A high ratio between synthesis and hydrolysis will lower the cost of activated side chain derivative. Web site: http://www.delphion.com/details?pn=US06060268__

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Penicillin G acylase, a gene encoding the same and a method for the production of this enzyme Inventor(s): Quax; Wilhelmus Johannes (Voorschoten, NL) Assignee(s): Gist-Brocades, N.V. (Delft, NL) Patent Number: 5,695,978 Date filed: April 15, 1994 Abstract: The invention provides a gene encoding penicillin G acylase, the enzyme encoded by said gene and a method for the production of said enzyme by incorporating said gene in a host and bringing the same to expression. The gene is preferably obtained from a strain of the microorganism Alcaligenes faecalis. Excerpt(s): This invention relates to a gene encoding penicillin G acylase, to penicillin G acylase encoded by this gene and to a method for the production of this enzyme. Penicillin G acylase (benzylpenicillin amidohydrolase, also named penicillin amidase; EC 3.5.1.11) is an enzyme used commercially to hydrolyse penicillin G or 3-desacetoxycephalosporin G to phenylacetic acid and 6-aminopenicillanic acid (6-APA) or 7aminodesacetoxycephalosporanic acid (7-ADCA), respectively, the most important intermediates for the industrial production of semi-synthetic penicillins and cephalosporins. This enzyme also catalyses the reverse reaction, viz. the N-acylation of 6-APA and 7-ADCA with organic esters to generate their corresponding N-acetylated penicillin and 3-cephem compounds, respectively. See the reviews of Vandamme, E. J., In: Microbial Enzymes and Bioconversions, E. H. Rose (Ed.), Economic Microbiology 5, 467-552 (1980); and P. B. Mahajan, Appl. Biochem. Biotechnol. 1, 83-86 (1982). Various types of microorganisms have been proposed in the literature as Penicillin G acylase producing strains useful for the deacylation of penicillin G and 3desacetoxycephalosporin G. Examples of such acylase producing microorganisms are certain strains of the species Escherichia coli, Kluyvera citrophila and Proteus rettgeri. It is to be noted that some penicillin G acylase activity has been described in the whole cell fraction of Alcaligenes faecalis (C. A. Claveridge et al., Nature 4733, 237-238 (1960)). However, no enzyme or some enzymes responsible for this activity from A. faecalis have been described up to now. Web site: http://www.delphion.com/details?pn=US05695978__

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Penicillin glycolate Inventor(s): Kapur; Jagdish C. (Delft, NL) Assignee(s): Gist-Brocades, B.V. (NL) Patent Number: 5,955,458 Date filed: March 26, 1998 Abstract: New solvates of penicillin, in particular amoxycillin glycolate has been provided for together with a simple one-step process to prepare the same. Excerpt(s): This invention relates to a glycolate form of a penicillin antibiotic as for instance amoxycillin or ampicillin. In particular this invention relates to a glycolate form of 6-(D-.beta.-amino-p-hydroxyphenylacetamido)-penicillanic acid (amoxycillin) which is substantially free of water, and to a process for the preparation thereof. The solvates of for instance amoxycillin or ampicillin may also be converted into non-toxic, pharmaceutically acceptable salts by a method known per se. Amoxycillin is known to

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exist in two forms, namely the crystalline trihydrate form and the mono hydrated amorphous form. The amoxycillin antibiotic is active against Gram-positive and Gramnegative bacteria and is useful as a therapeutic and prophylactic agent against bacterial infections in man including animals. British patent No. 1286199 describes a process whereby amoxycillin containing a minimum water content of 3-5% can be prepared by drying an alkanolate of amoxycillin trihydrate. However, it has been described that the intermediate alkanolate form is not stable and is subjected to a potency loss after a few days. Web site: http://www.delphion.com/details?pn=US05955458__ •

Process for 7-aminodesacetoxycephalosporanic acid Inventor(s): Lopez; Jorge L. (Natick, MA) Assignee(s): Sepracor, Inc. (Marlborough, MA) Patent Number: 5,521,068 Date filed: February 9, 1995 Abstract: The invention relates to an improved process for converting 6acylaminopenicillanic acid (6-AAPA) to 6-aminopenicillanic acid (6-APA). The process employs a solution or suspension of penicillin acylase from which the product is separated after reaction by ultrafiltration through a particular class of polymer membranes. The process of the invention may also be applied to the production of 7aminodesacetoxycephalosporanic acid (7-ADCA) and can be incorporated into an improved, streamlined process for obtaining 6-APA from fermentation broths. Excerpt(s): The invention relates to a process for converting 6-acylaminopenicillanic acid (6-AAPA) to 6-aminopenicillanic acid (6-APA) or 7acylaminodesacetoxycephalosporanic acid (7-AADCA) to 7aminodesacetoxycephalosporanic acid (7-ADCA). Enzyme processes used for the manufacture of 6-APA or 7-ADCA rely on the use of enzyme which has been immobilized on a suitable support. This makes separation of the reaction products from the biocatalyst a simple procedure. The reaction is carried out in aqueous media at elevated temperatures (e.g. 28.degree.-37.degree. C.). Several different reactor configurations have been described in the literature, with stirred tank reactors and packed bed reactors being the most popular. In almost all cases, the enzyme is immobilized on an inert support of some type so that it can be used for multiple batches. In the case of the stirred tank batch reactor, substrate penicillin (in the form of its potassium salt) is charged to a large vessel containing the immobilized enzyme. The reaction pH is maintained in the desired range through the controlled addition of a weak base such as dilute ammonium hydroxide or caustic. The reaction is allowed to proceed to 95-99% conversion, at which point the immobilized enzyme is filtered off and the 6-APA/acid/water filtrate discharged to a downstream recovery operation. The crystalline 6-APA product is precipitated by the addition of inorganic acid and recovered by simple filtration and drying. The phenylacetic acid (in the PenG case) or the phenoxyacetic acid (in the case of PenV) is extracted into an organic solvent and recycled back upstream in the process to the penicillin fermentation step. These immobilized enzyme processes have been in use for over 20 years. In the early development of commercial 6-APA processes, the need to immobilize the enzyme was necessitated in part by the cost of the enzyme which had to be reused many times in order to make its cost contribution to the final product as low as possible. By immobilizing the enzyme on a solid support, the separation of the aqueous product

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solution from the catalyst became simply a matter of passing the reactor contents through filters capable of retaining the enzyme support. The size difference between the products and the catalyst is in the order of 10.sup.5 when the catalyst is immobilized, so that crude filters would suffice. Web site: http://www.delphion.com/details?pn=US05521068__ •

Process for increasing the production of penicillin G (benzylpenicillin) in Penicillium chrysogenum by expression of the PCL gene Inventor(s): Barredo Fuente; Jose Luis (Leon, ES), Diez Garcia; Bruno (Leon, ES), Fernandez Canon; Jose Manuel (Madrid, ES), Garcia Alonso; Belen (Leon, ES), Luengo Rodriguez; Jose Maria (Leon, ES), Martinez Blanco; Honorina (Leon, ES), Minambres Rodriguez; Baltasar (Leon, ES), Moreno Valle; Miguel Angel (Leon, ES), Rodriguez Olivera; Elias (Leon, ES), Salto Maldonado; Francisco (Madrid, ES), Schleissner Sanchez; Carmen (Leon, ES) Assignee(s): Antibioticos S.A. (Madrid, ES) Patent Number: 6,251,655 Date filed: October 28, 1998 Abstract: An isolated DNA encoding phenyl acetyl-CoA-ligase and a process of increasing the production of penicillin G in a strain of Penicillium chrysogenum by transforming the strain with the isolated DNA. Also vectors and host organisms having the isolated DNA. Excerpt(s): This invention describes a new process for obtaining strains of Penicillium chrysogenum with greater penicillin G production capacity, by the introduction and expression in the control strain of an exogenous gene which codes for the enzyme phenylacetyl-CoA ligase and which originates from the bacterium Pseudomonas putida. The biochemical and genetic studies carried out to date (Ref. 5) have allowed all he enzymes of the penicillin G specific biosynthetic pathway to be identified and their genes to be characterized, with the exception of the enzyme phenylacetyl-CoA ligase, which it has not been possible to purify and the gene of which is unknown at the moment. In addition, the amounts of the different biosynthetic enzymes (ACVS, IPNS and AT) detected in different strains of Penicillium chrysogenum (both in those whose production of penicillin G is low and in other strains used industrially) are sufficiently high to eliminate the possibility of any of them being considered a limiting stage in the biosynthesis of penicillin G (Ref. 7-8). For this reason a study was commenced of the enzyme phenylacetyl-CoA ligase (PCL), the only enzyme in the pathway for which the sequence is not fully known. The absence of detectable amounts of enzyme in all the strains of Penicillium chrysogenum studied means that different microorganisms have to be selected for their ability to grow in a medium of defined composition (minimal medium, MM) containing phenylacetic acid (PA) as the sole carbon source (Ref. 9), and also that the existence of phenylacetyl-CoA ligase activity has to be assessed in all the selected strains. Of all the microorganisms isolated, a strain of Pseudomonas putida U was selected which breaks down phenylacetic acid aerobically by means of an undescribed degradation pathway involving a new enzyme: phenylacetyl-CoA ligase (EC 6.2.1.30). This enzyme was purified to homogeneity and characterized biochemically (Ref. 9). The Pseudomonas putida U enzyme, which we will hereinafter call PLC, presents some optimal physicochemical conditions which are very similar to the IPNS and AT of Penicillium chrysogenum, and so it was thought that the three enzymes could work together in vitro. It was shown that the PCL of Pseudomonas

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putida U and the IPNS and AT of Penicillium chrysogenum could be linked in vitro and used in this form for the production of both penicillin G and other penicillins in the laboratory (Ref. 10). These results, which are described in Spanish Patents Nos. P8902421 and 2016476 A6, allowed the possibility to be suggested that the PCL of Pseudomonas putida U might be expressed in Penicillium chrysogenum and that, if this enzyme was a limiting stage in the biosynthetic pathway, greater production of penicillin G might be achieved. b) the others in which this activity could not be detected (called PCL-). Web site: http://www.delphion.com/details?pn=US06251655__ •

Process for making (2S,5S)-5-fluoromethylornithine Inventor(s): Ducep; Jean-Bernard (Sundhoffen, FR), Jund; Karin (Strasbourg, FR) Assignee(s): Merrell Pharmaceuticals, Inc. (Cincinnati, OH) Patent Number: 5,637,768 Date filed: July 18, 1995 Abstract: The present invention is directed to a process for making (2S,5S)-5fluoromethylornithine through the reaction of wet penicillin acylase with (2R,5R) and (2S,5S)-6-fluoromethyl-3-(phenylactyl)-amino-2-piperidone and the addition of an acid to the resulting product. Excerpt(s): This application is a 371 of PCT/US93/11283 filed Nov. 19, 1993. The present invention comprises the use of certain inhibitors of ornithine aminotransferase, and more preferably, certain 5-substituted ornithine derivatives for the treatment of dementia of the Alzheimer's type (DAT) alone and in combination with other agents. The ammonium ion (NH.sub.4 +) serves a major role in the maintenance of acid-base balance, but is toxic in high concentrations. By the body it is produced from many precursors (nucleic acids, proteins, amino acids, hexosamines, primary amines) by different reactions, and introduced into the body by exogenous sources such as the break down of dietary proteins by intestinal bacteria. Web site: http://www.delphion.com/details?pn=US05637768__

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Process for preparation on 3-substituted cephem compound Inventor(s): Sasaoka; Michio (Itano-gun, JP), Shiroi; Takashi (Itano-gun, JP), Tanaka; Hideo (Okayama, JP), Torii; Shigeru (Akaiwa-gun, JP) Assignee(s): Otsuka Kagaku Kabushiki Kaisha (Osaka, JP) Patent Number: 5,656,755 Date filed: July 6, 1995 Abstract: An object of the invention is to provide a process for preparing a 3-substituted cephem compound from an allenyl-.beta.-lactam compound which can be easily produced from an inexpensive penicillin compound by a simple reaction procedure.The process of the invention comprises reacting an allenyl-.beta.-lactam compound with an organohalogen compound in the presence of a metal having a standard oxidationreduction potential of -0.3 (V/SCE) or less in an amount at least equimolar with the allenyl-.beta.-lactam compound and 0.0001 to 0.5 mole, per mole of the allenyl-.beta.lactam compound, of a metal compound having a higher standard oxidation-reduction potential than said metal.

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Excerpt(s): The present invention relates to a process for preparing a 3-substituted cephem compound from an allenyl-.beta.-lactam compound which can be easily produced from an inexpensive penicillin compound by a simple reaction procedure. The 3-substituted cephem compound prepared by the process of the present invention is useful as an antibacterial agent having a wide antibacterial spectrum (e.g., Japanese Unexamined Patent Publications Nos. 119593/1973, 37788/1986, 51688/1987, 211287/1988 and 313482/1989). Japanese Unexamined Patent Publication No.119593/1973 discloses a process for preparing a 3-substituted cephem compound by coupling a carbonyl compound with a 3-phosphoranilideneethyl cephalosporin compound derived from a 3-halogenomethyl cephalosporin compound. Web site: http://www.delphion.com/details?pn=US05656755__ •

Process for the production of 7-ADCA via expandase activity on penicillin G Inventor(s): Bovenberg; Roelof Ary Lans (Rotterdam, NL), Koekman; Bertus Pieter (Schipluiden, NL), Schipper; Dirk (Delft, NL), Vollebregt; Adrianus Wilhelmus Hermanus (Naaldwijk, NL) Assignee(s): DSM N.V. (NL) Patent Number: 6,020,151 Date filed: February 18, 1998 Abstract: A process is taught for the preparation and recovery of 7aminodesacetoxycephalosporanic acid (7-ADCA) via enzymatic ring expansion activity on penicillin G, using a Penicillium chrysogenum transformant strain expressing expandase. Excerpt(s): The present invention concerns a biosynthetic process for preparation and recovery of 7-aminodesacetoxycephalosporanic acid (7-ADCA).beta.-Lactam antibiotics constitute the most important group of antibiotic compounds, with a long history of clinical use. Among this group, the prominent ones are the penicillins and cephalosporins. These compounds are naturally produced by the filamentous fungi Penicillium chrysogenum and Acremonium chrysogenum, respectively. As a result of classical strain improvement techniques, the production levels of the antibiotics in Penicillium chrysogenum and Acremonium chrysogenum have increased dramatically over the past decades. With the increasing knowledge of the biosynthetic pathways leading to penicillins and cephalosporins, and the advent of recombinant DNA technology, new tools for the improvement of production strains and for the in vivo derivatization of the compounds have become available. Web site: http://www.delphion.com/details?pn=US06020151__

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Processes for the production of 6-.alpha.-aminoacyl-penicillin and 7-.alpha. Inventor(s): Diago; Jose (Granollers, ES), Ludescher; Johannes (Breitenbach, AT) Assignee(s): Biochemie Gesellschaft m.b.H. (Kundl, AT) Patent Number: 5,840,885 Date filed: June 6, 1995

Patents 137

Abstract: A new process is described for the production of 6-alpha-amino-penicillins and 7-alpha-amino-desacetoxy-cephalosporins free from halogen-containing solvents by acylating 6-APA, 7-ADCA or a derivative thereof in a halogen-free solvent. Excerpt(s): This invention relates to a process for the production of highly pure 6-alphaaminoacyl-penicillins and 7-alpha-aminoacyl-desacetoxy-cephalosporins which on the industrial scale is economical to operate, and is environmentally acceptable, avoiding the use of halogen-containing solvents such as methylene chloride. Many processes have been investigated for the industrial production of 6-alpha-aminoacyl-penicillins and 7alpha-aminoacyl-desacetoxy-cephalosporins. Such processes must meet the necessary criteria for adoption on a commercial scale e.g. high yield, economy and ease of operation, including easy and effective purification of the end product, and few reaction steps. Processes which have been operated commercially on a large scale have required the use of halogen-containing solvents such as methylene chloride, despite the fact that these solvents are difficult to recycle or dispose of in an environmentally acceptable manner. The 6-alpha-aminoacyl-penicillins and 7-alpha-aminoacyl-desacetoxycephalosporins produced also inevitably contain trace amounts of solvents and in the case of halogen-containing solvents such as methylene chloride, this is undesirable since there are fears that these could be carcinogenic. In the literature there is no general or clear teaching of how varying reaction conditions, reactants, solvents or other factors in the synthesis of 6-alpha-aminoacyl-penicillins and 7-alpha-aminoacyl-desacetoxycephalosporins and their solvates affect yields, purity etc. This may be due to the fact that the penicillin and cephalosporin nucleus is very labile, several reactive moieties are present. The art is thus very empirical. Web site: http://www.delphion.com/details?pn=US05840885__ •

Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic Inventor(s): Eek; Arne T. (Trosa, SE), Sj ostrand; Sven Erik (S odert alje, SE) Assignee(s): ASTRA Aktiebolag (Sodertalje, SE) Patent Number: 5,629,305 Date filed: May 16, 1995 Abstract: A synergistic pharmaceutical combination and composition are disclosed for the treatment of gastritis and peptic ulcer containing a therapeutic amount of a proton pump inhibitor such as e.g., omeprazole or lansoprazole, which increases intragastric pH, and a therapeutic amount of an acid degradable antibacterial compound such as a penicillin or a macrolide. In particular, the combination is directed to the treatment of infections caused by Helicobacter pylori by raising the bioavailability of acid degradable antibacterial compounds. Excerpt(s): The present invention relates to a combination of a substance with inhibiting effect on the gastric acid secretion, thus a substance which increases the intragastric pH e.g. proton pump inhibitors, histamin-H.sub.2 -blockers and one or more antibacterial compounds which are acid degradable. Helicobacter pylori is affected by certain antibiotic compounds e.g. macrolides and penicillins as has been shown in vitro and in vivo. However, these products are degraded into nonantibacterial metabolites in the presence of gastric acid, which drastically reduces their antibacterial efficacy. In view of the widespread use of antimicrobial pharmaceuticals in the treatment of infectious diseases or for other purposes and the consequent emergence of drug-resistant strains,

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increased incidence of microbial substitution due to disturbance of the normal bacterial flora, changes in profile of infectious diseases, etc., there has been a constant demand for the development of new antimicrobial agents or combinations thereof. Web site: http://www.delphion.com/details?pn=US05629305__ •

Synthesis of beta-lactam antibiotics with immobilized penicillin amidase Inventor(s): Ilhan; Ferhat (Atahesir, DE), Kraemer; Dieter (Mainz, DE) Assignee(s): Unifar Kimya Sanayi ve Ticaret A.S. (Istanbul, TM) Patent Number: 6,218,138 Date filed: May 26, 1999 Abstract: Beta-lactam antibiotics are synthesized by reacting an amino-beta-lactam component with a corresponding amino-group-containing acylating side-chain component in the presence of penicillin amidase from E. coli covalently immobilized on support particles. The resulting beta-lactam antibiotic product is solubilized by adding an acid such as sulfuric acid to lower the pH to 1.0 at a temperature in the range of 0.degree. C. to +5.degree. C. The immobilized penicillin amidase is substantially inactivated by the acid. After separating the beta-lactam antibiotic product, the immobilized penicillin amidase is substantially reactivated for reuse in antibiotic synthesis by treatment with a buffer having about a neutral pH. Antibiotics that can be produced include ampicillin, amoxicillin, cephalexin, cefaclor and cefadroxil. Support particles that can be used include particles having a macroporous structure and a particle diameter of 10-1000.mu.m, particles having oxirane groups, particles made of a synthetic polymer and inorganic particles such as porous glass particles. Excerpt(s): The present invention relates to a method of synthesis of.beta.-lactam antibiotics. It has long been known that beta-lactam antibiotics can be formed from their respective nucleus and side-chain components via enzymatic pathways (C. A. Claridge et al., Nature, Vol. 187;237, 1960). From more recent studies it is known that a betalactam antibiotic, for example amoxicillin, synthesized via enzymatic pathways, has higher purity and accordingly lower toxicity than amoxicillin synthesized by chemical pathways (PCT WO 94/17800). Web site: http://www.delphion.com/details?pn=US06218138__

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

10

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

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Antibiotic product, use and formulation thereof Inventor(s): Isbister, James D.; (Potomac, MD), Rudnic, Edward M.; (N. Potomac, MD), Treacy, Donald J. JR.; (Arnold, MD), Wassink, Sandra E.; (Frederick, MD) Correspondence: Carella, Byrne Bain, Gilfillan,; Cecchi, Stewart & Olstein; Six Becker Farm Road; Roseland; NJ; 07068; US Patent Application Number: 20020136764 Date filed: December 20, 2001 Abstract: An antibiotic product, in particular a betalactam such as cephalosporin (in particular cefuroxime and/or cefpodoxime) or a penicillin (in particular axmoxicillin or dicloxacillin) is comprised of at least three dosages forms, each of which has a different release profile, with the C.sub.max for the antibiotic product being reached in less than about twelve hours. In one embodiment, there is an immediate release dosage form, as well as two or more delayed release dosage forms, with each of the dosage forms having a different release profile, wherein each reaches a C.sub.max at different times. Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 09/792,092, filed on Feb. 22, 2000, which is a continuation-in-part of U.S. application Ser. No. 09/687,229, filed on Oct. 13, 2000, and also claims the priority of U.S. Provisional Application Serial No. 60/184,546 filed on Feb. 24, 2000. This invention relates to an antibiotic product, as well as the use and formulation thereof. The invention further relates to betalactam antibiotic products and in particular to products that include a cephalosporin, such as cefuroxime and/or cefpodoxime or a penicillin such as amoxicillin or dicloxacillin, as well as derivatives, metabolites and any active isomers thereof. A wide variety of antibiotics have been used, and will be used, in order to combat bacterial infection. In general, such antibiotics can be administered by a repeated dosing of immediate release dosage forms, which results in poor compliance or as a controlled release formulation (slow release) at higher administered doses. The present invention is directed to providing for an improved antibiotic product. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Compositions for freezing dog sperm and method of freezing the dog sperm utilizing the compositions and artificial insemination method employing the frozen dog sperm Inventor(s): Sub, Son Hwa; (Seongnam-city, KR) Correspondence: Peninsula IP Group; A Professional Law Corporation; Suite 101; 2290 North First Street; San Jose; CA; 95131; US Patent Application Number: 20030082509 Date filed: October 25, 2001 Abstract: Disclosed herein is a composition and method for freezing dog sperm. The composition is based upon 100 ml of distilled water, 0.25 to 4.5 g of sodium citrate, 0.45 to 4.0 g of dextrose, 0.01 to 0.3 g of penicillin, 50,000 to 500,000 IU of streptomycin. 0.25 to 0.45 g of catalase, 0.045 to 0.25 g of yolk, 1.5 to 15 ml of glycerol and 0.02 to 0.1 ug of dog serum. The method for freezing dog sperm includes the steps of (a) collecting male dog sperm by a massage method or electrical shock, (b) centrifuging the collected sperm to separate and remove the upper fluid leaving only the lower sperm, (c) mixing equal volumes of the lower sperm and the composition and primarily refrigerating the mixture, (d) further adding the composition to the mixture obtained in the step (c) to

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reduce the volumetric ratio of sperm to the composition to 1:2, and secondarily refrigerating the resulting mixture, and (e) adding liquid nitrogen to the mixture obtained in the step (d) and freezing the mixture. Excerpt(s): The present invention relates to compositions for freezing dog sperm, a method of freezing the dog sperm utilizing the compositions and an artificial insemination method employing the frozen dog sperm. More particularly, the present invention relates to compositions for freezing dog sperm in which the number of spermatozoa living in the sperm and the shape and viability thereof are retained when the sperm is thawed within a predetermined time after it is frozen, a method of freezing the dog sperm utilizing the compositions, and an artificial insemination method involving thawing the frozen dog sperm at a suitable place and time and inserting the same into the vagina of the female dog. According to recent industrial development, genetic engineering has become an important field of study. Genetic engineering is necessary for the preservation and development of good breeds and the prolongation of the human life span, and has advanced to a considerably high level, beyond the fundamental stage. In the case of breeding livestock or pets, artificial insemination using liquid sperm allows fertilization of several female animals by mixing the sperm collected from a male animal with a diluent fluid to increase the volume of fluid available for injection. Thus, in performing the artificial insemination, superior or pure sperm is collected and several female animals can be simultaneously fertilized, thereby producing superior breeds and preserving pure breeds. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Crystals of penicillin and process for the production thereof Inventor(s): Kawahara, Ichiro; (Tokushima-shi, JP), Shimabayashi, Akihiro; (Tokushimashi, JP) Correspondence: Armstrong,westerman & Hattori, Llp; 1725 K Street, NW.; Suite 1000; Washington; DC; 20006; US Patent Application Number: 20020193588 Date filed: April 8, 2002 Abstract: The crystal of the invention is crystal of diphenylmethyl 2-methyl-2triazolylmethylpenam-3-carboxylate which is stable substantially without decomposition or degradation of properties even when left to stand at room temperature for 1 year. The crystal of the invention can be prepared by a process comprising the steps of concentrating a solution containing diphenylmethyl 2-methyl-2triazolylmethylpenam-3-carboxylate represented by the formula (2) 1wherein Ph is a phenyl group, diluting the concentrate with acetic ester and mixing the diluted solution with hexane or a solvent mixture of hexane and acetic ester to crystallize the diphenylmethyl 2-methyl-2-triazolylmethylpenam-3-carboxylate. Excerpt(s): The present invention relates to crystalline penicillin and a process for preparing the same, and more specifically to diphenylmethyl 2-methyl-2triazolylmethylpenam-3-carboxylate crystal and a process for preparing the same. Tazobactam has a very low antibacterial activity so that it is not used as an antibiotic per se. But it exhibits a beta-lactamase inhibitory activity when irreversibly bonded to betalactamases produced by microorganisms. For this reason, tazobactam may be used in mixture with known antibiotics prone to be inactivated by beta-lactamase to allow them to exhibit their inherent antibacterial activity against beta-lactamase-producing

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microorganisms (Katsuji SAKAI, Recent Antibiotics Manual, 10.sup.th edition, page 113). Tazobactam has a chemical structure of having 1,2,3-triazolylmethyl group in the 3-position. Tazobactam is prepared essentially via an intermediate for synthesis of tazobactam such as TMPB, p-nitrobenzyl 2-methyl-2-triazolylmethylpenam-3carboxylate or the like. Using TMPB, a high-purity tazobactam can be prepared in a high yield by an industrially simple and inexpensive process. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Diagnostic assay for antibiotic tolerance Inventor(s): Atkinson, Robyn M.; (Memphis, TN), Tuomanen, Elaine I.; (Germantown, TN) Correspondence: ST. Jude Children's Research Hospital; Office OF Technology Licensing; 332 N. Lauderdale; Memphis; TN; 38105; US Patent Application Number: 20020164623 Date filed: November 13, 2001 Abstract: Allelic variation in the vex2, pep27 and vncS genes of bacteria responsible for tolerance to antibiotics such as penicillin and vancomycin, is taught. Methods for identifying antibiotic tolerant bacteria and subjects infected with such bacteria, particularly antibiotic tolerant Streptococcus pneumoniae, are provided. Test kits and components useful for performing such methods, particularly including oligonucleotide primers, are also provided. Excerpt(s): This invention relates to the field of diagnostics based on DNA sequence information. Antimicrobial resistance to multiple antibiotics is a significant and well described clinical problem; however, a less well-characterized phenomenon, antimicrobial tolerance, has emerged in pathogenic isolates of Streptococcus pneumoniae with potentially serious effects on patient outcome. Tolerance describes the ability of bacteria to stop growing in the presence of an antibiotic, while surviving to resume growth once the antibiotic is remove; Incidence of tolerance to vancomycin, the antibiotic of last resort for Gram-positive infections, has increased to 8% in the past few years. Tolerance has also been implicated in-poor patient outcome with pneumococcal meningitis, mortality 30% versus non-tolerant 5% (unpublished data). In 1997, a locus was identified that is believed to control the activation of the major pneumococcal autolytic enzyme LytA, which is the enzyme whose loss of function is associated with tolerance. Novak R. B. et al, "Emergence of vancomycin tolerance in Streptococcus pneumoniae`, Nature :590-593 (1999). The operon, vex/pep27/vncr/s, encodes for a signal peptide, Pep27, that is transported out of the cell via the Vex dedicated transporter. Novak, R. et al., "Signal transduction by a death signal peptide: uncovering the mechanism of bacterial killing by penicillin", Molec Cell. 5:49-57 (2000). Pep27 is believed to be a quorum sensing peptide. Novak et al., id. (2000). Once it reaches a critical density in the supernatant, it signals through the two-component regulatory system, VncS and VncR, which subsequently induces activation of LytA. Novak et al., id. (2000). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Fusion molecules and treatment of IgE-mediated allergic diseases Inventor(s): Saxon, Andrew; (Santa Monica, CA), Zhang, Ke; (Los Angeles, CA), Zhu, Daocheng; (Los Angeles, CA) Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 91614; US Patent Application Number: 20030082190 Date filed: May 1, 2001 Abstract: The invention concerns bifunctional fusion molecules for the treatment of IgEmediated allergic conditions and Fc.epsilon.RI-mediated autoimmune conditions. The invention provides a new therapeutic approach for the treatment of both acute and latephase allergic responses due to ingestion, inhalation, cutaneous and parenteral exposure to allergens, responses including asthma, allergic rhinitis, atopic dermatitis, severe food allergies, chronic urticaria and angioedema, as well as anaphylactic reactions due to exposures such as bee stings or penicillin allergy. In addition, the invention provides for a novel, safer and more efficacious form of allergy vaccination. Excerpt(s): The invention concerns a new approach for the management of IgE-mediated allergic diseases and other disorders mediated through IgE receptors (Fc.epsilon.Rs) using novel fusion molecules that are able to complex with an Fc.epsilon.R and an inhibitory receptor expressed on mast cells, basophils, or B cells, including inhibitory receptors having an immune receptor tyrosine-based inhibitory (ITIM) motif. Immunoglobulin receptors (also referred to as Fc receptors) are cell-surface receptors binding the constant region of immunoglobulins, and mediate various immunoglobulin functions other than antigen binding. Fc receptors for IgE molecules are found on many cell types of the immune system (Fridman, W., FASEB J, 5(12):2684-90 (1991)). There are two different receptors currently known for IgE. IgE mediates its biological responses as an antibody through the multichain high-affinity receptor, Fc.epsilon.RI, and the lowaffinity receptor, Fc.epsilon.RI. The high-affinity Fc.epsilon.RI, expressed on the surface of mast cells, basophils, and Langerhans cells, belongs to the immunoglobulin gene superfamily, and has a tetrameric structure composed of an.alpha.-chain, a.beta.-chain and two disulfide-linked.gamma.-chains (Adamczewski, M., and Kinet, J. P., Chemical Immun., 59:173-190 (1994)) that are required for receptor expression and signal transduction (Tunon de Lara, Rev. Mal. Respir., 13(1):27-36 (1996)). The.alpha.-chain of the receptor interacts with the distal portion of the third constant domain of the IgE heavy chain. The specific amino acids of human IgE involved in binding to human Fc.epsilon.RI have been identified as including Arg-408, Ser-41 1, Lys-415, Glu-452, Arg465, and Met-469 (Presta et al., J. Biol. Chem. 269:26368-73 (1994)). The interaction is highly specific with a binding constant of about 10.sup.10 M.sup.-1. The low-affinity Fc.epsilon.RII receptor, represented on the surface of inflammatory cells, including eosinophils, leukocytes, B lymphocytes, and platelets, did not evolve from the immunoglobulin superfamily but has substantial homology with several animal lectins (Yodoi et al., Ciba Found. Symp., 147:133-148 (1989)) and is made up of a transmembrane chain with an intracytoplasmic NH2 terminus. The low-affinity receptor, Fc.epsilon.RII (CD23) is currently known to have two forms (Fc.epsilon.RIIa and Fc.epsilon.RIIb), both of which have been cloned and sequenced. They differ only in the N-terminal cytoplasmic region, the extracellular domains being identical. Fc.epsilon.RIIa is normally expressed on B cells, while Fc.epsilon.RIIb is expressed on T cells, B cells, monocytes and eosinophils upon induction by the cytokine IL-4. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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ISOPENICILLIN N SYNTHETASE AND SYNTHETASE ENZYMES AND METHODS

DEACETOXYCEPHALOSPORIN

C

Inventor(s): BALDWIN, JACK E; (OXFORD, GB), CLIFTON, IAN; (OXFORD, GB), HAJDU, JANOS; (UPPSALA, SE), HENSGENS, CHARLES M. H.; (GRONINGEN, NL), ROACH, PETER L; (OXFORD, GB), SCHOFIELD, CHRISTOPHER J; (OXFORD, GB) Correspondence: Nixon & Vanderhye; 1100 North Glebe Road; 8th Floor; Arlington; VA; 222014714 Patent Application Number: 20030088058 Date filed: May 19, 1999 Abstract: A three-dimensional structure is described of a complex of isopenicillin N synthase (IPNS) with Fe and its substrate ACV. This structure is used to design modified enzymes IPNS, DAOCS, DACS, DAOC/DACS and other related enzymes of the penicillin and cephalosporin biosynthesis pathway, which modified enzymes may accept unnatural substrates or improve production efficiency or produce improved products. Specific modifications of specific amino acid residues are proposed and exemplified. Excerpt(s): All commercially used penicillin and cephalosporin antibiotics and their derivatives are produced from fermentation derived materials containing a.beta.-lactam ring. A range of organisms, including both prokaryotes and eukaryotes, and conditions may be used for their fermentation. Some are produced directly by fermentation followed by isolation. Others are produced by modification of materials produced by fermentation. Commercially used cephalosporins (also known as cephems) may be produced by modification of either fermentation derived penicillins or cephalosporins. 1. Three amino acids (L-.alpha.-aminoadipic acid, L-cysteine, L-valine) are condensed to form a tripeptide: L-.delta.-.alpha.-aminoadip- oyl-L-cysteinyl-D-valine (ACV). During this process the L-valinyl residue is converted to a D-valinyl residue. This process is catalysed in vivo by the enzyme ACV synthetase and is common to both penicillin and cephalosporin biosynthesis. 2. ACV is converted to isopenicillin N in a step catalysed by the enzyme isopenicillin N synthase (IPNS). This step is common to both penicillin and cephalosporin biosynthesis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

METHOD FOR PREPARING A BETA-LACTAM ANTIBIOTIC Inventor(s): DE VROOM, ERIK; (LEIDEN, NL), KAPUR, JAGDISH CHANDER; (DELFT, NL), VAN DER DOES, THOMAS; (DELFT, NL) Correspondence: Morrison & Foerster Llp; 3811 Valley Centre Drive; Suite 500; San Diego; CA; 92130-2332; US Patent Application Number: 20020006642 Date filed: May 3, 1999 Abstract: The invention relates to a method for preparing a.beta.-lactam antibiotic, wherein an N-substituted.beta.-lactam, having general formula (I), wherein R.sub.0 is hydrogen or C.sub.1-3 alkoxy; Y is CH.sub.2, oxygen, sulfur, or an oxidized form of sulfur; Z is (a), (b), (c) or (d), wherein R.sub.1 is hydrogen, hydroxy, halogen, C.sub.1-3 alkoxy, optionally substituted, optionally containing one or more heteroatoms, saturated or unsaturated, branched or straight C.sub.1-5 alkyl, preferably methyl, optionally

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substituted, optionally containing one or more heteroatoms C.sub.5-8 cycloalkyl, optionally substituted aryl or heteroaryl, or optionally substituted benzyl; and X is (CH.sub.2).sub.m-A-(CH.sub.2).sub.n, wherein m and n are the same or different and are chosen from the group of integers 0, 1, 2, 3 or 4 and A is CH.dbd.CH, C.dbd.C, CHB, C.dbd.O, optionally substituted nitrogen, oxygen, sulfur or an optionally oxidized form of sulfur, and B is hydrogen, halogen, hydroxy, C.sub.1-3 alkoxy, or optionally substituted methyl, or a salt thereof, is contacted with at least one dicarboxylate acylase, or a functional equivalent thereof, and reacted with a precursor for a side chain of the.beta.-lactam antibiotic in the presence of at least one penicillin acylase, or a functional equivalent thereof. Excerpt(s): The invention relates to a method for preparing a.beta.-lactam antibiotic. The class of.beta.-lactam antibiotics, such as penicillin and cephalosporin antibiotics comprises a great variety of compounds, all having their own activity profile. In general,.beta.-lactam antibiotics consist of a nucleus, the so-called.beta.-lactam nucleus, which is linked through its primary amino group to the so-called side chain via a linear amide bond.beta.-Lactam nuclei are very important intermediates in the preparation of semi-synthetic penicillin and cephalosporin antibiotics. The routes to prepare these semi-synthetic penicillins and cephalosporins mostly start from fermentation products such as penicillin G, penicillin V and Cephalosporin C, which are converted to the corresponding.beta.-lactam nuclei, for instance in a manner as is disclosed in K. Matsumoto, Bioprocess. Techn., 16, (1993), 67-88, J. G. Shewale & H. Sivaraman, Process Biochemistry, August 1989, 146-154, T. A. Savidge, Biotechnology of Industrial Antibiotics (Ed. E. J. Vandamme) Marcel Dekker, New York, 1984, or J. G. Shewale et al., Process Biochemistry International, June 1990, 97-103. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method of milling pharmaceutical preparation Inventor(s): Lemanczyk, Stephen M.; (Syracuse, NY) Correspondence: Michael P. Williams; Bond, Schoeneck & King, Pllc; One Lincoln Center; Syracuse; NY; 13202; US Patent Application Number: 20020185558 Date filed: June 12, 2001 Abstract: An apparatus for the preparation of penicillin G procaine comprising a first vessel containing a suspension that includes particles of penicillin G procaine. A first conduit connects the first vessel to a microfluidizer and the suspension passes through the microfluidizer to a second conduit having a mesh screen. The particles pass through said microfluidizer whereby said particles are reduced in particle size and are delivered by the second conduit to a holding vessel. Excerpt(s): The present invention is directed toward an apparatus and method of milling a pharmaceutical preparation and more specifically is directed toward milling particles formed in aqueous suspension. Pharmaceutical preparations are manufactured and prepared for end use utilizing numerous manufacturing and synthesis methods. Advantageously, some pharmaceuticals can be prepared in aqueous suspensions in situ. One particular pharmaceutical preparation of interest in the present application and well known in the art is penicillin G procaine, which can be produced in situ by the reaction of procaine HCL and potassium penicillin G. The resulting product is an aqueous suspension that contains large particles of penicillin G procaine. However, in

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order for the penicillin product to be useful to the end user, such as a veterinarian, the particles must be of a suitable particle size that will allow for the easy and efficient application of the pharmaceutical to the patient. There are many methods available for reducing the particle size of penicillin G procaine. For instance, one known method is to process the preparation using a mill containing glass or plastic beads that break up the agglomerates through mechanical interaction between the beads and preparation within the mill. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Mutated penicillin expandase and process for preparing 7- ADCA using the same Inventor(s): Chia-Li, Wei; (Taipei, TW), Jyh-Shing, Hsu; (Taipei, TW), Ying-Chieh, Tsai; (Taipei, TW), Yunn-Bor, Yang; (Taipei, TW) Correspondence: Pennie & Edmonds Llp; 1667 K Street NW; Suite 1000; Washington; DC; 20006 Patent Application Number: 20030186354 Date filed: September 9, 2002 Abstract: A mutated expandase enzyme having higher activity on penicillin G is provided to produce 7-aminodeacetoxycephalosporanic acid (7-ADCA), which mutated expandase enzyme has one or more amino acid substitutions selected form methionine 73, glycine 79, valine 275, leucine 277, cysteine 281, glycine 300, asparagine 304, isoleucine 305, threonine 91, alanine 106, cysteine 155, tyrosine 184, methionine 188 and histidine 244, provided that the amino acid substitution at the residue position of asparagine 304 is not N304L and the amino acid substitution at the residue position of cysteine 155 is C155Y. Excerpt(s): The present application is a continuation-in-part application of U.S. Ser. No. 10/105,319 filed on Mar. 26, 2002. The present invention relates to a mutated penicillin expandase having high substrate specificity to penicillin G, recombinant cells expressing the mutated expandase, and a process of preparing 7aminodeacetoxycephalosporanic acid (7-ADCA) using the mutated expandase. 7aminodeacetoxycephalosporanic acid (7-ADCA) is one of the important intermediates for the production of cephalosporins cefalexin, cefradine, and cefadroxil which are antibiotic compounds commonly and long used in humans and animals. The industrial process for synthesizing 7-ADCA mainly includes two steps: a chemical ring expansion of penicillin G to phenylacetyl-7-ADCA and an enzymatic side chain cleavage of phenylacetyl-7-ADCA. However, the chemical reaction of the ring expansion is complex and expensive, and the by-products and the organic solvents (such as pyridine and HBr) are toxic to the environment. Therefore, an enzymatic reaction is greatly desirable to replace such chemical reaction. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Novel compounds Inventor(s): Burnham, Martin Karl Russel; (Betchworth, GB), Hodgson, John Edward; (Betchworth, GB), Normansell, Ian David; (Worthing, GB) Correspondence: Glaxosmithkline; Corporate Intellectual Property - Uw2220; P.O. Box 1539; King OF Prussia; PA; 19406-0939; US Patent Application Number: 20030180834 Date filed: March 21, 2003 Abstract: DNA sequences obtained from S. clavuligerus ATCC 27064, recombinant vectors incorporating such sequences and hosts transformed with such vectors are disclosed.The DNA comprises one or more genes coding for one or more enzymes involved in the biosynthesis of penicillin and cephalosporin.beta.-lactams and such enzymes are expressed by hosts into which the recombinant vectors are transformed.The DNA and the enzymes encoded thereby have utility in the preparation of penicillins and cephalosporins, both known and novel, possessing pharmacological, especially antimicrobial, activity. Excerpt(s): The present invention relates to recombinant DNA molecules, and in particular to recombinant vectors for use in the transformation of a microbial host which contain inserted DNA fragments carrying one or more genes coding for one or more enzymes involved in the biosynthesis of.beta.-lactam antibiotics, especially penicillins and cephalosporins. Progress in understanding the biosynthesis of.beta.-lactam antibiotics produced by micro-organisms such as Streptomyces clavuligerus has been slow. Nevertheless it has been established that the biosynthetic pathways of certain penicillins and cephalosporins (including cephamycins) are closely related. Isopenicillin N is an intermediate in the biosynthesis of both groups of compounds and is formed by the action of a `cyclase` enzyme on the tripeptide.delta.(L-.alpha.-aminoadipyl)-Lcysteinyl-D-valine (sometimes referred to as LLD-ACV or, more simply, ACV as used hereinbelow). The intermediate isopenicillin N may be converted either into penicillin G or, by the action of an `epimerase` enzyme, into penicillin N and it is from the latter that various cephalosporins and cephamycins may be derived by a multi-step pathway following an initial ring-expansion with an `expandase` enzyme. A recent summary of the state of the art is given by J. F. Martin and P. Liras in Trends in Biotechnology, 1985, 3, 39-44. Thus, in the biosynthesis of Cephamycin C, penicillin N is converted into deacetoxycephalosporin C which is then converted by a dioxygenase enzyme into desacetylcephalosporin C. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Pencillin biosensor Inventor(s): Han, In Suk; (Sandy, UT), Han, Man-Hee; (Salt Lake City, UT), Lew, Seok; (Salt Lake City, UT) Correspondence: Robert Mallinckrodt; M-biotech, INC.; Suite C; 2411 South 1070 West; Salt Lake City; UT; 84119; US Patent Application Number: 20030119174 Date filed: December 21, 2001 Abstract: The penicillin biosensor (10) has a pH-sensitive polymeric hydrogel (30) in a rigid enclosure (20). The hydrogel includes an immobilized enzyme such as

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penicillinase. The enzyme catalyzes a chemical reaction consuming penicillin and producing penicillic acid. The hydrogel changes its osmotic pressure in proportion to the concentration of the penicillic acid. By measuring the change in osmotic pressure with a pressure transducer (40), the biosensor (10) is able to accurately measure the concentration of penicillin. A battery (64) powered monitoring device, connected to the biosensor (10) through electrical wires, is operably programmed to display the penicillin concentration in a computer (62) as well as to activate LED or buzzer as an alert in case that the measured concentration of penicillin is over the threshold concentration. Excerpt(s): This invention relates to sensors for detecting penicillin in a fluid. Applicants make reference to U.S. Pat. No. 6,268,161 issued Jul. 31, 2001, entitled Biosensor, which is directed to a sensor for measuring concentration of organic molecules. This application has a common inventor to the patent and this application and the patent are assigned to a common assignee. A major problem in the U.S. dairy industry is ensuring that the milk supply does not contain significant levels of penicillin residues, which cause severe allergic reactions including anaphylactic shock in about 10 to 20% of the population. The presence of penicillin residues in milk is due to the widespread use of penicillin, ampicillin, cephapirin and amoxicillin for treatment of mastitis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

PENICILLIN CONVERSION Inventor(s): ADRIO, JOSE L.; (LEON, ES), BAEZ-VASQUEZ, MARCO A.; (MONTERREY N.L., MX), CHO, HIROSHI; (TOKYO, JP), DEMAIN, ARNOLD L.; (WELLESLEY, MA), FERNANDEZ, MARIA-JOSEFA E.; (MADRID, ES), HINTERMANN, GILBERTO; (CAMBRIDGE, MA), PIRET, JACQUELINE M.; (CAMBRIDGE, MA) Correspondence: C. Hunter Baker, M.D., PH.D.; Choate Hall & Stewart; Exchange Place; 53 State Street; Boston; MA; 02109-2891; US Patent Application Number: 20010006795 Date filed: April 22, 1999 Abstract: The present invention provides a biological system for expanding the dethiazolidine ring of penicillins into the dehydrothiazine ring of cephalosporins or cephalosporin precursors. In particular, the invention defines reaction conditions under which expandase enzyme can convert penicillin substrates other than penicillin N into cephalosporins. The invention therefore provides a relatively inexpensive, uncomplicated, and environmentally friendly biological system for cephalosporin production from penicillins, which system can replace the synthetic chemical approaches currently utilized. In particular, the invention provides a system for producing DOAG and/or DAG, which can be enzymatically converted into 7-ADCA and 7-ADAC, which, in turn, can be enzymatically or chemically converted into valuable cephalosporins of commerce. Excerpt(s): The present application claims priority to U.S. Ser. No. 60/082,800, filed Apr. 23, 1998, the entire contents of which are incorporated herein by reference. Various efforts have been made to utilize the C. acremonium or S. clavuligerus expandase enzyme either alone or with a hydroxylase enzyme to convert penicillins other than penicillin N into a cephalosporin or cephalosporin intermediate or substrate. Such

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efforts have almost uniformly failed. Many researchers have reported that the C. acremonium and S. clavuligerus expandase enzymes have very narrow specificity and fails to expand penicillins other than penicillin N and certain very close relatives. For example, Kohsaka and Demain, the original discoverers of C. acremonium expandase, have reported that only penicillin N, and not penicillin G or 6-aminopenicillanic acid (6-APA), are substrates for expandase activity in crude extracts (Kohsaka et al., Biochem. Biophys. Res. Commun. 70(2):1976:465-473, 1976; Demain et al., U.S. Pat. No. 4,178,210, issued Dec. 11, 1979). Further work by this group has demonstrated that partially purified enzyme does not expand adipyl-6-APA, ampicillin, or penicillin G (Kupka et al., FEMS Microbiol. Lett. 16:1-6, 1983). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

PROCESS FOR THE FERMENTATIVE PRODUCTION OF PENICILLIN Inventor(s): KERKHOF, PIETER THEODORUS; (HOOGVLIET, NL), KUIPERS, RIENK HENDRIK; (KZ GOUDA, NL), WALRAVEN, HUBERTUS GERARDUS MARIA; (TM RIJSWIJK, NL) Correspondence: Morrison & Foerster Llp; 3811 Valley Centre Drive; Suite 500; San Diego; CA; 92130-2332; US Patent Application Number: 20020058302 Date filed: October 22, 1999 Abstract: The present invention discloses an improved process for the preparation of 6amino penicillanic acid (6-APA) from a fermentatively produced N-substituted penicillin comprising the steps of extraction of the N-substituted penicillin compound as present in a fermentation broth or fluid to an organic solvent, back extraction of the N-substituted penicillin compound to water, treatment of the aqueous phase with a penicillin acylase and isolation of the 6-APA from the thus-obtained conversion solution by crystallization. Further improvements comprise extraction of the side chain to an organic solvent and isolation of 6-APA from the thus-obtained aqueous phase using a specific crystallization process. Excerpt(s): The invention relates to a process for the preparation of penicillins, which are deacylated at the 6-amino group, by the fermentation of a penicillin producing microorganism in the presence of a side chain precursor and by deacylation of fermentatively produced N-substituted penicillin. 6-Amino penicillanic acid (6-APA) is an important intermediate in the pharmaceutical industry which is in general obtained through chemical or enzymatic cleavage (`deacylation`) of penicillin G or penicillin V. Penicillins themselves are obtained from fermentation using strains of Penicillium chrysogenum. In a typical penicillin G recovery process, the broth is filtered and washed, and penicillin G is extracted to butyl acetate or methyl isobutyl ketone after acidification of the filtrate. The solvent is then decolorized with aid of active carbon and the penicillin G acid is back-extracted to water upon neutralization with an aqueous potassium salt solution such as potassium acetate. This solution is admixed with sufficient butanol, the water content is reduced using evaporation of the butanol-water azeotrope, whereupon the penicillin G crystals formed are recovered by filtration and subsequent washing and drying. In another process the crystalline material is directly obtained from the organic solution by addition of potassium acetate or other potassium salts and evaporation of the azeotrope, whereupon the crystals are filtered, washed with butanol, filtered and dried. For penicillin V the same process can be applied. However, due to better stability of penicillin V under acidic conditions, penicillin V can also be

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crystallized in the acid form instead of the potassium salt form, without economical unacceptable losses. 6-Amino penicillanic acid is in general obtained from a solution of dissolved solid penicillin G or V, which is then contacted with immobilized penicillin G acylase or penicillin V acylase, respectively. The conversion solution is subsequently fed to a crystallizer where the solid product is formed by precipitation at a pH of about 3.5 to 4.5. Generally, in this crystallization process the pH is lowered stepwise to avoid contamination of the final product 6-APA with high side chain levels and coloured compounds. In addition, solvents like methanol, ethanol, iso propyl alcohol, are added to avoid this unacceptable contamination. It will be clear that these types of production routes to 6-APA are lengthy and costly. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Protein fragment complementation assay (PCA) for the detection of protein-protein, protein-small molecule and protein nucleic acid interactions based on the E. coli TEM-1 beta-lactamase Inventor(s): Galarneau, Andre; (Ste-Julie, CA), Michnick, Stephen William Watson; (Montreal, CA) Correspondence: Isaac A. Angres; Suite 301; 2001 Jefferson Davis Highway; Arlington; VA; 22202; US Patent Application Number: 20030108869 Date filed: May 31, 2001 Abstract: The present invention describes an assay method comprising: (A) generating (1) at least a first fragment of a reporter molecule linked to a first interacting domain and at least a second fragment of a reporter molecule linked to a second interacting domain, or (2) nucleic acid molecules that code for (A)(1) and subsequently allowing said nucleic acid molecules to produce their coded products; then, (B) allowing interaction of said domains; and (C) detecting reconstituted reporter molecule activity, where said reporter molecule can react with a penicillin- or a cephalosporin-class substrate. Excerpt(s): The present invention relates generally to protein complementation assays (PCA) and more specifically to PCA assays based on the E. coli TEM-1.beta.-Lactamase for the detection of protein-protein, protein-small molecule and protein nucleic acid interactions. Applicants' have previously described oligomerization domain-assisted complementation of enzyme fragments as a general strategy for detecting proteinprotein, protein small molecule and protein nucleic acid interactions (ref. 9). In the present invention, we describe assays based on the E. coli TEM-1.beta.-Lactamase (Accession number: AAB59737). In the present invention, applicants' disclose three assays in mammalian cells: (1), an in vitro colorimetric assay using the substrate nitrocefin, and (2) an in vivo positive/negative fluorescence assay using the substrate CCF2/AM. The invention is also directed to positive and negative survival assays using cephalosporin-cytotoxic pro-drug conjugates, as well as a series of.beta.-lactamase point mutations that would be predicted to enhance the efficiency of the.beta.-lactamase PCA. The TEM-1.beta.-lactamase is a member of a family of bacterial enzymes that hydrolyze antibiotics of the penicillin and cephalosporin class, thus imparting resistance to bacteria expressing these enzymes. TEM-1.beta.-lactamase is the standard ampicillin resistance gene included in most plasmids used in molecular biology. The threedimensional structure, proposed catalytic mechanism and optimal substrates and inhibitors have been well documented. TEM-1.beta.-Lactamase is a small (29 kiloDaltons) and monomeric protein consisting of 286 amino acids. The first 23 amino

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acids constitute a secretory signal peptide.beta.-lactamases catalyses the irreversible hydrolysis of the amide bond of.beta.-lactam rings in penicillin or cephalosporin compounds.beta.-lactamases are secreted into the periplasmic space of gram-negative strains or into the outer media by their gram-positive counterparts where they normally act. However, they will accumulate in the cytoplasm when expressed in E. coli or other prokaryotic or eukaryotic cells if the secreting signal peptide is genetically deleted, without effecting catalytic activity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

SERUM-AND STEROID-FREE CULTURE MEDIA FOR CEREBELLAR GRANULE NEURONS Inventor(s): Belcher, Scott M.; (Little Rock, AR) Correspondence: Christine J. Daugherty; Wright, Lindsey & Jennings Llp; 320 North Rollston, Suite 102; Fayetteville; AR; 72701; US Patent Application Number: 20020132345 Date filed: August 9, 2001 Abstract: The invention is a system for maintenance and high-throughput analysis of cerebellar granule neurons in tissue culture plates under chemically defined conditions. The invention includes serum-free granule culture medium, which is composed of high glucose Dulbecco's Modified Eagle Media (DMEM), NaHCO3, sodium pyruvate, and HEPES, which is subsequently adjusted to pH 7.2. The HEPES buffered DMEM is then supplemented with L-glutamine, KCl, bovine albumin, insulin, transferrin, selenium, penicillin, and streptomycin. Unlike proprietary neuronal culture media, this invention does not include any serum, steroid hormones, phenol red, or added anti-oxidants. The serum-free granule culture medium is then placed in conventional poly-lysine coated tissue culture plates in order to conduct subsequent assays. The invention also includes the ability to package the complete neuronal culture system into a "kit" for isolation, maintenance, treatment, and analysis of cerebellar neurons. A kit would include all the necessary culture medium preparations, tissue culture plates with an appropriate cellular attachment matrix, reagents, disposables and protocols. The kit could be used to evaluate neuronal viability, growth, the role of steroid hormones on neuronal function, drug or toxicant-induced changes in gene expression, or other bioassays. In addition, the invention will be useful in the field of pharmocogenomics because of the ability to analyze small sample sizes. Excerpt(s): The present application claims the benefit of U.S. provisional patent application No. 60/275,767, filed Mar. 14, 2001, which is incorporated herein by reference. The present invention relates to neuronal culture media that may be used for high-throughput analyses. The ability to maintain isolated neurons in primary culture has been critical in advancing our understanding of the functional basis of the nervous system. In primary neuronal culture studies, the use of defined culture conditions is essential for controlling the concentration of components, such as hormones and growth factors, which may affect the growth and development of cultured neurons. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Therapeutic treatment for sexual dysfunction Inventor(s): Koppel, Gay A.; (Indianapolis, IN) Correspondence: Barnes & Thornburg; 11 South Meridian Street; Indianapolis; IN; 46204; US Patent Application Number: 20030008858 Date filed: June 18, 2002 Abstract: A method for improving sexual function is described. A mammal suffering from sexual dysfunction or otherwise in need of enhanced sexual function is administered a compound selected from those that are capable of inhibiting the activity of.beta.-lactams, penicillin-binding protein, carboxypeptidase,. Such compounds, including particularly.beta.-lactam ring-containing compounds, can be used to formulate pharmaceutical formulations useful for improving sexual function. Excerpt(s): This application claims priority under 35 U.S.C.sctn.119(e) to U.S. Provisional Application Serial No. 60/299,060, filed on Jun. 18, 2001. This invention relates to a method for improving sexual function. More particularly, this invention is directed to the use of compounds capable of exhibiting specific binding affinity to and inhibiting the activity of certain bacterial enzymes and structurally related mammalian enzymes for improving sexual function and for reducing or eliminating the indicia of sexual dysfunction in a mammal either suffering from such disability or exposed to conditions tending to engender such disability. Sexual dysfunction is characterized by a disturbance in the processes that are involved in the sexual response cycle or by pain associated with sexual intercourse. The sexual response cycle comprises the four phases of desire, excitement, orgasm and resolution. Disorders of sexual response may occur at one or more of these phases. The sexual dysfunctions include sexual desire disorders, sexual arousal disorders, orgasmic disorders and sexual pain disorders. Sexual dysfunctions cause marked distress and interpersonal difficulty. While progress has been made in the treatment of such disorders, there remains significant need for alternative therapeutic approaches. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with penicillin, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “penicillin” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on penicillin. You can also use this procedure to view pending patent applications concerning penicillin. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 7. BOOKS ON PENICILLIN Overview This chapter provides bibliographic book references relating to penicillin. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on penicillin include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “penicillin” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on penicillin: •

Drug Prescribing in Renal Failure: Dosing Guidelines for Adults. 4th ed Source: Philadelphia, PA: American College of Physicians. 1999. 176 p. Contact: Available from American College of Physicians (ACP). 190 N. Independence Mall West, Philadelphia, PA 19106-1572. (800) 523-1546 or (215) 351-2600. PRICE: $21.00 for ACP members; $28.00 for nonmembers. ISBN: 0943126762. Summary: This handbook presents tables of drugs used in the treatment of renal failure. The drugs are listed by generic name in alphabetical order under subdivisions based on similarity of structure and pharmacological action (e.g., penicillins, cephalosporins, and aminoglycosides are grouped together as antibiotics). For each drug, information is included on pharmacology (percent excreted unchanged, half-life in normal people and in end-stage renal failure, percent plasma protein binding, volume of distribution, dosage adjustment for renal failure, and whether the drug is used as a supplement for dialysis. Major drug categories include antimicrobial agents; antihypertensive and

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cardiovascular agents; sedatives, hypnotics, and drugs used in psychiatry; analgesics; and miscellaneous agents. An introductory outline discusses bioavailability, body distribution, metabolism, renal excretion, pharmacokinetics, dosimetry in renal disease, renal function, acute renal failure, initial versus maintenance doses, therapeutic drug monitoring, and adverse drug reactions. A bibliography and drug index are appended.

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

Alexander Fleming and Penicillin by William Howard Hughes; ISBN: 0850781205; http://www.amazon.com/exec/obidos/ASIN/0850781205/icongroupinterna

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Alexander Fleming and the Story of Penicillin (Unlocking the Secrets of Science) by John Bankston; ISBN: 1584151064; http://www.amazon.com/exec/obidos/ASIN/1584151064/icongroupinterna

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Alexander Fleming: Conquering Disease With Penicillin (Makers of Modern Science Series) by Steven Otfinoski; ISBN: 0816027528; http://www.amazon.com/exec/obidos/ASIN/0816027528/icongroupinterna

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Alexander Fleming: Discoverer of Penicillin (Book Report Biographies) by Ted Gottfried; ISBN: 0531113701; http://www.amazon.com/exec/obidos/ASIN/0531113701/icongroupinterna

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Alexander Fleming: Penicillin (The Scientists Who Have Changed the World) by Beverley Birch; ISBN: 1850151849; http://www.amazon.com/exec/obidos/ASIN/1850151849/icongroupinterna

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Alexander Fleming: The Man Who Discovered Penicillin (Great Minds of Science) by Salvatore Tocci; ISBN: 0766019985; http://www.amazon.com/exec/obidos/ASIN/0766019985/icongroupinterna

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Biosynthesis and enzymic hydrolysis of penicillins and cephalosporins by E. P. Abraham; ISBN: 0860081036; http://www.amazon.com/exec/obidos/ASIN/0860081036/icongroupinterna

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Breakthrough, the True Story of Penicillin by Francine Jacobs; ISBN: 0396085792; http://www.amazon.com/exec/obidos/ASIN/0396085792/icongroupinterna

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Cephalosporins and penicillins: chemistry and biology by Edwin Harold Flynn; ISBN: 012261450X; http://www.amazon.com/exec/obidos/ASIN/012261450X/icongroupinterna

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Chemistry of Penicillin by Hans T. Clarke (Editor) (1949); ISBN: 0691079226; http://www.amazon.com/exec/obidos/ASIN/0691079226/icongroupinterna

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Discovery of Penicillin (Bbc Study Tapes); ISBN: 9997245970; http://www.amazon.com/exec/obidos/ASIN/9997245970/icongroupinterna

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Florey: The Man Who Made Penicillin by Lennard Bickel (1996); ISBN: 0522847129; http://www.amazon.com/exec/obidos/ASIN/0522847129/icongroupinterna

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From pills to penicillin : the Beecham story : a personal account by H. G. Lazell; ISBN: 0434409006; http://www.amazon.com/exec/obidos/ASIN/0434409006/icongroupinterna

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How to take your medicine : penicillins (SuDoc HE 20.4010/a:P 37) by U.S. Dept of Health and Human Services; ISBN: B000106XSW; http://www.amazon.com/exec/obidos/ASIN/B000106XSW/icongroupinterna

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Howard Florey, Penicillin and After by Trevor I. Williams; ISBN: 0198581734; http://www.amazon.com/exec/obidos/ASIN/0198581734/icongroupinterna

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Howard Florey: The Man Who Developed Penicillin (Headliners) by Diana Chase, et al; ISBN: 0732905257; http://www.amazon.com/exec/obidos/ASIN/0732905257/icongroupinterna

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Impacts of antibiotic-resistant bacteria : Thanks to penicillin-- He will come home! (SuDoc Y 3.T 22/2:2 AN 8); ISBN: 0160483387; http://www.amazon.com/exec/obidos/ASIN/0160483387/icongroupinterna

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In Search of Penicillin by David, Wilson; ISBN: 0394401085; http://www.amazon.com/exec/obidos/ASIN/0394401085/icongroupinterna

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Jewish Penicillin: Mother Wonderful's Profusely Illustrated Guide to the Proper Preparation of Chicken Soup by Myra Chanin; ISBN: 0892862432; http://www.amazon.com/exec/obidos/ASIN/0892862432/icongroupinterna

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Life of Sir Alexander Fleming Discoverer of Penicillin by A. Maurois; ISBN: 0525145389; http://www.amazon.com/exec/obidos/ASIN/0525145389/icongroupinterna

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Magic Bean - in Fact: the Penicillin Puzzle: Big Book (Literacy Edition: Magic Bean); ISBN: 1863744274; http://www.amazon.com/exec/obidos/ASIN/1863744274/icongroupinterna

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Man Who Discovered Penicillin by Bullock; ISBN: 0571053211; http://www.amazon.com/exec/obidos/ASIN/0571053211/icongroupinterna

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Miracle Cure: The Story of Penicillin and the Golden Age of Antibiotics by Milton Wainwright, John Wainwright; ISBN: 0631164928; http://www.amazon.com/exec/obidos/ASIN/0631164928/icongroupinterna

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NTP technical report on the toxicology and carcinogenesis studies of Penicillin VK (CAS no. 132-98-9) in F344/N rats and B6C3F b1 s mice (gavage studies) (SuDoc HE 20.3159/2:336) by U.S. Dept of Health and Human Services; ISBN: B000102BBA; http://www.amazon.com/exec/obidos/ASIN/B000102BBA/icongroupinterna

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Organic Chemistry: Case Study Four: Penicillin and Beyond: the Betalactam Antibiotics (S344 Organic Chemistry: a Synthesis Approach) by S344 Course Team; ISBN: 0749280379; http://www.amazon.com/exec/obidos/ASIN/0749280379/icongroupinterna

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Penicillin fifty years after Fleming : a Royal Society discussion, held on 2 and 3 May 1979; ISBN: 0854031405; http://www.amazon.com/exec/obidos/ASIN/0854031405/icongroupinterna

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Penicillin in perspective by David Wilson; ISBN: 0571108393; http://www.amazon.com/exec/obidos/ASIN/0571108393/icongroupinterna

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Penicillin: A Breakthrough in Medicine (Point of Impact) by Richard Tames; ISBN: 1575724170; http://www.amazon.com/exec/obidos/ASIN/1575724170/icongroupinterna

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Penicillin: A Paradigm for Biotechnology by Richard I. Mateles (Editor); ISBN: 1891545019; http://www.amazon.com/exec/obidos/ASIN/1891545019/icongroupinterna

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Penicillin: Meeting the Challenge by Gladys L. Hobby, Leon H. Schmidt (Designer) (1985); ISBN: 0300032250; http://www.amazon.com/exec/obidos/ASIN/0300032250/icongroupinterna

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Penicillin: The Magic Spore by Edward Amatetti (2002); ISBN: 0971471711; http://www.amazon.com/exec/obidos/ASIN/0971471711/icongroupinterna

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Penicillins and cephalosporins : [proceedings of the ninth International Congress of Chemotherapy held in London, July, 1975]; ISBN: 0306382253; http://www.amazon.com/exec/obidos/ASIN/0306382253/icongroupinterna

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Penny, the Medicine Maker: The Story of Penicillin. by Sherrie S. Epstein; ISBN: 082250006X; http://www.amazon.com/exec/obidos/ASIN/082250006X/icongroupinterna

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Post Penicillin Antibiotics: from Acceptance to Resistance (Wellcome Witnesses to Twentieth Century Medicine) by E.M. Tansey (Editor), L.A. Reynolds (Editor) (2000); ISBN: 1841290122; http://www.amazon.com/exec/obidos/ASIN/1841290122/icongroupinterna

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Praise the Lord and Pass the Penicillin: Memoir of a Combat Medic in the Pacific in World War II by Dean W. Andersen; ISBN: 078641670X; http://www.amazon.com/exec/obidos/ASIN/078641670X/icongroupinterna

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Rise up to life: a biography of Howard Walter Florey who gave penicillin to the world by Lennard Bickel; ISBN: 0207954542; http://www.amazon.com/exec/obidos/ASIN/0207954542/icongroupinterna

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Sir Alexander Fleming: Man of Penicillin by John Malkin (1985); ISBN: 0907526063; http://www.amazon.com/exec/obidos/ASIN/0907526063/icongroupinterna

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The bacterial DD-carboxypeptidase-transpeptidase enzyme system : a new insight into the mode of action of penicillin by J. M. Ghuysen; ISBN: 0860081729; http://www.amazon.com/exec/obidos/ASIN/0860081729/icongroupinterna

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The Beta-lactam Antibiotic: Penicillins and Cephalosporins in Perspective by Sydney Selwyn, et al; ISBN: 0340225238; http://www.amazon.com/exec/obidos/ASIN/0340225238/icongroupinterna

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The birth of penicillin, and the disarming of microbes by Ronald Hare; ISBN: 0049250051; http://www.amazon.com/exec/obidos/ASIN/0049250051/icongroupinterna

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The Enchanted Ring : The Untold Story of Penicillin by John C. Sheehan (Author); ISBN: 0262690853; http://www.amazon.com/exec/obidos/ASIN/0262690853/icongroupinterna

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The Greatest Good to the Greatest Number: Penicillin Rationing on the American Home Front, 1940-1945 (American University Studies, Series Ix, Histor) by David

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Parrish Adams (1991); ISBN: 0820412848; http://www.amazon.com/exec/obidos/ASIN/0820412848/icongroupinterna •

The Life of Ernst Chain: Penicillin and Beyond by Ronald William Clark; ISBN: 0312484194; http://www.amazon.com/exec/obidos/ASIN/0312484194/icongroupinterna

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The Mold in Dr. Florey's Coat : The Story of Penicillin and the Modern Age of Medical Miracles by Eric Lax (Author) (2004); ISBN: 0805067906; http://www.amazon.com/exec/obidos/ASIN/0805067906/icongroupinterna

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The Penicillin Fermentation: A Model for Secondary Metabolite Production by S. John Pirt (1993); ISBN: 187468510X; http://www.amazon.com/exec/obidos/ASIN/187468510X/icongroupinterna

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The Target of Penicillin: The Murein Sacculus of Bacterial Cell Walls: Architecture and Growth: Proceedings by R. Hakenbeck (Editor) (1983); ISBN: 3110097052; http://www.amazon.com/exec/obidos/ASIN/3110097052/icongroupinterna

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The World Market for Medicaments Containing Antibiotics in Dosage Form or Retail Packings Excluding Penicillins and Streptomycins: A 2004 Global Trade Perspective [DOWNLOAD: PDF]; ISBN: B000134BXS; http://www.amazon.com/exec/obidos/ASIN/B000134BXS/icongroupinterna

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Turning Points in History: Penicillin / Pearl Harbor / the Fall of the Berlin Wall / the End of Apartheid / the Moon Landing / the Printing Press (Turning Points in History) by Richard Tames (2001); ISBN: 0431069298; http://www.amazon.com/exec/obidos/ASIN/0431069298/icongroupinterna

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Yellow Magic: The Story of Penicillin by J. D. Ratcliff; ISBN: 0827442564; http://www.amazon.com/exec/obidos/ASIN/0827442564/icongroupinterna

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “penicillin” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:11 •

Actinomycosis, with special reference to its treatment with penicillin. Author: Wilenius, Runar Leonard,; Year: 1974; Helsinki [Mercator] 1953

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Acute otitis media; comparative therapeutic results of sulphonamide and penicillin administered in various forms. Author: Rudberg, Ragnar D.; Year: 1965; Gothenburg, 1954

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In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

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Antibiotics; a survey of penicillin, streptomycin, and other antimicrobial substances from fungi, actinomycetes, bacteria, and plants, by H. W. Florey [and others]. Author: Florey, Howard,; Year: 1958; London, Oxford Univ. Press, 1949-

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Investigation of penicillin and streptomycin concentrations in the perilymph of the cat following parenteral administration. Author: Vrabec, Donald Paul,; Year: 1962; [Minneapolis] 1965

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NTP technical report on the toxicology and carcinogenesis studies of penicillin VK (CAS no. 132-98-9) in F344 Author: Dunnick, June K.; Year: 1997; Research Triangle Park, N.C.: U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health; Springfield, VA: Available for sale from the National Technical Information Service, [1988]

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Penicillin [by] Harold L. Hirsch and Lawrence E. Putnam. Author: Hirsch, Harold L.; Year: 1979; New York, Medical Encyclopedia [c1958]

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Penicillin allergy; clinical and immunologic aspects. Edited by Gordon T. Stewart and John P. McGovern. Author: McGovern, John P.,; Year: 2003; Springfield, Ill., Thomas [c1970]

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Penicillin and other antibiotics. Author: Hayward, Elizabeth Gardner.; Year: 1945; [New York?] Scudder, Stevens; Clark, c1949

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Penicillin and streptomycin in the treatment of infections, by Chester S. Keefer and Donald G. Anderson, ed. by Henry A. Christian. Author: Keefer, Chester S. (Chester Scott),; Year: 1965; New York, Oxford Univ. Press, 1950

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Penicillin in the treatment of infections, by Chester S. Keefer and Donald G. Anderson, ed. by Henry A. Christian. Author: Keefer, Chester S. (Chester Scott),; Year: 1957; New York, Oxford Univ. Press [c1945]

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Penicillin prophylaxis in obstetrics. Author: Widholm, Olof.; Year: 1977; Helsinki, 1958

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Penicillin therapy, including streptomycin, tyrothricin and other antibiotic therapy. Author: Kolmer, John Albert,; Year: 1961; New York [etc.] Appleton-Century [1947]

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Penicillin. Author: Thompson, T. O.; Year: 1966; [Calcutta, 1945]

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Penicillin-resistant gonorrhea: January 1977 through December 1979: 622 [i. e. 117] citations Author: National Library of Medicine (U.S.); Year: 1996; [Bethesda, Md.]: Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, [1979]

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Penicillium notatum (penicillin) in homoeopathy. Author: Subaraju, Gottemukkula.; Year: 1961; Bhimavaram, India, 1961

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Resistance of bacteria to the penicillins: in honor of Sir Charles Harington. Ed. by A. V. S. de Reuck and Margaret P. Cameron. Author: Ciba Foundation.; Year: 1965; Boston, Little, Brown, 1962

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Spirochetes in late seronegative syphilis, penicillin notwithstanding. Author: Smith, J. Lawton (Joseph Lawton),; Year: 1947; Springfield, Ill., Thomas [c1969]

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The birth of penicillin and the disarming of microbes. Author: Hare, Ronald.; Year: 1949; London, Allen and Unwin [1970]; ISBN: 049250051

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The penicillin group of drugs. Author: Stewart, Gordon T. (Gordon Thallon); Year: 1978; Amsterdam, New York, Elsevier, 1965

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Treatment with penicillin and other antibiotics. An introduction to chemotherapy. Author: Bate, John Gordon,; Year: 1952; London, Faber; Faber [1954]

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Chapters on Penicillin In order to find chapters that specifically relate to penicillin, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and penicillin using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “penicillin” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on penicillin: •

Allergy Source: in Little, J.W., et al. Dental Management of the Medically Compromised Patient. 5th ed. St. Louis, MO: Mosby, Inc. 1997. p. 443-465. Contact: Available from Harcourt Health Sciences. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 325-4177. Fax (800) 874-6418. Website: www.harcourthealth.com. PRICE: $48.00 plus shipping and handling. ISBN: 0815156340. Summary: A working knowledge of the multitude of compromised health states is essential for dental professionals, as the majority of medically compromised patients need or want oral health care. This chapter on allergy is from a text that provides the dental practitioner with an up to date reference work describing the dental management of patients with selected medical problems. In this chapter, the authors outline four reasons for the dentist to know about allergy: to identify patients with a true allergic history (to prevent medical emergencies in the dental setting); to recognize oral soft tissue changes that might be caused by an allergic reaction; to identify and plan appropriate dental care for patients who have severe alteration of their immune system because of radiation, drug therapy, or immune deficiency disorders; and to recognize the signs and symptoms of acute allergic reactions and manage these problems appropriately. The authors discuss incidence and prevalence, pathophysiology and complications, signs and symptoms (clinical presentation and laboratory findings), the classification of sensitivity, nonallergic reactions, the medical management of patients with allergies, and the dental management of this population. In the last section, the authors consider allergies to penicillin, analgesics (aspirin, primarily), rubber products, and dental materials and products. 6 figures. 41 tables. 45 references.

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Otosyphilis and Otologic Manifestations of AIDS Source: in Canalis, R.F. and Lambert, P.R., eds. Ear: Comprehensive Otology. Philadelphia, PA: Lippincott Williams and Wilkins. 2000. p. 587-599. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-3030. Fax (301) 223-2300. Website: www.lww.com. PRICE: $179.00 plus shipping and handling. ISBN: 078171558X. Summary: Although syphilis was particularly prevalent in the prepenicillin ear, its current role in ear pathology, particularly in sensorineural hearing loss, demands renewed attention. This chapter on otosyphilis and the otologic manifestations of AIDS is from a textbook that offers complete coverage of the field of clinical otology (study of the ear). The book is oriented to serve both the otolaryngology resident as a practical learning tool and the practicing otolaryngologist as an updated reference source of clinical and basic information. Topics include incidence, pathology, clinical features,

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diagnosis, treatment, and otologic manifestations in HIV infection and AIDS, including background and pathophysiology of HIV infection, temporal bone studies, and otologic manifestations in HIV infection. Clinical features of otosyphilis including hearing loss, tinnitus (ringing or other sounds in the ears), and dizziness in varying degrees. Hearing loss may fluctuate and disproportionately affect speech discrimination. Otosyphilis is treated with prolonged high dose penicillin and prednisone (prednisone may be withheld in immunocompromised patients). Patients with HIV may have syphilis from before their HIV infection or may have coincident (at the same time) syphilis infection. If HIV status is unknown, patients with suspected otosyphilis should be tested for HIV. 6 figures. 111 references. •

Reactions to Drugs and Materials, and Drug Interactions Source: in Scully, C. and Cawson, R.A. Medical Problems in Dentistry. 4th ed. Woburn, MA: Butterworth-Heinemann. 1998. p. 506-528. Contact: Available from Butterworth-Heinemann. 225 Wildwood Avenue, Woburn, MA 01801-2041. (800) 366-2665 or (781) 904-2500. Fax (800) 446-6520 or (781) 933-6333. E-mail: [email protected]. Website: www.bh.com. PRICE: $110.00. ISBN: 0723610568. Summary: Drugs used routinely in dentistry rarely cause significant adverse effects unless used recklessly. The chief dangers are those of general anesthesia, particularly with intravenous agents, and occasionally of allergic reactions. This chapter on reactions to drugs and materials, and drug interactions, is from a text that covers the general medical and surgical conditions relevant to the oral health care sciences. Topics include hypersensitivity to drugs used in dentistry, reactions to penicillin, the management of anaphylaxis, cephalosporins, reactions to intravenous anesthetic agents, halothane hepatitis, allergic reactions to muscle relaxants and related compounds, reactions to materials used in dentistry (including resins, latex, and other materials), adverse effects of drugs used in dentistry in the medically compromised patient, and the oral side effects of drugs (notably, xerostomia, or dry mouth). In each section, the authors focus on dental aspects and patient care strategies. The chapter includes a summary of the points covered. Appendices offer extensive charts of drugs and drug reactions. 4 appendices. 2 tables. 33 references.

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Antibiotics for Oral and Maxillofacial Infections Source: in Newman, M.G. and van Winkelhoff, A.J., eds. Antibiotic and Antimicrobial Use in Dental Practice. 2nd ed. Chicago, IL: Quintessence Publishing Co, Inc. 2001. p. 157-173. Contact: Available from Quintessence Publishing Co, Inc. 551 Kimberly Drive, Carol Stream, IL 60188-9981. (800) 621-0387 or (630) 682-3223. Fax (630) 682-3288. E-mail: [email protected]. Website: www.quintpub.com. PRICE: $32.00 plus shipping and handling. ISBN: 0867153970. Summary: Infections of the oral and maxillofacial region, although commonly encountered by dentists, can be challenging to manage. This chapter on antibiotics for the treatment of oral and maxillofacial infections is from a textbook that integrates basic facts and principles of antibiotic therapy with recently-emerged concepts of care. The author presents guidelines for using a combination of antibiotics and surgery to manage minor orofacial and odontogenic (arising from the tissues that produce teeth) infections in the office setting. Topics include the microbiology of odontogenic infections; the natural course of odontogenic infections, i.e., cellulitis, abscess, and sinus tract; the spread of infection; the role of depressed host defenses, due to chemotherapy, metabolic

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diseases, organ transplants, or myeloproliferative diseases; and the use of dental spectrum antibiotics, including penicillin, extended spectrum penicillins, cephalosporins, erythromycin, clarithromycin, clindamycin, tetracycline, metronidazole, and fluoroquinolones. The author also reviews the principles of therapy, including determination of severity of the infection, evaluation of host defenses, surgical treatment, antibiotic choice, antibiotic administration, follow up, and side effects and secondary infection. The chapter concludes with a discussion of wound infection prophylaxis and special considerations, including sinus perforations, avulsed teeth, osteomyelitis, dry socket (alveolar osteitis), pericoronitis, routine extractions, and impacted third molars (wisdom teeth). Important principles, key facts, and clinical insights are highlighted and the chapter concludes with a list of references. 3 figures. 4 tables. 7 references. •

Selecting Therapy for Uncomplicated UTI: Viewpoint from the USA Source: in Harrison, L.H. Management of Urinary Tract Infections. London: Royal Society of Medicine. 1990. p. 7-13. Contact: Available from Royal Society of Medicine. Barbara Selves, Publications Department, 1 Wimpole Street, London. W1M 8AE. PRICE: $20 US plus shipping and handling. ISBN: 1853151114. Summary: This article, from the proceedings of an international conference on the management of urinary tract infections (UTIs), discusses the United States' viewpoint on selecting therapy for uncomplicated UTI. The author delineates four criteria to be considered in selecting therapy: the antibiotic must attain adequate concentrations in the urine; the agent of choice should have a minimal effect on normal flora in the intestine; minimal effect on flora in the vagina; and agents with a low total cost are preferred for routine use. The author prefers the use of nitrofurantoin or penicillin VK in routine use, avoiding possible hypersensitivity reactions where they may be a concern. 2 tables. 21 references. (AA-M).

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Streptococcal Toxic Shock Syndrome Associated With Necrotizing Fasciitis Source: in Coggins, C.H.; Hancock, E.W.; Levitt, L.J., eds. Annual Review of Medicine, Volume 51, 2000. Palo Alto, CA: Annual Reviews, Inc. 2000. p. 271-288. Contact: Available from Annual Reviews. 4139 El Camino Way, P.O. Box 10139, Palo Alto, CA 94303-0139. (650) 493-4400. E-mail: [email protected]. Website: www.AnnualReviews.org. Summary: This chapter provides health professionals with information on the demographics, symptoms, signs, diagnosis, clinical course, and treatment of streptococcal toxic shock syndrome (strep TSS) with associated necrotizing fasciitis. Strep TSS is the early onset of shock and organ failure associated with any infection caused by Streptococcus pyogenes. It is a rapidly progressive process that kills 30 to 60 percent of patients in 72 to 96 hours. The initial symptoms of strep TSS depend largely on the site of primary infection. Of all patients with strep TSS, 20 percent experience an influenza like syndrome characterized by fever, chills, myalgia, and diarrhea. In patients who develop deep soft tissue infections, such as necrotizing fasciitis or intrauterine infection, severe pain is the most common initial symptom of strep TSS. Violaceous bullae, hypotension, fever, and evidence of organ failure are late clinical manifestations. Diagnosis is not difficult when all the clinical features of strep TSS are manifest; however, the signs and symptoms may be quite subtle early in the course of illness, and laboratory tests may provide valuable clues to the diagnosis. The challenge to clinicians

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is to make an early diagnosis and to intervene with aggressive fluid replacement, emergent surgical debridement, and general supportive measures. Superantigens such as pyrogenic exotoxin A interact with monocytes and T lymphocytes in unique ways, resulting in T cell proliferation and watershed production of monokines and lymphokines. Penicillin, though efficacious in mild S. pyogenes infection, is less effective in severe infections because of its short postantibiotic effect, inoculum effect, and reduced activity against stationary phase organisms. Emerging treatments for strep TSS include clindamycin and intravenous gamma globulin. 2 tables and 81 references. (AA-M). •

Chapter 201: Bacterial Skin Infections Source: in Berkow, R., ed. The Merck Manual of Medical Information: Home Edition (online version). Rahway, NJ: Merck and Company, Inc. 2000. 6 p. Contact: Available online from Merck and Company, Inc. (800) 819-9456. Website: www.merck.com/pubs/mmanual_home/contents.htm. Also available from your local book store. PRICE: $29.95 plus shipping. Summary: This chapter provides the general public and people who have bacterial skin infections with information on the symptoms and treatment of impetigo, folliculitis, boils, carbuncles, erysipelas, cellulitis, paronychia, staphylococcal scalded skin syndrome, and erythrasma. Although many types of bacteria can infect the skin, the most common are Staphylococcus and Streptococcus. People at high risk of contracting skin infections include people who have diabetes or acquired immunodeficiency syndrome. Keeping the skin undamaged and clean usually prevents infections. Impetigo, which is caused by Staphylococcus or Streptococcus, is a skin infection that leads to the formation of small pus filled blisters. An oral antibiotic is used to treat impetigo. Folliculitis, which is caused by infection with Staphylococcus, causes hair follicles to become irritated and reddened. Boils, which are caused by staphylococcal infection around hair follicles, are large, tender, swollen, raised areas with a pus filled center. Carbuncles are clusters of boils. These three infections can be prevented by keeping the skin clean with a liquid soap containing an antibacterial agent. Moist heat can be used to help a boil drain spontaneously. Antibiotics are also used to treat boils and carbuncles. Erysipelas, which is caused by Streptococcus, is characterized by a shiny, red, slightly swollen, tender rash, often with small blisters. Antibiotics are used to treat this infection. Cellulitis, which is usually caused by streptococcal or staphylococcal infection, produces swelling, tenderness, warmth, and redness of the skin. Treatment involves taking penicillin or a penicillin type drug. Paronychia, which can be caused by many different bacteria or by fungi, is an infection around the edge of a fingernail or toenail. Hot compresses and warm soaks help relieve symptoms and fight infection. A doctor may need to drain the infection. Antibiotics and antifungals may also be prescribed. Staphylococcal scaled skin syndrome causes the top layer of skin to peel off as though burned. Infants, young children, and people with depressed immune systems are usually affected. Diagnosis is based on examination or culture of a skin sample. Oral or intravenous penicillin type antibiotics are used to treat this syndrome. Erythrasma, an infection of the top layers of the skin caused by Corynebacterium minutissimum, often occurs in areas where skin touches skin. An oral antibiotic can eliminate the infection.

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Chapter 12-E: Infectious Disorders: Rheumatic Fever Source: in Klippel, J.H., et al., eds. Primer on the Rheumatic Diseases. 12th ed. Atlanta, GA: Arthritis Foundation. 2001. p. 279-283.

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Contact: Available from Arthritis Foundation. P.O. Box 1616, Alpharetta, GA 300091616. (800) 207-8633. Fax (credit card orders only) (770) 442-9742. Website: www.arthritis.org. PRICE: $69.95 plus shipping and handling. ISBN: 0912423293. Summary: This section of a chapter on infectious disorders provides health professionals with information on the epidemiology, pathogenesis, clinical features, diagnosis, and treatment of rheumatic fever. The disease is a delayed, nonsuppurative sequela of a pharyngeal infection by group A streptococci. Although the tissues of patients who have rheumatic fever show little evidence of group A streptococci infection, there is epidemiologic evidence indirectly implicating the bacteria in the initiation of the disease. Clinical features of rheumatic fever include arthritis that affects several joints in quick succession for a short time, heart murmurs, cardiomegaly, congestive heart failure, and pericarditis. Rheumatic heart disease, the most severe sequelae of acute rheumatic fever, occurs 10 to 20 years after the original attack and is the major cause of acquired valvular disease. Other clinical features include chorea, subcutaneous nodules, and erythema marginatum. Although the diagnosis of rheumatic fever cannot be established readily by laboratory tests, helpful tests include serial chest radiographs, electrocardiograms, streptococcal antibody tests, and acute phase reactant tests. Most cases can be treated with antiinflammatory agents, usually aspirin. Oral prednisone may be used to treat carditis. Antibiotic therapy with penicillin should be initiated and maintained for at least 10 days, whether or not signs of pharyngitis are present. Antibiotic prophylaxis with penicillin should start immediately after resolution of the acute episode and continue until the patient is a young adult. 1 figure, 1 table, and 16 references. •

Whipple's Disease Source: in Brandt, L., et al., eds. Clinical Practice of Gastroenterology. Volume One. Philadelphia, PA: Current Medicine. 1999. p. 523-527. Contact: Available from W.B. Saunders Company. Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 545-2522. Fax (800) 874-6418 or (407) 352-3445. Website: www.wbsaunders.com. PRICE: $235.00 plus shipping and handling. ISBN: 0443065209 (two volume set); 0443065217 (volume 1); 0443065225 (volume 2). Summary: Whipple's disease is a multisystem, infectious disorder that usually causes a malabsorption syndrome variably accompanied by involvement of other organ systems, especially the joints, lymph nodes, heart, and central nervous system. This chapter on Whipple's disease is from a lengthy textbook that brings practitioners up to date on the complexities of gastroenterology practice, focusing on the essentials of patient care. The author of this chapter describes the epidemiology, cause, and pathologic features of the disease, along with the clinical presentation, diagnostic tests, treatment recommendations, and followup of patients with Whipple's disease. Whipple's disease is caused by a bacterium, Tropheryma whippleii. Antibiotic therapy must be given for an extended period to prevent relapse and death. Treatment involves a 2 week course of intravenous antibiotics that cross the blood brain barrier, such as penicillin G procaine, streptomycin, or a third generation cephalosporin. This regimen should by followed by a 1 year course of oral antibiotics. It may be necessary to correct fluid and electrolyte imbalances and replace vitamins and nutrients in patients who are deficient because of malabsorption. About one third of patients have relapses, which are usually severe and involve the central nervous system, gastrointestinal tract, joints, or cardiovascular system; mortality is significantly higher in patients who have a relapse of Whipple's disease than those who present with symptoms of the disease for the first time. 3 figures. 1 table. 18 references.

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CHAPTER 8. MULTIMEDIA ON PENICILLIN Overview In this chapter, we show you how to keep current on multimedia sources of information on penicillin. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.

Video Recordings An excellent source of multimedia information on penicillin is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “penicillin” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Videorecording (videotape, videocassette, etc.).” Type “penicillin” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on penicillin: •

Cause of AIDS: Fact and Speculation, Part 2 and 3 Contact: V Tape, 401 Richmond Street West, Toronto, (416) 351-1317. Summary: The part two of this video series reports on the AIDS activism in Europe, and the attention that activists are turning to AIDS research. The focus of research has always been on HIV. This videotape features researchers who question the relationship between HIV and AIDS. For example, they question the fact that in-vitro observations do not necessarily apply to HIV activity in the body. There is no proven mechanism by which HIV causes AIDS, and only a fraction of T cells are actively infected with HIV. They point out that there is no applicable animal model, and there is no correlation between actual viral activity and the disease progression. The fact that AIDS is almost always accompanied by antibodies does not mean, according to AIDS researchers interviewed, that HIV causes AIDS. The researchers interviewed state that the antibodies could be a consequence of an immunosuppressive condition, rather than a cause of AIDS. The part three of the video examines and explores the possible causes of AIDS. According to the narrator, the relationship between HIV and AIDS is being

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questioned by researchers because the actual mechanism by which HIV destroys T-cells is unknown. There appears to be an association between a history of certain STDS and becoming HIV- positive. The 1992 AIDS Conference in Amsterdam studied the relationship between AIDS and STDs. A number of conference presenters found that patients with a history of STD had a greater and more rapid rate of AIDS progression. The remainder of the video is devoted to an examination of the work being conducted by a cadre of researchers in the U.S. and abroad. These scientists have uncovered an overwhelming association between syphilis and HIV. The stages and symptoms of syphilis are described. Syphilis' ability to mimic other diseases has traditionally made it difficult to diagnose accurately. It is vital to obtain immediate and appropriate treatment. A historical overview of syphilis notes the emergence of penicillin as the accepted treatment for all stages and manifestations. The efficacy penicillin in later stages is questionable. Researchers discuss their doubts and questions regarding: penicillin's ability to treat syphilis bacteria once it penetrates the CNS, how and whether the disease remains latent in the b. •

The Health Century, Episode One: The Fight Against Infectious Disease; From Yellow Fever to AIDS Contact: Maryland Public Television, Public Broadcasting System Video, 11767 Owings Mills Blvd, Owings Mills, MD, 21117, (301) 356-5600. Summary: This videorecording, part of a series broadcast on Maryland Public Television, examines the history of infectious diseases up through the current epidemic of Acquired immunodeficiency syndrome (AIDS). Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), and Cecil Fox, a senior scientist at the National Institutes of Health (NIH), appear in an opening segment that discusses AIDS and the work being done on developing a vaccine. NIH's work in funding research programs is discussed. After pointing out that AIDS research is also feeding results back into other fields, the videorecording turns to the history of NIH, which goes back to the cholera epidemic of 1878, when a one-man staff began work in a New York City laboratory. Moving on through history, the videorecording looks at epidemics of pellagra, influenza, and polio, examining the research that went into developing penicillin and the massive efforts that went into producing the polio vaccine. During the last 15 minutes of the program, Dr. Michael Clement of San Francisco General Hospital talks about azidothymidine (AZT) and treating persons with Human immunodeficiency virus (HIV) infection, and Dr. Robert Gallo, co-discoverer of HIV, talks about research methods.

Bibliography: Multimedia on Penicillin The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in penicillin (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on penicillin: •

Discovery of penicillin [sound recording] Source: Audio-Forum; Year: 1983; Format: Sound recording; London: BBC, [1983]

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Penicillin [videorecording] Source: a presentation of the Marshfield Regional Video Network, Marshfield Clinic, Marshfield, WI; produced by St. Joseph's Hospital and Marshfield Clinic; Year: 1982; Format: Videorecording; Marshfield, WI: The Network, 1982

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Penicillin [videorecording]: discovering the truth Source: [presented by] Films for the Humanities & Sciences; a BBC-TV production, in association with Australian Broadcasting Corporation, WGBH, Boston; Year: 1998; Format: Videorecording; Princeton, N.J.: Films for the Humanities & Sciences, c1998

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Penicillin [videorecording]: first of the miracle drugs Source: produced by Media Centre, in association with the Department of Botany and its Cryptogamic Herbarium, University of Toronto; Year: 1987; Format: Videorecording; [Toronto, Ont.]: University of Toronto, c1987

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Penicillin and venereal disease [motion picture] Source: presented by the U.S. Public Health Service, in cooperation with state and local health departments; Year: 1947; Format: Motion picture; United States: The Service, [1947]

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Penicillin-resistant streptococcus pneumoniae [videorecording]: clinical manifestations and management Source: Stephen H. Zinner; Year: 1999; Format: Videorecording; [S.l.]: Center for Advanced Medical Education, 1999

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Penicillins [videorecording] Source: [produced by] Hahnemann Medical College & Hospital and World Video Corp; Year: 1981; Format: Videorecording; Philadelphia, PA: Antibiotic Group, c1981

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CHAPTER 9. PERIODICALS AND NEWS ON PENICILLIN Overview In this chapter, we suggest a number of news sources and present various periodicals that cover penicillin.

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

Penicillin might do more harm than good in severe leptospirosis patients Source: Reuters Medical News Date: August 15, 2003

•

FDA approves Bayer's Avelox for penicillin-resistant streptococcus Source: Reuters Industry Breifing Date: March 03, 2003

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•

FDA approves Avelox for penicillin-resistant S. pneumoniae Source: Reuters Medical News Date: March 03, 2003

•

Anaphylaxis risk with IV vitamin K low, comparable to that of penicillin Source: Reuters Medical News Date: November 18, 2002

•

Once resolved, penicillin allergy does not redevelop with repeated courses Source: Reuters Medical News Date: April 08, 2002

•

Many physicians lack current data on penicillin allergy Source: Reuters Medical News Date: January 23, 2002

•

Many docs lack latest info on penicillin allergy Source: Reuters Health eLine Date: January 22, 2002

•

Penicillin resistance increased in children after beta lactam use Source: Reuters Industry Breifing Date: January 03, 2002

•

Penicillin potency should be revisited Source: Reuters Industry Breifing Date: November 20, 2001

•

FDA suggests doxycycline, penicillin G procaine doses for inhalation anthrax Source: Reuters Medical News Date: October 30, 2001

•

UK study shows too few meningitis victims get penicillin Source: Reuters Industry Breifing Date: August 15, 2001

•

UK study shows too few meningitis patients receive penicillin Source: Reuters Medical News Date: August 15, 2001

•

Patients often wrong about penicillin allergies Source: Reuters Health eLine Date: May 15, 2001 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine.

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Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “penicillin” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “penicillin” (or synonyms). If you know the name of a company that is relevant to penicillin, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “penicillin” (or synonyms).

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

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periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

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CHAPTER 10. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for penicillin. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with penicillin. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The

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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to penicillin: Erythromycins •

Systemic - U.S. Brands: E.E.S.; E-Base; E-Mycin; ERYC; EryPed; Ery-Tab; Erythro; Erythrocin; Erythrocot; Ilosone; Ilotycin; My-E; PCE; Wintrocin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202223.html

Penicillins •

Systemic - U.S. Brands: Amoxil; Bactocill; Beepen-VK; Betapen-VK; Bicillin L-A; Cloxapen; Crysticillin 300 A.S.; Dycill; Dynapen; Geocillin; Geopen; Ledercillin VK; Mezlin; Nafcil; Nallpen; Omnipen; Omnipen-N; Pathocil; Pen Vee K; Pentids; Permapen; Pfizerpen; Pfizerpen-AS; Pi http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202446.html

Penicillins and Beta-Lactamase Inhibitors •

Systemic - U.S. Brands: Augmentin; Timentin; Unasyn; Zosyn http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202705.html

Spectinomycin •

Systemic - U.S. Brands: Trobicin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202530.html

Vancomycin •

Systemic - U.S. Brands: Vancocin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202590.html

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html.

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Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.

Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to penicillin by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/. Scroll down the page, and on the left toolbar, click on “Orphan Drug Designation Database.” On this page (http://www.rarediseases.org/search/noddsearch.html), type “penicillin” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for penicillin: •

Benzylpenicillin, benzylpenicilloic, benzylpenillo (trade name: PRE-PEN/MDM) http://www.rarediseases.org/nord/search/nodd_full?code=583

If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

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APPENDICES

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

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute12: •

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

12

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

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•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.13 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:14 •

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

13

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 14 See http://www.nlm.nih.gov/databases/databases.html.

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•

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

•

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

A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to one of the following: Brochure/Pamphlet, Fact Sheet, or Information Package, and “penicillin” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For the publication date, select “All Years.” Select your preferred language and the format option “Fact Sheet.” Type “penicillin” (or synonyms) into the “For these words:” box. The following is a sample result: •

Fatal and Severe Hepatitis Associated with Rifampin and Pyrazinamide for the Treatment of Latent Tuberculosis Infection--New York and Georgia, 2000 Source: Morbidity and Mortality Weekly Report Weekly Apr 20 2001;50(15):289-291. Summary: This report presents two case reports to illustrate that the two-month regimen of rifampin (RIF) and pyrazinamide (PZA) for the treatment of latent tuberculosis infection (LBTI) can cause severe hepatitis in some people. The first case is that of a 53-year-old incarcerated man who was treated with 600 mg RIF and 1750 mg PZA daily while receiving treatment for hypertension. The patient died of liver necrosis and failure as a result of hepatitis following LTBI treatment. The second case is that of a 59-year-old woman who received 600 mg RIF and 2000 mg PZA for LTBI. She was also receiving treatment for nasal allergies and asthma and had a history of anaphylactic reactions to penicillin and an estrogen sulfates blend. On the 49th and last day of treatment this patient was admitted to a hospital because of jaundice and altered mental states. After treatment with 40 mg prednisone daily, the patient recovered. In these cases biochemical monitoring did not help avoid liver injury. The report advises that patients with LTBI and risk factors for active TB should be offered treatment and should receive instruction and reminders about the symptoms of hepatitis and of stopping medication if symptoms develop. Cases of severe hepatitis that develop in patients being treated for LTBI should be reported to the CDC.

•

1998 Guidelines for Treatment of Sexually Transmitted Diseases Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://cdcnpin.org. Summary: This report provides guidelines for the medical treatment of sexually transmitted diseases (STDs). The report provides a brief overview of clinical and counseling prevention/intervention strategies for human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and STDs. The report examines the screening of and the special concerns associated with pregnant women, adolescents, and children exposed to HIV/AIDS and/or STDs. It describes the HIV antibody test, HIV counseling, initial medical care, and partner notification. Specific medical treatment

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of STDs are explained; the STDs are identified by their manifestation on the body (such as genital ulcers are characterized by herpes and syphilis). It covers treatments available for genital ulcer diseases, congenital syphilis, urethritis and cervicitis, vaginal discharge, pelvic inflammatory disease, epididymitis, and human papillomavirus infection. The report also examines methods to treat procititis, proctocolitis, enteritis, and ectoparasitic infections. It concludes by addressing special concerns related to STDs; sexual assault, cervical cancer, patients with a history of penicillin allergies, and vaccine-preventable diseases.

The NLM Gateway15 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.16 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “penicillin” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 65590 568 543 815 7 67523

HSTAT17 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.18 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.19 Simply search by “penicillin” (or synonyms) at the following Web site: http://text.nlm.nih.gov. 15

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

16

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 17 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 18 19

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

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

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Coffee Break: Tutorials for Biologists20 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.21 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.22 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

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

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

•

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

20 Adapted 21

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

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 22 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on penicillin can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to penicillin. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to penicillin. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “penicillin”:

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•

Other guides Anthrax http://www.nlm.nih.gov/medlineplus/anthrax.html Dental Health http://www.nlm.nih.gov/medlineplus/dentalhealth.html Streptococcal Infections http://www.nlm.nih.gov/medlineplus/streptococcalinfections.html Syphilis http://www.nlm.nih.gov/medlineplus/syphilis.html

You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on penicillin. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •

Update: Penicillin G Availability Source: MMWR Morbidity and Mortality Weekly Report January 28, 2000;49(3):61. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://cdcnpin.org. Summary: This information sheet discusses the availability of penicillin G after the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) announced a shortage of penicillin G for intravenous injection as a result of decreased production by a major manufacturer in October 1999. The information sheet provides information on emergency sources of penicillin G during this incident, and the CDC requests case reports from physicians about patients with neurosyphilis or congenital syphilis who were treated with an alternative regimen from September 1, 1999 to February 15, 2000. The National Guideline Clearinghouse™

The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site

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located at http://www.guideline.gov/ by using the keyword “penicillin” (or synonyms). The following was recently posted: •

Management of patients who have a history of penicillin allergy. Sexually transmitted diseases treatment guidelines 2002 Source: Centers for Disease Control and Prevention - Federal Government Agency [U.S.]; 1993 (revised 2002 May 10); 3 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3235&nbr=2461&a mp;string=penicillin Healthfinder™

Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

Doxycycline and Penicillin G Procaine for Inhalational Anthrax (Post-Exposure) Summary: This drug information sheet from FDA's Center for Drug Evaluation and Research provides recommendations for the antibiotics doxycycline and penicillin G procaine for treatment of inhalational anthrax. Source: Center for Drug Evaluation and Research, U.S. Food and Drug Administration http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6368 The NIH Search Utility

The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to penicillin. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

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

•

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

•

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

•

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

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•

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

•

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

•

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

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

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

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

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.23

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

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

23

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

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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)24: •

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

•

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

•

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

•

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

•

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

•

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

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

24

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

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•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

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•

Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

•

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

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•

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

•

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

•

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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PENICILLIN DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Abortion: 1. The premature expulsion from the uterus of the products of conception - of the embryo, or of a nonviable fetus. The four classic symptoms, usually present in each type of abortion, are uterine contractions, uterine haemorrhage, softening and dilatation of the cervix, and presentation or expulsion of all or part of the products of conception. 2. Premature stoppage of a natural or a pathological process. [EU] Abscess: Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. [NIH] Acatalasia: A rare autosomal recessive disorder resulting from the absence of catalase activity. Though usually asymptomatic, a syndrome of oral ulcerations and gangrene may be present. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] ACE: Angiotensin-coverting enzyme. A drug used to decrease pressure inside blood vessels. [NIH]

Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylgalactosamine: The N-acetyl derivative of galactosamine. [NIH] Acetylglucosamine: The N-acetyl derivative of glucosamine. [NIH] Acidity: The quality of being acid or sour; containing acid (hydrogen ions). [EU] Acoustic: Having to do with sound or hearing. [NIH] Acquired Immunodeficiency Syndrome: An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive Tlymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993. [NIH] Acremonium: A mitosporic fungal genus with many reported ascomycetous teleomorphs. Cephalosporin antibiotics are derived from this genus. [NIH] Acrylonitrile: A highly poisonous compound used widely in the manufacture of plastics, adhesives and synthetic rubber. [NIH]

200 Penicillin

Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Acylation: The addition of an organic acid radical into a molecule. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adsorption: The condensation of gases, liquids, or dissolved substances on the surfaces of solids. It includes adsorptive phenomena of bacteria and viruses as well as of tissues treated with exogenous drugs and chemicals. [NIH] Adsorptive: It captures volatile compounds by binding them to agents such as activated carbon or adsorptive resins. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]

Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the

Dictionary 201

stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allergic Rhinitis: Inflammation of the nasal mucous membrane associated with hay fever; fits may be provoked by substances in the working environment. [NIH] Allylamine: Possesses an unusual and selective cytotoxicity for vascular smooth muscle cells in dogs and rats. Useful for experiments dealing with arterial injury, myocardial fibrosis or cardiac decompensation. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy,

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magnet therapy, spiritual healing, and meditation. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Amber: A yellowish fossil resin, the gum of several species of coniferous trees, found in the alluvial deposits of northeastern Germany. It is used in molecular biology in the analysis of organic matter fossilized in amber. [NIH] Amebiasis: Infection with any of various amebae. It is an asymptomatic carrier state in most individuals, but diseases ranging from chronic, mild diarrhea to fulminant dysentery may occur. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amoxicillin: A broad-spectrum semisynthetic antibiotic similar to ampicillin except that its resistance to gastric acid permits higher serum levels with oral administration. [NIH] Amphetamine: A powerful central nervous system stimulant and sympathomimetic. Amphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulation of release of monamines, and inhibiting monoamine oxidase. Amphetamine is also a drug of abuse and a psychotomimetic. The l- and the d,l-forms are included here. The l-form has less central nervous system activity but stronger cardiovascular effects. The d-form is dextroamphetamine. [NIH] Ampicillin: Semi-synthetic derivative of penicillin that functions as an orally active broadspectrum antibiotic. [NIH] Ampicillin Resistance: Nonsusceptibility of a microbe to the action of ampicillin, a penicillin derivative that interferes with cell wall synthesis. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular

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fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anaphylaxis: An acute hypersensitivity reaction due to exposure to a previously encountered antigen. The reaction may include rapidly progressing urticaria, respiratory distress, vascular collapse, systemic shock, and death. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anergy: Absence of immune response to particular substances. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Angioedema: A vascular reaction involving the deep dermis or subcutaneous or submucal tissues, representing localized edema caused by dilatation and increased permeability of the capillaries, and characterized by development of giant wheals. [EU] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anode: Electrode held at a positive potential with respect to a cathode. [NIH] Anthrax: An acute bacterial infection caused by ingestion of bacillus organisms. Carnivores may become infected from ingestion of infected carcasses. It is transmitted to humans by

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contact with infected animals or contaminated animal products. The most common form in humans is cutaneous anthrax. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibiotic Prophylaxis: Use of antibiotics before, during, or after a diagnostic, therapeutic, or surgical procedure to prevent infectious complications. [NIH] Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antidote: A remedy for counteracting a poison. [EU] Antifungals: Drugs that treat infections caused by fungi. [NIH] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antispasmodic: An agent that relieves spasm. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the

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pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Aqueous: Having to do with water. [NIH] Archaea: One of the three domains of life (the others being bacteria and Eucarya), formerly called Archaebacteria under the taxon Bacteria, but now considered separate and distinct. They are characterized by: 1) the presence of characteristic tRNAs and ribosomal RNAs; 2) the absence of peptidoglycan cell walls; 3) the presence of ether-linked lipids built from branched-chain subunits; and 4) their occurrence in unusual habitats. While archaea resemble bacteria in morphology and genomic organization, they resemble eukarya in their method of genomic replication. The domain contains at least three kingdoms: crenarchaeota, euryarchaeota, and korarchaeota. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatic: Having a spicy odour. [EU] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astringents: Agents, usually topical, that cause the contraction of tissues for the control of bleeding or secretions. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Atmospheric Pressure: The pressure at any point in an atmosphere due solely to the weight of the atmospheric gases above the point concerned. [NIH] Atopic: Pertaining to an atopen or to atopy; allergic. [EU] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Auditory: Pertaining to the sense of hearing. [EU] Auscultation: Act of listening for sounds within the body. [NIH] Autolysis: The spontaneous disintegration of tissues or cells by the action of their own autogenous enzymes. [NIH] Azithromycin: A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. [NIH] Bacillus: A genus of Bacillaceae that are spore-forming, rod-shaped cells. Most species are saprophytic soil forms with only a few species being pathogenic. [NIH] Bacteremia: The presence of viable bacteria circulating in the blood. Fever, chills,

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tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacteriostatic: 1. Inhibiting the growth or multiplication of bacteria. 2. An agent that inhibits the growth or multiplication of bacteria. [EU] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Barbiturate: A drug with sedative and hypnotic effects. Barbiturates have been used as sedatives and anesthetics, and they have been used to treat the convulsions associated with epilepsy. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Benzodiazepines: A two-ring heterocyclic compound consisting of a benzene ring fused to a diazepine ring. Permitted is any degree of hydrogenation, any substituents and any Hisomer. [NIH] Beta-Lactam Resistance: Nonsusceptibility of an organism to the action of the beta-lactam antibiotics. [NIH] Beta-Lactamases: Enzymes found in many bacteria which catalyze the hydrolysis of the

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amide bond in the beta-lactam ring. Well known antibiotics destroyed by these enzymes are penicillins and cephalosporins. EC 3.5.2.6. [NIH] Bicuculline: Isoquinoline alkaloid from Dicentra cucullaria and other plants that is a competitive antagonist at GABA-A receptors and thus causes convulsions. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassays: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biofilms: Films of bacteria or other microbial organisms, usually embedded in extracellular polymers such as implanted medical devices, which adhere to surfaces submerged in, or subjected to, aquatic environments (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed). Biofilms consist of multilayers of microbial cells glued together to form microbial communities which are highly resistant to both phagocytes and antibiotics. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopsy specimen: Tissue removed from the body and examined under a microscope to determine whether disease is present. [NIH] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH]

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Bioterrorism: The use of biological agents in terrorism. This includes the malevolent use of bacteria, viruses, or toxins against people, animals, or plants. [NIH] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] Bladder: The organ that stores urine. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood Volume: Volume of circulating blood. It is the sum of the plasma volume and erythrocyte volume. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Broad Ligament: A broad fold of peritoneum that extends from the side of the uterus to the wall of the pelvis. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH]

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Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Buccal mucosa: The inner lining of the cheeks and lips. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Candidiasis: Infection with a fungus of the genus Candida. It is usually a superficial infection of the moist cutaneous areas of the body, and is generally caused by C. albicans; it most commonly involves the skin (dermatocandidiasis), oral mucous membranes (thrush, def. 1), respiratory tract (bronchocandidiasis), and vagina (vaginitis). Rarely there is a systemic infection or endocarditis. Called also moniliasis, candidosis, oidiomycosis, and formerly blastodendriosis. [EU] Candidosis: An infection caused by an opportunistic yeasts that tends to proliferate and become pathologic when the environment is favorable and the host resistance is weakened. [NIH]

Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsular: Cataract which is initiated by an opacification at the surface of the lens. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbapenems: A group of beta-lactam antibiotics in which the sulfur atom in the thiazolidine ring of the penicillin molecule is replaced by a carbon atom. Thienamycins are a subgroup of carbapenems which have a sulfur atom as the first constituent of the side chain. [NIH]

Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carboxy: Cannabinoid. [NIH] Carboxylic Acids: Organic compounds containing the carboxy group (-COOH). This group of compounds includes amino acids and fatty acids. Carboxylic acids can be saturated, unsaturated, or aromatic. [NIH] Carboxypeptidases: Enzymes that act at a free C-terminus of a polypeptide to liberate a single amino acid residue. They are further divided based on their catalytic mechanism into serine-type carboxypeptidases EC 3.4.16; metallocarboxypeptidases, EC 3.4.17; and cysteinetype carboxypeptidases, EC 3.4.18. EC 3.4.-. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH]

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Cardiomegaly: Hypertrophy or enlargement of the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular Agents: Agents that affect the rate or intensity of cardiac contraction, blood vessel diameter, or blood volume. [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Catalase: An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Catastrophic Illness: An acute or prolonged illness usually considered to be life-threatening or with the threat of serious residual disability. Treatment may be radical and is frequently costly. [NIH] Cathode: An electrode, usually an incandescent filament of tungsten, which emits electrons in an X-ray tube. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Caustic: An escharotic or corrosive agent. Called also cauterant. [EU] Cefaclor: Semisynthetic, broad-spectrum antibiotic derivative of cephalexin. [NIH] Cefadroxil: Long-acting, broad-spectrum, water-soluble, cephalexin derivative. [NIH] Cefixime: A third-generation cephalosporin antibiotic that is stable to hydrolysis by betalactamases. [NIH] Cefotaxime: Semisynthetic broad-spectrum cephalosporin. [NIH] Cefotetan: A semisynthetic cephamycin antibiotic that is administered intravenously or intramuscularly. The drug is highly resistant to a broad spectrum of beta-lactamases and is active against a wide range of both aerobic and anaerobic gram-positive and gram-negative microorganisms. It has a high rate of efficacy in many types of infections and to date no severe side effects have been noted. [NIH] Ceftazidime: Semisynthetic, broad-spectrum antibacterial derived from cephaloridine and used especially for Pseudomonas and other gram-negative infections in debilitated patients. [NIH]

Ceftizoxime: A semisynthetic cephalosporin antibiotic which can be administered

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intravenously or by suppository. The drug is highly resistant to a broad spectrum of betalactamases and is active against a wide range of both aerobic and anaerobic gram-positive and gram-negative organisms. It has few side effects and is reported to be safe and effective in aged patients and in patients with hematologic disorders. [NIH] Ceftriaxone: Broad-spectrum cephalosporin antibiotic with a very long half-life and high penetrability to usually inaccessible infections, including those involving the meninges, eyes, inner ears, and urinary tract. [NIH] Cefuroxime: Broad-spectrum cephalosporin antibiotic resistant to beta-lactamase. It has been proposed for infections with gram-negative and gram-positive organisms, gonorrhea, and haemophilus. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Cellulitis: An acute, diffuse, and suppurative inflammation of loose connective tissue, particularly the deep subcutaneous tissues, and sometimes muscle, which is most commonly seen as a result of infection of a wound, ulcer, or other skin lesions. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Cephalexin: A semisynthetic cephalosporin antibiotic with antimicrobial activity similar to that of cephaloridine or cephalothin, but somewhat less potent. It is effective against both gram-positive and gram-negative organisms. [NIH] Cephaloridine: A cephalosporin antibiotic. [NIH] Cephalosporins: A group of broad-spectrum antibiotics first isolated from the Mediterranean fungus Acremonium (Cephalosporium acremonium). They contain the betalactam moiety thia-azabicyclo-octenecarboxylic acid also called 7-aminocephalosporanic acid. [NIH] Cephalothin: A cephalosporin antibiotic. [NIH] Cephamycins: Naturally occurring family of beta-lactam cephalosporin-type antibiotics

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having a 7-methoxy group and possessing marked resistance to the action of beta-lactamases from gram-positive and gram-negative organisms. [NIH] Cephapirin: Cephalosporin antibiotic, partly plasma-bound, that is effective against gramnegative and gram-positive organisms. [NIH] Cephradine: A semi-synthetic cephalosporin antibiotic. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chelating Agents: Organic chemicals that form two or more coordination bonds with a central metal ion. Heterocyclic rings are formed with the central metal atom as part of the ring. Some biological systems form metal chelates, e.g., the iron-binding porphyrin group of hemoglobin and the magnesium-binding chlorophyll of plants. (From Hawley's Condensed Chemical Dictionary, 12th ed) They are used chemically to remove ions from solutions, medicinally against microorganisms, to treat metal poisoning, and in chemotherapy protocols. [NIH] Chelation: Combination with a metal in complexes in which the metal is part of a ring. [EU] Chemical Warfare: Tactical warfare using incendiary mixtures, smokes, or irritant, burning, or asphyxiating gases. [NIH] Chemical Warfare Agents: Chemicals that are used to cause the disturbance, disease, or death of humans during war. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chloral Hydrate: A hypnotic and sedative used in the treatment of insomnia. The safety margin is too narrow for chloral hydrate to be used as a general anesthetic in humans, but it is commonly used for that purpose in animal experiments. It is no longer considered useful as an anti-anxiety medication. [NIH] Chloralose: A derivative of chloral hydrate that was used as a sedative but has been

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replaced by safer and more effective drugs. Its most common use is as a general anesthetic in animal experiments. [NIH] Chloroform: A commonly used laboratory solvent. It was previously used as an anesthetic, but was banned from use in the U.S. due to its suspected carcinogenecity. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Cholecystectomy: Surgical removal of the gallbladder. [NIH] Cholecystitis: Inflammation of the gallbladder. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Chorea: Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Cilastatin: A renal dehydropeptidase-I and leukotriene D4 dipeptidase inhibitor. Since the antibiotic, imipenem, is hydrolyzed by dehydropeptidase-I, which resides in the brush border of the renal tubule, cilastatin is administered with imipenem to increase its effectiveness. The drug also inhibits the metabolism of leukotriene D4 to leukeotriene E4. [NIH]

Ciprofloxacin: A carboxyfluoroquinoline antimicrobial agent that is effective against a wide range of microorganisms. It has been successfully and safely used in the treatment of resistant respiratory, skin, bone, joint, gastrointestinal, urinary, and genital infections. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clarithromycin: A semisynthetic macrolide antibiotic derived from erythromycin that is active against a variety of microorganisms. It can inhibit protein synthesis in bacteria by reversibly binding to the 50S ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation. [NIH] Claviceps: A genus of ascomycetous fungi, family Clavicipitaceae, order Hypocreales, parasitic on various grasses. The sclerotia contain several toxic alkaloids. Claviceps purpurea on rye causes ergotism. [NIH]

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Clavulanic Acid: Clavulanic acid (C8H9O5N) and its salts and esters. The acid is a suicide inhibitor of bacterial beta-lactamase enzymes from Streptomyces clavuligerus. Administered alone, it has only weak antibacterial activity against most organisms, but given in combination with beta-lactam antibiotics prevents antibiotic inactivation by microbial lactamase. [NIH] Cleave: A double-stranded cut in DNA with a restriction endonuclease. [NIH] Clindamycin: An antibacterial agent that is a semisynthetic analog of lincomycin. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cochlear: Of or pertaining to the cochlea. [EU] Cochlear Diseases: Diseases of the cochlea, the part of the inner ear that is concerned with hearing. [NIH] Cod Liver Oil: Oil obtained from fresh livers of the cod family, Gadidae. It is a source of vitamins A and D. [NIH] Codeine: An opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough. [NIH] Codons: Any triplet of nucleotides (coding unit) in DNA or RNA (if RNA is the carrier of primary genetic information as in some viruses) that codes for particular amino acid or signals the beginning or end of the message. [NIH] Coenzymes: Substances that are necessary for the action or enhancement of action of an enzyme. Many vitamins are coenzymes. [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Coliphages: Viruses whose host is Escherichia coli. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic

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substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Commensal: 1. Living on or within another organism, and deriving benefit without injuring or benefiting the other individual. 2. An organism living on or within another, but not causing injury to the host. [EU] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such

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as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Consensus Sequence: A theoretical representative nucleotide or amino acid sequence in which each nucleotide or amino acid is the one which occurs most frequently at that site in the different sequences which occur in nature. The phrase also refers to an actual sequence which approximates the theoretical consensus. A known conserved sequence set is represented by a consensus sequence. Commonly observed supersecondary protein structures (amino acid motifs) are often formed by conserved sequences. [NIH] Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a consensus sequence. Amino acid motifs are often composed of conserved sequences. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU]

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Continuum: An area over which the vegetation or animal population is of constantly changing composition so that homogeneous, separate communities cannot be distinguished. [NIH]

Contracture: A condition of fixed high resistance to passive stretch of a muscle, resulting from fibrosis of the tissues supporting the muscles or the joints, or from disorders of the muscle fibres. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cryptosporidiosis: Parasitic intestinal infection with severe diarrhea caused by a protozoan, Cryptosporidium. It occurs in both animals and humans. [NIH] Crystallization: The formation of crystals; conversion to a crystalline form. [EU] Culture Media: Any liquid or solid preparation made specifically for the growth, storage, or transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as agar or gelatin. [NIH] Curare: Plant extracts from several species, including Strychnos toxifera, S. castelnaei, S. crevauxii, and Chondodendron tomentosum, that produce paralysis of skeletal muscle and are used adjunctively with general anesthesia. These extracts are toxic and must be used with the administration of artificial respiration. [NIH]

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Curative: Tending to overcome disease and promote recovery. [EU] Curettage: Removal of tissue with a curette, a spoon-shaped instrument with a sharp edge. [NIH]

Cutaneous: Having to do with the skin. [NIH] Cyclin: Molecule that regulates the cell cycle. [NIH] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cysteinyl: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Cystitis: Inflammation of the urinary bladder. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytokinesis: Division of the rest of cell. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Daunorubicin: Very toxic anthracycline aminoglycoside antibiotic isolated from Streptomyces peucetius and others, used in treatment of leukemias and other neoplasms. [NIH]

Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decision Making: The process of making a selective intellectual judgment when presented with several complex alternatives consisting of several variables, and usually defining a course of action or an idea. [NIH] Decontamination: The removal of contaminating material, such as radioactive materials, biological materials, or chemical warfare agents, from a person or object. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydration: The condition that results from excessive loss of body water. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH]

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Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Care: The total of dental diagnostic, preventive, and restorative services provided to meet the needs of a patient (from Illustrated Dictionary of Dentistry, 1982). [NIH] Dental Caries: Localized destruction of the tooth surface initiated by decalcification of the enamel followed by enzymatic lysis of organic structures and leading to cavity formation. If left unchecked, the cavity may penetrate the enamel and dentin and reach the pulp. The three most prominent theories used to explain the etiology of the disase are that acids produced by bacteria lead to decalcification; that micro-organisms destroy the enamel protein; or that keratolytic micro-organisms produce chelates that lead to decalcification. [NIH]

Dental Materials: Materials used in the production of dental bases, restorations, impressions, prostheses, etc. [NIH] Dental Plaque: A film that attaches to teeth, often causing dental caries and gingivitis. It is composed of mucins, secreted from salivary glands, and microorganisms. [NIH] Dental Records: Data collected during dental examination for the purpose of study, diagnosis, or treatment planning. [NIH] Dentists: Individuals licensed to practice dentistry. [NIH] Dentition: The teeth in the dental arch; ordinarily used to designate the natural teeth in position in their alveoli. [EU] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Dermatitis: Any inflammation of the skin. [NIH] Dermatology: A medical specialty concerned with the skin, its structure, functions, diseases, and treatment. [NIH] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties. [NIH] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which results in a change in the social, political, and economic structures. [NIH] Dexamethasone: (11 beta,16 alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4diene-3,20-dione. An anti-inflammatory glucocorticoid used either in the free alcohol or esterified form in treatment of conditions that respond generally to cortisone. [NIH] Dextroamphetamine: The d-form of amphetamine. It is a central nervous system stimulant and a sympathomimetic. It has also been used in the treatment of narcolepsy and of attention deficit disorders and hyperactivity in children. Dextroamphetamine has multiple

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mechanisms of action including blocking uptake of adrenergics and dopamine, stimulating release of monamines, and inhibiting monoamine oxidase. It is also a drug of abuse and a psychotomimetic. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Diastolic: Of or pertaining to the diastole. [EU] Dietary Proteins: Proteins obtained from foods. They are the main source of the essential amino acids. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dilatation: The act of dilating. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Disaccharides: Sugars composed of two monosaccharides linked by glycoside bonds. [NIH] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH]

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Domesticated: Species in which the evolutionary process has been influenced by humans to meet their needs. [NIH] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dormancy: The period when an organism (i. e., a virus or a bacterium) is in the body but not producing any ill effects. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] Dosimetry: All the methods either of measuring directly, or of measuring indirectly and computing, absorbed dose, absorbed dose rate, exposure, exposure rate, dose equivalent, and the science associated with these methods. [NIH] Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetics. It is a hydroxy derivative of daunorubicin and is used in treatment of both leukemia and solid tumors. [NIH] Doxycycline: A synthetic tetracycline derivative with a range of antimicrobial activity and mode of action similar to that of tetracycline, but more effective against many species. Animal studies suggest that it may cause less tooth staining than other tetracyclines. [NIH] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Monitoring: The process of observing, recording, or detecting the effects of a chemical substance administered to an individual therapeutically or diagnostically. [NIH] Drug Residues: Drugs and their metabolites which are found in the edible tissues and milk of animals after their medication with specific drugs. This term can also apply to drugs found in adipose tissue of humans after drug treatment. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects

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of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dyspepsia: Impaired digestion, especially after eating. [NIH] Ectopic: Pertaining to or characterized by ectopia. [EU] Ectopic Pregnancy: The pregnancy occurring elsewhere than in the cavity of the uterus. [NIH]

Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Electroacupuncture: A form of acupuncture using low frequency electrically stimulated needles to produce analgesia and anesthesia and to treat disease. [NIH] Electrolysis: Destruction by passage of a galvanic electric current, as in disintegration of a chemical compound in solution. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

Electroplating: Coating with a metal or alloy by electrolysis. [NIH] Emaciation: Clinical manifestation of excessive leanness usually caused by disease or a lack of nutrition. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryo Transfer: Removal of a mammalian embryo from one environment and replacement in the same or a new environment. The embryo is usually in the pre-nidation phase, i.e., a blastocyst. The process includes embryo or blastocyst transplantation or transfer after in vitro fertilization and transfer of the inner cell mass of the blastocyst. It is not used for transfer of differentiated embryonic tissue, e.g., germ layer cells. [NIH] Emollient: Softening or soothing; called also malactic. [EU]

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Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Empiric: Empirical; depending upon experience or observation alone, without using scientific method or theory. [EU] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Empyema: Presence of pus in a hollow organ or body cavity. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]

Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary disorder or as a complication of or in association with another disease. [EU] Endocardium: The innermost layer of the heart, comprised of endothelial cells. [NIH] Endocrine Glands: Ductless glands that secrete substances which are released directly into the circulation and which influence metabolism and other body functions. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Endoscopy: Endoscopic examination, therapy or surgery performed on interior parts of the body. [NIH] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enflurane: An extremely stable inhalation anesthetic that allows rapid adjustments of anesthesia depth with little change in pulse or respiratory rate. [NIH] Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. [NIH]

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Enteritis: Inflammation of the intestine, applied chiefly to inflammation of the small intestine; see also enterocolitis. [EU] Enterocolitis: Inflammation of the intestinal mucosa of the small and large bowel. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Environmental Monitoring: The monitoring of the level of toxins, chemical pollutants, microbial contaminants, or other harmful substances in the environment or workplace by measuring the amounts of these toxicants in the bodies of people and animals in that environment, among other methods. It also includes the measurement of environmental exposure. Levels in humans and animals are used as indicators of toxic levels of undesirable chemicals. [NIH] Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Activation: Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1) activation by ions (activators); 2) activation by cofactors (coenzymes); and 3) conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Eosinophilia: Abnormal increase in eosinophils in the blood, tissues or organs. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]

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Ergot: Cataract due to ergot poisoning caused by eating of rye cereals contaminated by a fungus. [NIH] Erysipelas: An acute infection of the skin caused by species of streptococcus. This disease most frequently affects infants, young children, and the elderly. Characteristics include pink-to-red lesions that spread rapidly and are warm to the touch. The commonest site of involvement is the face. [NIH] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythema Chronicum Migrans: A deep type of gyrate erythema that follows a bite by an ixodid tick; it is a stage-1 manifestation of Lyme disease. The site of the bite is characterized by a red papule that expands peripherally as a nonscaling, palpable band that clears centrally. This condition is often associated with systemic symptoms such as chills, fever, headache, malaise, nausea, vomiting, fatigue, backache, and stiff neck. [NIH] Erythrasma: A chronic bacterial infection of major folds of the skin, caused by Corynebacterium minutissimum. [NIH] Erythroblasts: Immature, nucleated erythrocytes occupying the stage of erythropoiesis that follows formation of erythroid progenitor cells and precedes formation of reticulocytes. Popularly called normoblasts. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythroid Progenitor Cells: Committed, erythroid stem cells derived from myeloid stem cells. The progenitor cells develop in two phases: erythroid burst-forming units (BFU-E) followed by erythroid colony-forming units (CFU-E). BFU-E differentiate into CFU-E on stimulation by erythropoietin, and then further differentiate into erythroblasts when stimulated by other factors. [NIH] Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Erythropoiesis: The production of erythrocytes. [EU] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estrogen: One of the two female sex hormones. [NIH] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Excisional: The surgical procedure of removing a tumor by cutting it out. The biopsy is then examined under a microscope. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU]

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Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exotoxin: Toxic substance excreted by living bacterial cells. [NIH] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]

Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [EU] Fallopian tube: The oviduct, a muscular tube about 10 cm long, lying in the upper border of the broad ligament. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fasciitis: Inflammation of the fascia. There are three major types: 1) Eosinophilic fasciitis, an inflammatory reaction with eosinophilia, producing hard thickened skin with an orangepeel configuration suggestive of scleroderma and considered by some a variant of scleroderma; 2) Necrotizing fasciitis, a serious fulminating infection (usually by a beta hemolytic Streptococcus) causing extensive necrosis of superficial fascia; 3) Nodular/Pseudosarcomatous/Proliferative fasciitis, characterized by a rapid growth of fibroblasts with mononuclear inflammatory cells and proliferating capillaries in soft tissue, often the forearm; it is not malignant but is sometimes mistaken for fibrosarcoma. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fermentation: An enzyme-induced chemical change in organic compounds that takes place in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH] Fertilization in Vitro: Fertilization of an egg outside the body when the egg is normally fertilized in the body. [NIH] Fertilizers: Substances or mixtures that are added to the soil to supply nutrients or to make available nutrients already present in the soil, in order to increase plant growth and productivity. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of

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the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosarcoma: A type of soft tissue sarcoma that begins in fibrous tissue, which holds bones, muscles, and other organs in place. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flatus: Gas passed through the rectum. [NIH] Flexion: In gynaecology, a displacement of the uterus in which the organ is bent so far forward or backward that an acute angle forms between the fundus and the cervix. [EU] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Follicles: Shafts through which hair grows. [NIH] Folliculitis: Inflammation of follicles, primarily hair follicles. [NIH] Food Technology: The application of knowledge to the food industry. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fosfomycin: An antibiotic produced by Streptomyces fradiae. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention

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of free radical damage is being actively investigated. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Furosemide: A sulfamyl saluretic and diuretic. It has a fast onset and short duration of action and is used in edema and chronic renal insufficiency. [NIH] Gallate: Antioxidant present in tea. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gamma irradiation: A type of radiation therapy that uses gamma radiation. Gamma radiation is a type of high-energy radiation that is different from x-rays. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gangrenous: A circumscribed, deep-seated, suppurative inflammation of the subcutaneous tissue of the eyelid discharging pus from several points. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Juices: Liquids produced in the stomach to help break down food and kill bacteria. [NIH]

Gastric Mucosa: Surface epithelium in the stomach that invaginates into the lamina propria, forming gastric pits. Tubular glands, characteristic of each region of the stomach (cardiac, gastric, and pyloric), empty into the gastric pits. The gastric mucosa is made up of several different kinds of cells. [NIH] Gastritis: Inflammation of the stomach. [EU] Gastroenterologist: A doctor who specializes in diagnosing and treating disorders of the digestive system. [NIH] Gastroenterology: A subspecialty of internal medicine concerned with the study of the physiology and diseases of the digestive system and related structures (esophagus, liver, gallbladder, and pancreas). [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gavage: Feeding by a tube passed into the stomach; called also tube feeding. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gels: Colloids with a solid continuous phase and liquid as the dispersed phase; gels may be

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unstable when, due to temperature or other cause, the solid phase liquifies; the resulting colloid is called a sol. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]

Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Giardiasis: An infection of the small intestine caused by the flagellated protozoan Giardia lamblia. It is spread via contaminated food and water and by direct person-to-person contact. [NIH] Gingivitis: Inflammation of the gingivae. Gingivitis associated with bony changes is referred to as periodontitis. Called also oulitis and ulitis. [EU] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomeruli: Plural of glomerulus. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic

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(drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]

Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycans: Heteropolysaccharides which contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages consisting of either N-acetylglucosamine or Nacetylgalactosamine. [NIH] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Goats: Any of numerous agile, hollow-horned ruminants of the genus Capra, closely related to the sheep. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonorrhea: Acute infectious disease characterized by primary invasion of the urogenital tract. The etiologic agent, Neisseria gonorrhoeae, was isolated by Neisser in 1879. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a

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primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-Negative Bacteria: Bacteria which lose crystal violet stain but are stained pink when treated by Gram's method. [NIH] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Gram-Positive Bacteria: Bacteria which retain the crystal violet stain when treated by Gram's method. [NIH] Granule: A small pill made from sucrose. [EU] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Granulocytopenia: A deficiency in the number of granulocytes, a type of white blood cell. [NIH]

Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [NIH] Guinea Pigs: A common name used for the family Caviidae. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. [NIH]

Gutta-Percha: Trans-Polyisoprene. Coagulated exudate isolated from several species of the tropical tree Palaquium (Sapotaceae). It is the trans-isomer of natural rubber and is used as a filling and impression material in dentistry and orthopedics and as an insulator in electronics. It has also been used as a rubber substitute. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Haemophilus: A genus of Pasteurellaceae that consists of several species occurring in animals and humans. Its organisms are described as gram-negative, facultatively anaerobic, coccobacillus or rod-shaped, and nonmotile. [NIH] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Hay Fever: A seasonal variety of allergic rhinitis, marked by acute conjunctivitis with lacrimation and itching, regarded as an allergic condition triggered by specific allergens. [NIH]

Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and

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other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heart Murmurs: Abnormal heart sounds heard during auscultation caused by alterations in the flow of blood into a chamber, through a valve, or by a valve opening or closing abnormally. They are classified by the time of occurrence during the cardiac cycle, the duration, and the intensity of the sound on a scale of I to V. [NIH] Heart Sounds: The sounds heard over the cardiac region produced by the functioning of the heart. There are four distinct sounds: the first occurs at the beginning of systole and is heard as a "lubb" sound; the second is produced by the closing of the aortic and pulmonary valves and is heard as a "dupp" sound; the third is produced by vibrations of the ventricular walls when suddenly distended by the rush of blood from the atria; and the fourth is produced by atrial contraction and ventricular filling but is rarely audible in the normal heart. The physiological concept of heart sounds is differentiated from the pathological heart murmurs. [NIH]

Helminths: Commonly known as parasitic worms, this group includes the acanthocephala, nematoda, and platyhelminths. Some authors consider certain species of leeches that can become temporarily parasitic as helminths. [NIH] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemin: Chloro(7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18dipropanoato(4-)-N(21),N(22),N(23),N(24)) ferrate(2-) dihydrogen. [NIH] Hemodiafiltration: The combination of hemodialysis and hemofiltration either simultaneously or sequentially. Convective transport (hemofiltration) may be better for removal of larger molecular weight substances and diffusive transport (hemodialysis) for smaller molecular weight solutes. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemofiltration: Extracorporeal ultrafiltration technique without hemodialysis for treatment of fluid overload and electrolyte disturbances affecting renal, cardiac, or pulmonary function. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin A: Normal adult human hemoglobin. The globin moiety consists of two alpha and two beta chains. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH]

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Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatitis A: Hepatitis caused by hepatovirus. It can be transmitted through fecal contamination of food or water. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hepatovirus: A genus of Picornaviridae causing infectious hepatitis naturally in humans and experimentally in other primates. It is transmitted through fecal contamination of food or water. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes Zoster: Acute vesicular inflammation. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Heterotrophic: Pertaining to organisms that are consumers and dependent on other organisms for their source of energy (food). [NIH] Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Human papillomavirus: HPV. A virus that causes abnormal tissue growth (warts) and is often associated with some types of cancer. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU]

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Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hydrogel: A network of cross-linked hydrophilic macromolecules used in biomedical applications. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrogenation: Specific method of reduction in which hydrogen is added to a substance by the direct use of gaseous hydrogen. [NIH] Hydrolases: Any member of the class of enzymes that catalyze the cleavage of the substrate and the addition of water to the resulting molecules, e.g., esterases, glycosidases (glycoside hydrolases), lipases, nucleotidases, peptidases (peptide hydrolases), and phosphatases (phosphoric monoester hydrolases). EC 3. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. [NIH] Hyperbaric: Characterized by greater than normal pressure or weight; applied to gases under greater than atmospheric pressure, as hyperbaric oxygen, or to a solution of greater specific gravity than another taken as a standard of reference. [EU] Hyperbaric oxygen: Oxygen that is at an atmospheric pressure higher than the pressure at sea level. Breathing hyperbaric oxygen to enhance the effectiveness of radiation therapy is being studied. [NIH] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH]

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Hypersensitivity, Immediate: Hypersensitivity reactions which occur within minutes of exposure to challenging antigen due to the release of histamine which follows the antigenantibody reaction and causes smooth muscle contraction and increased vascular permeability. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypospadias: A developmental anomaly in the male in which the urethra opens on the underside of the penis or on the perineum. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypoxic: Having too little oxygen. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Imipenem: Semisynthetic thienamycin that has a wide spectrum of antibacterial activity against gram-negative and gram-positive aerobic and anaerobic bacteria, including many multiresistant strains. It is stable to beta-lactamases. Clinical studies have demonstrated high efficacy in the treatment of infections of various body systems. Its effectiveness is enhanced when it is administered in combination with cilastatin, a renal dipeptidase inhibitor. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunocompromised Host: A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunodeficiency syndrome: The inability of the body to produce an immune response. [NIH]

Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH]

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Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Impetigo: A common superficial bacterial infection caused by staphylococcus aureus or group A beta-hemolytic streptococci. Characteristics include pustular lesions that rupture and discharge a thin, amber-colored fluid that dries and forms a crust. This condition is commonly located on the face, especially about the mouth and nose. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Infestation: Parasitic attack or subsistence on the skin and/or its appendages, as by insects, mites, or ticks; sometimes used to denote parasitic invasion of the organs and tissues, as by helminths. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease.

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[NIH]

Influenza: An acute viral infection involving the respiratory tract. It is marked by inflammation of the nasal mucosa, the pharynx, and conjunctiva, and by headache and severe, often generalized, myalgia. [NIH] Information Systems: Integrated set of files, procedures, and equipment for the storage, manipulation, and retrieval of information. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Inoculum: The spores or tissues of a pathogen that serve to initiate disease in a plant. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inpatients: Persons admitted to health facilities which provide board and room, for the purpose of observation, care, diagnosis or treatment. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]

Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of

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digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracranial Hypertension: Increased pressure within the cranial vault. This may result from several conditions, including hydrocephalus; brain edema; intracranial masses; severe systemic hypertension; pseudotumor cerebri; and other disorders. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intramuscular injection: IM. Injection into a muscle. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Ion Exchange: Reversible chemical reaction between a solid, often an ION exchange resin, and a fluid whereby ions may be exchanged from one substance to another. This technique is used in water purification, in research, and in industry. [NIH] Ion Exchange Resins: High molecular weight, insoluble polymers which contain functional groups that are capable of undergoing exchange reactions (ion exchange) with either cations or anions. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Irritants: Drugs that act locally on cutaneous or mucosal surfaces to produce inflammation; those that cause redness due to hyperemia are rubefacients; those that raise blisters are vesicants and those that penetrate sebaceous glands and cause abscesses are pustulants; tear gases and mustard gases are also irritants. [NIH] Isoleucine: An essential branched-chain amino acid found in many proteins. It is an isomer of LEUCINE. It is important in hemoglobin synthesis and regulation of blood sugar and energy levels. [NIH] Ixodid: A tick of the genus Ixodes. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels

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under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH] Laceration: 1. The act of tearing. 2. A torn, ragged, mangled wound. [EU] Lanthanum: The prototypical element in the rare earth family of metals. It has the atomic symbol La, atomic number 57, and atomic weight 138.91. Lanthanide ion is used in experimental biology as a calcium antagonist; lanthanum oxide improves the optical properties of glass. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lectins: Protein or glycoprotein substances, usually of plant origin, that bind to sugar moieties in cell walls or membranes and thereby change the physiology of the membrane to cause agglutination, mitosis, or other biochemical changes in the cell. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Leptospirosis: Infections with bacteria of the genus Leptospira. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Levofloxacin: A substance used to treat bacterial infections. It belongs to the family of drugs called quinolone antibiotics. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligase: An enzyme that repairs single stranded discontinuities in double-stranded DNA molecules in the cell. Purified DNA ligase is used in gene cloning to join DNA molecules together. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Lincomycin: (2S-trans)-Methyl 6,8-dideoxy-6-(((1-methyl-4-propyl-2pyrrolidinyl)carbonyl)amino)-1-thio-D-erythro-alpha-D-galacto-octopyranoside. An antibiotic produced by Streptomyces lincolnensis var. lincolnensis. It has been used in the

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treatment of staphylococcal, streptococcal, and Bacteroides fragilis infections. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Lockjaw: Inability to open the mouth due to tonic contracture of the muscles of the jaw. [NIH]

Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphocyte Count: A count of the number of lymphocytes in the blood. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokines: Soluble protein factors generated by activated lymphocytes that affect other cells, primarily those involved in cellular immunity. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lysostaphin: A 25 kD peptidase produced by Staphylococcus simulans which cleaves a glycine-glcyine bond unique to an inter-peptide cross-bridge of the Staphylococcus aureus

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cell wall. EC 3.4.24.75. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macrolides: A group of organic compounds that contain a macrocyclic lactone ring linked glycosidically to one or more sugar moieties. [NIH] Maculopapular: Both macular and papular, as an eruption consisting of both macules and papules; sometimes erroneously used to designate a papule that is only slightly elevated. [EU]

Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malabsorption syndrome: A group of symptoms such as gas, bloating, abdominal pain, and diarrhea resulting from the body's inability to properly absorb nutrients. [NIH] Malaise: A vague feeling of bodily discomfort. [EU] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammary: Pertaining to the mamma, or breast. [EU] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mass Media: Instruments or technological means of communication that reach large numbers of people with a common message: press, radio, television, etc. [NIH] Masseter Muscle: A masticatory muscle whose action is closing the jaws. [NIH] Mastitis: Inflammatory disease of the breast, or mammary gland. [NIH] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH]

Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH]

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Melanin: The substance that gives the skin its color. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Meningococcal Infections: Infections with bacteria of the species neisseria meningitidis. [NIH]

Meningococcal Vaccines: Vaccines or candidate vaccines used to prevent infection with Neisseria meningitidis. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Methanol: A colorless, flammable liquid used in the manufacture of formaldehyde and acetic acid, in chemical synthesis, antifreeze, and as a solvent. Ingestion of methanol is toxic and may cause blindness. [NIH] Methicillin Resistance: Non-susceptibility of a microbe to the action of methicillin, a semisynthetic penicillin derivative. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] Methyldopa: An alpha-2 adrenergic agonist that has both central and peripheral nervous system effects. Its primary clinical use is as an antihypertensive agent. Before its alphaadrenergic actions became clear, methyldopa was thought to act by inhibiting decarboxylation of DOPA leading to depletion of norepinephrine or by conversion to and release as the false transmitter alpha-methylnorepinephrine. [NIH] Methylene Chloride: A chlorinated hydrocarbon that has been used as an inhalation anesthetic and acts as a narcotic in high concentrations. Its primary use is as a solvent in

Dictionary 243

manufacturing and food technology. [NIH] Metronidazole: Antiprotozoal used in amebiasis, trichomoniasis, giardiasis, and as treponemacide in livestock. It has also been proposed as a radiation sensitizer for hypoxic cells. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985, p133), this substance may reasonably be anticipated to be a carcinogen (Merck, 11th ed). [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbicide: Any substance (gels, creams, suppositories, etc.) that can reduce transmission of sexually transmitted infections. [NIH] Microbiological: Pertaining to microbiology : the science that deals with microorganisms, including algae, bacteria, fungi, protozoa and viruses. [EU] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Migrans: Infestation of the dermis by various larvae, characterized by bizarre red irregular lines which are broad at one end and fade at the other, produced by burrowing larvae. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Milk Thistle: The plant Silybum marianum in the family Asteraceae containing the bioflavonoid complex silymarin. For centuries this has been used traditionally to treat liver disease. [NIH] Mitomycin: An antineoplastic antibiotic produced by Streptomyces caespitosus. It acts as a bi- or trifunctional alkylating agent causing cross-linking of DNA and inhibition of DNA synthesis. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular mass: The sum of the atomic masses of all atoms in a molecule, based on a scale in which the atomic masses of hydrogen, carbon, nitrogen, and oxygen are 1, 12, 14, and 16, respectively. For example, the molecular mass of water, which has two atoms of hydrogen and one atom of oxygen, is 18 (i.e., 2 + 16). [NIH] Molecular Structure: The location of the atoms, groups or ions relative to one another in a

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molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoamine: Enzyme that breaks down dopamine in the astrocytes and microglia. [NIH] Monobactams: Monocyclic, bacterially produced or semisynthetic beta-lactam antibiotics. They lack the double ring construction of the traditional beta-lactam antibiotics and can be easily synthesized. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Monokines: Soluble mediators of the immune response that are neither antibodies nor complement. They are produced largely, but not exclusively, by monocytes and macrophages. [NIH] Mononuclear: A cell with one nucleus. [NIH] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]

Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motor nerve: An efferent nerve conveying an impulse that excites muscular contraction. [NIH]

Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucociliary: Pertaining to or affecting the mucus membrane and hairs (including eyelashes, nose hair, .): mucociliary clearing: the clearance of mucus by ciliary movement ( particularly in the respiratory system). [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Multivariate Analysis: A set of techniques used when variation in several variables has to be studied simultaneously. In statistics, multivariate analysis is interpreted as any analytic method that allows simultaneous study of two or more dependent variables. [NIH] Muramidase: A basic enzyme that is present in saliva, tears, egg white, and many animal fluids. It functions as an antibacterial agent. The enzyme catalyzes the hydrolysis of 1,4-beta-

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linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in peptidoglycan and between N-acetyl-D-glucosamine residues in chitodextrin. EC 3.2.1.17. [NIH]

Muscle relaxant: An agent that specifically aids in reducing muscle tension, as those acting at the polysynaptic neurons of motor nerves (e.g. meprobamate) or at the myoneural junction (curare and related compounds). [EU] Muscle tension: A force in a material tending to produce extension; the state of being stretched. [NIH] Mustard Gas: Severe irritant and vesicant of skin, eyes, and lungs. It may cause blindness and lethal lung edema and was formerly used as a war gas. The substance has been proposed as a cytostatic and for treatment of psoriasis. It has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP-85-002, 1985) (Merck, 11th ed). [NIH] Mutate: To change the genetic material of a cell. Then changes (mutations) can be harmful, beneficial, or have no effect. [NIH] Myalgia: Pain in a muscle or muscles. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myositis: Inflammation of a voluntary muscle. [EU] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] Nasopharynx: The nasal part of the pharynx, lying above the level of the soft palate. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Nebramycin: A complex of antibiotic substances produced by Streptomyces tenebrarius. [NIH]

Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neisseria: A genus of gram-negative, aerobic, coccoid bacteria whose organisms are part of the normal flora of the oropharynx, nasopharynx, and genitourinary tract. Some species are primary pathogens for humans. [NIH] Neisseria meningitidis: A species of gram-negative, aerobic bacteria found in cerebrospinal fluid as the causative agent of cerebrospinal meningitis (meningitis, meningococcal) as well as in venereal discharges and blood. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU]

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Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nephrotoxic: Toxic or destructive to kidney cells. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Netilmicin: Semisynthetic 1-N-ethyl derivative of sisomycin, an aminoglycoside antibiotic with action similar to gentamicin, but less ear and kidney toxicity. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuraminidase: An enzyme that catalyzes the hydrolysis of alpha-2,3, alpha-2,6-, and alpha-2,8-glycosidic linkages (at a decreasing rate, respectively) of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid, and synthetic substrate. (From Enzyme Nomenclature, 1992) EC 3.2.1.18. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neurosyphilis: A late form of syphilis that affects the brain and may lead to dementia and death. [NIH] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]

Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutralization: An act or process of neutralizing. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [NIH] Nitrofurantoin: A urinary anti-infective agent effective against most gram-positive and gram-negative organisms. Although sulfonamides and antibiotics are usually the agents of

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choice for urinary tract infections, nitrofurantoin is widely used for prophylaxis and longterm suppression. [NIH] Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nosocomial: Pertaining to or originating in the hospital, said of an infection not present or incubating prior to admittance to the hospital, but generally occurring 72 hours after admittance; the term is usually used to refer to patient disease, but hospital personnel may also acquire nosocomial infection. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleotidases: A class of enzymes that catalyze the conversion of a nucleotide and water to a nucleoside and orthophosphate. EC 3.1.3.-. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Observational study: An epidemiologic study that does not involve any intervention, experimental or otherwise. Such a study may be one in which nature is allowed to take its course, with changes in one characteristic being studied in relation to changes in other characteristics. Analytical epidemiologic methods, such as case-control and cohort study designs, are properly called observational epidemiology because the investigator is observing without intervention other than to record, classify, count, and statistically analyze results. [NIH] Obstetrics: A medical-surgical specialty concerned with management and care of women during pregnancy, parturition, and the puerperium. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odour: A volatile emanation that is perceived by the sense of smell. [EU] Ofloxacin: An orally administered broad-spectrum quinolone antibacterial drug active against most gram-negative and gram-positive bacteria. [NIH] Ointments: Semisolid preparations used topically for protective emollient effects or as a

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vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Oligosaccharides: Carbohydrates consisting of between two and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. [NIH] Omeprazole: A highly effective inhibitor of gastric acid secretion used in the therapy of gastric ulcers and Zollinger-Ellison syndrome. The drug inhibits the H(+)-K(+)-ATPase (H(+)-K(+)-exchanging ATPase) in a pH-dependent manner. This ATPase is considered the proton pump in the secretory membrane of the parietal cell. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Orgasm: The crisis of sexual excitement in either humans or animals. [NIH] Ornithine: An amino acid produced in the urea cycle by the splitting off of urea from arginine. [NIH] Orofacial: Of or relating to the mouth and face. [EU] Orthopedics: A surgical specialty which utilizes medical, surgical, and physical methods to treat and correct deformities, diseases, and injuries to the skeletal system, its articulations, and associated structures. [NIH] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteomyelitis: Inflammation of bone caused by a pyogenic organism. It may remain localized or may spread through the bone to involve the marrow, cortex, cancellous tissue, and periosteum. [EU] Otitis: Inflammation of the ear, which may be marked by pain, fever, abnormalities of hearing, hearing loss, tinnitus, and vertigo. [EU] Otitis Media: Inflammation of the middle ear. [NIH]

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Otitis Media with Effusion: Inflammation of the middle ear with a clear pale yellowcolored transudate. [NIH] Otolaryngologist: A doctor who specializes in treating diseases of the ear, nose, and throat. Also called an ENT doctor. [NIH] Otolaryngology: A surgical specialty concerned with the study and treatment of disorders of the ear, nose, and throat. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxides: Binary compounds of oxygen containing the anion O(2-). The anion combines with metals to form alkaline oxides and non-metals to form acidic oxides. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Papillomavirus: A genus of Papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH] Papule: A small circumscribed, superficial, solid elevation of the skin. [EU] Paralysis: Loss of ability to move all or part of the body. [NIH] Paranasal Sinuses: Air-filled extensions of the respiratory part of the nasal cavity into the frontal, ethmoid, sphenoid, and maxillary cranial bones. They vary in size and form in different individuals and are lined by the ciliated mucous membranes of the nasal cavity.

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[NIH]

Paraparesis: Mild to moderate loss of bilateral lower extremity motor function, which may be a manifestation of spinal cord diseases; peripheral nervous system diseases; muscular diseases; intracranial hypertension; parasagittal brain lesions; and other conditions. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Paresis: A general term referring to a mild to moderate degree of muscular weakness, occasionally used as a synonym for paralysis (severe or complete loss of motor function). In the older literature, paresis often referred specifically to paretic neurosyphilis. "General paresis" and "general paralysis" may still carry that connotation. Bilateral lower extremity paresis is referred to as paraparesis. [NIH] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Paronychia: Inflammation involving the folds of tissue surrounding the nail. Called also perionychia. [EU] Parturition: The act or process of given birth to a child. [EU] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Pelvic: Pertaining to the pelvis. [EU] Pelvic inflammatory disease: A bacteriological disease sometimes associated with intrauterine device (IUD) usage. [NIH] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillic Acid: A mycotoxin with antibiotic and carcinogenic activity produced by various strains of Penicillium, by Aspergillus ochraceus and Aspergillus melleus. Has been found in tobacco, sausages, and corn. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Penicillin Amidase: An enzyme catalyzing the hydrolysis of penicillin to penicin and a carboxylic acid anion. EC 3.5.1.11. [NIH] Penicillin G: A penicillin derivative commonly used in the form of its sodium or potassium salts in the treatment of a variety of infections. It is effective against most gram-positive bacteria and against gram-negative cocci. It has also been used as an experimental convulsant because of its actions on GABA mediated synaptic transmission. [NIH] Penicillin Resistance: Nonsusceptibility of an organism to the action of penicillins. [NIH] Penicillin V: A broad-spectrum penicillin antibiotic used orally in the treatment of mild to moderate infections by susceptible gram-positive organisms. [NIH]

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Penicillinase: A beta-lactamase preferentially cleaving penicillins. (Dorland, 28th ed) EC 3.5.2.-. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Pepsin A: Formed from pig pepsinogen by cleavage of one peptide bond. The enzyme is a single polypeptide chain and is inhibited by methyl 2-diaazoacetamidohexanoate. It cleaves peptides preferentially at the carbonyl linkages of phenylalanine or leucine and acts as the principal digestive enzyme of gastric juice. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptic Ulcer: Ulcer that occurs in those portions of the alimentary tract which come into contact with gastric juice containing pepsin and acid. It occurs when the amount of acid and pepsin is sufficient to overcome the gastric mucosal barrier. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Chain Elongation: The process whereby an amino acid is joined through a substituted amide linkage to a chain of peptides. [NIH] Peptide Hydrolases: A subclass of enzymes from the hydrolase class that catalyze the hydrolysis of peptide bonds. Exopeptidases and endopeptidases make up the sub-subclasses for this group. EC 3.4. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perianal: Located around the anus. [EU] Pericarditis: Inflammation of the pericardium. [EU] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Pericoronitis: Inflammation of the gingiva surrounding the crown of a tooth. [NIH] Perilymph: The fluid contained within the space separating the membranous from the osseous labyrinth of the ear. [NIH] Perineum: The area between the anus and the sex organs. [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontal Pocket: An abnormal extension of a gingival sulcus accompanied by the apical migration of the epithelial attachment and bone resorption. [NIH] Periodontitis: Inflammation of the periodontal membrane; also called periodontitis simplex. [NIH]

Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH]

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Periplasm: The space between the inner and outer membranes of a cell that is shared with the cell wall. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Petechiae: Pinpoint, unraised, round red spots under the skin caused by bleeding. [NIH] Petrolatum: A colloidal system of semisolid hydrocarbons obtained from petroleum. It is used as an ointment base, topical protectant, and lubricant. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [NIH] Pharmacodynamics: The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of actions and effects of drugs with their chemical structure; also, such effects on the actions of a particular drug or drugs. [EU] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharyngitis: Inflammation of the throat. [NIH] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenolphthalein: An acid-base indicator which is colorless in acid solution, but turns pink to red as the solution becomes alkaline. It is used medicinally as a cathartic. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphoric Monoester Hydrolases: A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. EC 3.1.3. [NIH]

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Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physicochemical: Pertaining to physics and chemistry. [EU] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Picrotoxin: A noncompetitive antagonist at GABA-A receptors and thus a convulsant. Picrotoxin blocks the GABA-activated chloride ionophore. Although it is most often used as a research tool, it has been used as a CNS stimulant and an antidote in poisoning by CNS depressants, especially the barbiturates. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Pneumococcal Infections: Infections with bacteria of the species Streptococcus pneumoniae. [NIH]

Pneumococcal Vaccines: Vaccines or candidate vaccines used to prevent infections with Streptococcus pneumoniae. [NIH]

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Pneumonia: Inflammation of the lungs. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]

Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polyploid: An organism with more than two chromosome sets in its vegetative cells. [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postoperative: After surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-synaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precipitation: The act or process of precipitating. [EU] Precursor: Something that precedes. In biological processes, a substance from which

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another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Pregnancy Outcome: Results of conception and ensuing pregnancy, including live birth, stillbirth, spontaneous abortion, induced abortion. The outcome may follow natural or artificial insemination or any of the various reproduction techniques, such as embryo transfer or fertilization in vitro. [NIH] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Procaine: A local anesthetic of the ester type that has a slow onset and a short duration of action. It is mainly used for infiltration anesthesia, peripheral nerve block, and spinal block. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1016). [NIH] Proctocolitis: Inflammation of the rectum and colon. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Proenzyme: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Propantheline: A muscarinic antagonist used as an antispasmodic, in rhinitis, in urinary incontinence, and in the treatment of ulcers. At high doses it has nicotinic effects resulting in neuromuscular blocking. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Propofol: A widely used anesthetic. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all

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free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prosthesis: An artificial replacement of a part of the body. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Protein Splicing: Excision of in-frame internal protein sequences (inteins) of a precursor protein, coupled with ligation of the flanking sequences (exteins). Protein splicing is an autocatalytic reaction and results in the production of two proteins from a single primary translation product: the intein and the mature protein. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Proton Pump: Integral membrane proteins that transport protons across a membrane against a concentration gradient. This transport is driven by hydrolysis of ATP by H(+)transporting ATP synthase. [NIH] Proton Pump Inhibitors: Medicines that stop the stomach's acid pump. Examples are omeprazole (oh-MEH-prah-zol) (Prilosec) and lansoprazole (lan-SOH-prah-zol) (Prevacid). [NIH]

Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Protozoan: 1. Any individual of the protozoa; protozoon. 2. Of or pertaining to the protozoa; protozoal. [EU] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and

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treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychotomimetic: Psychosis miming. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Puerperium: Period from delivery of the placenta until return of the reproductive organs to their normal nonpregnant morphologic state. In humans, the puerperium generally lasts for six to eight weeks. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Pustular: Pertaining to or of the nature of a pustule; consisting of pustules (= a visible collection of pus within or beneath the epidermis). [EU] Pyelitis: Inflammation of the pelvis of the kidney. It is attended by pain and tenderness in the loins, irritability of the bladder, remittent fever, bloody or purulent urine, diarrhoea, vomiting, and a peculiar pain on flexion of the thigh. [EU] Pyelonephritis: Inflammation of the kidney and its pelvis, beginning in the interstitium and rapidly extending to involve the tubules, glomeruli, and blood vessels; due to bacterial infection. [EU] Pyogenic: Producing pus; pyopoietic (= liquid inflammation product made up of cells and a thin fluid called liquor puris). [EU] Pyrazinamide: A pyrazine that is used therapeutically as an antitubercular agent. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Pyrogenic: Inducing fever. [EU] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Racemic: Optically inactive but resolvable in the way of all racemic compounds. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the

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waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recur: To occur again. Recurrence is the return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regulon: In eukaryotes, a genetic unit consisting of a noncontiguous group of genes under the control of a single regulator gene. In bacteria, regulons are global regulatory systems

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involved in the interplay of pleiotropic regulatory domains. These regulatory systems consist of several operons. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Relaxant: 1. Lessening or reducing tension. 2. An agent that lessens tension. [EU] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Repopulation: The replacement of functional cells, usually by proliferation, following or during irradiation. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Reproduction Techniques: Methods pertaining to the generation of new individuals. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Reticulocytes: Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic "reticulum" (not the same as the endoplasmic reticulum), hence the name reticulocytes. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Ribonucleoside Diphosphate Reductase: An enzyme of the oxidoreductase class that catalyzes the formation of 2'-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. (From Dorland, 27th ed) EC 1.17.4.1. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Ristocetin: An antibiotic mixture of two components, A and B, obtained from Nocardia lurida (or the same substance produced by any other means). It is no longer used clinically because of its toxicity. It causes platelet agglutination and blood coagulation and is used to

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assay those functions in vitro. [NIH] Rod: A reception for vision, located in the retina. [NIH] Root Planing: A procedure for smoothing of the roughened root surface or cementum of a tooth after subgingival curettage or scaling, as part of periodontal therapy. [NIH] Rubber: A high-molecular-weight polymeric elastomer derived from the milk juice (latex) of Hevea brasiliensis and other trees. It is a substance that can be stretched at room temperature to atleast twice its original length and after releasing the stress, retractrapidly, and recover its original dimensions fully. Synthetic rubber is made from many different chemicals, including styrene, acrylonitrile, ethylene, propylene, and isoprene. [NIH] Ruminants: A suborder of the order Artiodactyla whose members have the distinguishing feature of a four-chambered stomach. Horns or antlers are usually present, at least in males. [NIH]

Rye: A hardy grain crop, Secale cereale, grown in northern climates. It is the most frequent host to ergot (claviceps), the toxic fungus. Its hybrid with wheat is triticale, another grain. [NIH]

Saccharomyces: A genus of ascomycetous fungi of the family Saccharomycetaceae, order saccharomycetales. [NIH] Saccharomyces cerevisiae: A species of the genus Saccharomyces, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement. [NIH] Saccharomycetales: An order of fungi in the phylum Ascomycota that multiply by budding. They include the telomorphic ascomycetous yeasts which are found in a very wide range of habitats. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Scarlet Fever: Infection with group A streptococci that is characterized by tonsillitis and pharyngitis. An erythematous rash is commonly present. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Schwannoma: A tumor of the peripheral nervous system that begins in the nerve sheath (protective covering). It is almost always benign, but rare malignant schwannomas have been reported. [NIH]

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Scleroderma: A chronic disorder marked by hardening and thickening of the skin. Scleroderma can be localized or it can affect the entire body (systemic). [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [NIH] Sebaceous gland: Gland that secretes sebum. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Septicaemia: A term originally used to denote a putrefactive process in the body, but now usually referring to infection with pyogenic micro-organisms; a genus of Diptera; the severe type of infection in which the blood stream is invaded by large numbers of the causal. [NIH] Septicemia: Systemic disease associated with the presence and persistence of pathogenic microorganisms or their toxins in the blood. Called also blood poisoning. [EU] Sequela: Any lesion or affection following or caused by an attack of disease. [EU] Sequence Analysis: A multistage process that includes the determination of a sequence (protein, carbohydrate, etc.), its fragmentation and analysis, and the interpretation of the resulting sequence information. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system,

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gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serotypes: A cause of haemorrhagic septicaemia (in cattle, sheep and pigs), fowl cholera of birds, pasteurellosis of rabbits, and gangrenous mastitis of ewes. It is also commonly found in atrophic rhinitis of pigs. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sexually Transmitted Diseases: Diseases due to or propagated by sexual contact. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Sigma Factor: A protein which is a subunit of RNA polymerase. It effects initiation of specific RNA chains from DNA. [NIH] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Silymarin: A mixture of flavonoids extracted from seeds of the milk thistle, Silybum marianum. It consists primarily of three isomers: silicristin, silidianin, and silybin, its major component. Silymarin displays antioxidant and membrane stabilizing activity. It protects various tissues and organs against chemical injury, and shows potential as an antihepatoxic agent. [NIH] Sinusitis: An inflammatory process of the mucous membranes of the paranasal sinuses that occurs in three stages: acute, subacute, and chronic. Sinusitis results from any condition causing ostial obstruction or from pathophysiologic changes in the mucociliary transport mechanism. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin test: A test for an immune response to a compound by placing it on or under the skin.

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[NIH]

Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Sodium Bicarbonate: A white, crystalline powder that is commonly used as a pH buffering agent, an electrolyte replenisher, systemic alkalizer and in topical cleansing solutions. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Spatial disorientation: Loss of orientation in space where person does not know which way is up. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectroscopic: The recognition of elements through their emission spectra. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spirochete: Lyme disease. [NIH] Spontaneous Abortion: The non-induced birth of an embryo or of fetus prior to the stage of viability at about 20 weeks of gestation. [NIH] Spores: The reproductive elements of lower organisms, such as protozoa, fungi, and cryptogamic plants. [NIH]

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Staphylococcal Infections: Infections with bacteria of the genus Staphylococcus. [NIH] Staphylococcal Scalded Skin Syndrome: A disease of infants due to group 2 phage type 17 staphylococci that produce an epidermolytic exotoxin. Superficial fine vesicles and bullae form and rupture easily, resulting in loss of large sheets of epidermis. [NIH] Staphylococcus: A genus of gram-positive, facultatively anaerobic, coccoid bacteria. Its organisms occur singly, in pairs, and in tetrads and characteristically divide in more than one plane to form irregular clusters. Natural populations of Staphylococcus are membranes of warm-blooded animals. Some species are opportunistic pathogens of humans and animals. [NIH] Staphylococcus aureus: Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications. [NIH] Steady state: Dynamic equilibrium. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem cell transplantation: A method of replacing immature blood-forming cells that were destroyed by cancer treatment. The stem cells are given to the person after treatment to help the bone marrow recover and continue producing healthy blood cells. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Streptococcal: Caused by infection due to any species of streptococcus. [NIH] Streptococcal Infections: Infections with bacteria of the genus Streptococcus. [NIH] Streptococci: A genus of spherical Gram-positive bacteria occurring in chains or pairs. They are widely distributed in nature, being important pathogens but often found as normal commensals in the mouth, skin, and intestine of humans and other animals. [NIH] Streptococcus: A genus of gram-positive, coccoid bacteria whose organisms occur in pairs

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or chains. No endospores are produced. Many species exist as commensals or parasites on man or animals with some being highly pathogenic. A few species are saprophytes and occur in the natural environment. [NIH] Streptococcus pneumoniae: A gram-positive organism found in the upper respiratory tract, inflammatory exudates, and various body fluids of normal and/or diseased humans and, rarely, domestic animals. [NIH] Streptomycin: O-2-Deoxy-2-(methylamino)-alpha-L-glucopyranosyl-(1-2)-O-5- deoxy-3-Cformyl-alpha-L-lyxofuranosyl-(1-4)-N,N'-bis(aminoiminomethyl)-D-streptamine. Antibiotic substance produced by the soil actinomycete Streptomyces griseus. It acts by inhibiting the initiation and elongation processes during protein synthesis. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Styrene: A colorless, toxic liquid with a strong aromatic odor. It is used to make rubbers, polymers and copolymers, and polystyrene plastics. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subcutaneous Emphysema: Presence of air or gas in the subcutaneous tissues of the body. [NIH]

Submandibular: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. [NIH] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] Sulbactam: A beta-lactamase inhibitor with very weak antibacterial action. The compound prevents antibiotic destruction of beta-lactam antibiotics by inhibiting beta-lactamases, thus extending their spectrum activity. Combinations of sulbactam with beta-lactam antibiotics have been used successfully for the therapy of infections caused by organisms resistant to the antibiotic alone. [NIH] Sulfates: Inorganic salts of sulfuric acid. [NIH] Sulfisoxazole: One of the antibacterial sulfonamides generally used for treatment of infections. It is bacteriostatic against a wide range of gram- negative and gram-positive

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organisms, but acquired resistance is common. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Sulfuric acid: A strong acid that, when concentrated is extemely corrosive to the skin and mucous membranes. It is used in making fertilizers, dyes, electroplating, and industrial explosives. [NIH] Superantigens: Microbial antigens that have in common an extremely potent activating effect on T-cells that bear a specific variable region. Superantigens cross-link the variable region with class II MHC proteins regardless of the peptide binding in the T-cell receptor's pocket. The result is a transient expansion and subsequent death and anergy of the T-cells with the appropriate variable regions. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH] Suppositories: A small cone-shaped medicament having cocoa butter or gelatin at its basis and usually intended for the treatment of local conditions in the rectum. [NIH] Suppository: A medicated mass adapted for introduction into the rectal, vaginal, or urethral orifice of the body, suppository bases are solid at room temperature but melt or dissolve at body temperature. Commonly used bases are cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. [EU] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]

Suspensions: Colloids with liquid continuous phase and solid dispersed phase; the term is used loosely also for solid-in-gas (aerosol) and other colloidal systems; water-insoluble drugs may be given as suspensions. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU]

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Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Syphilis: A contagious venereal disease caused by the spirochete Treponema pallidum. [NIH]

Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Tachypnea: Rapid breathing. [NIH] Tear Gases: Gases that irritate the eyes, throat, or skin. Severe lacrimation develops upon irritation of the eyes. [NIH] Teichoic Acids: Bacterial polysaccharides that are rich in phosphodiester linkages. They are the major components of the cell walls and membranes of many bacteria. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Tetanus: A disease caused by tetanospasmin, a powerful protein toxin produced by Clostridium tetani. Tetanus usually occurs after an acute injury, such as a puncture wound or laceration. Generalized tetanus, the most common form, is characterized by tetanic muscular contractions and hyperreflexia. Localized tetanus presents itself as a mild condition with manifestations restricted to muscles near the wound. It may progress to the generalized form. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Tetracycline Resistance: Nonsusceptibility of a microbe (usually a bacterium) to the action of tetracycline, which binds to the 30S ribosomal subunit and prevents the normal binding of aminoacyl-tRNA. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin.

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(Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thrush: A disease due to infection with species of fungi of the genus Candida. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Ticks: Blood-sucking arachnids of the order Acarina. [NIH] Tinnitus: Sounds that are perceived in the absence of any external noise source which may take the form of buzzing, ringing, clicking, pulsations, and other noises. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tissue Preservation: The process by which a tissue or aggregate of cells is kept alive outside of the organism from which it was derived (i.e., kept from decay by means of a chemical agent, cooling, or a fluid substitute that mimics the natural state within the organism). [NIH] Tobramycin: An aminoglycoside, broad-spectrum antibiotic produced by Streptomyces tenebrarius. It is effective against gram-negative bacteria, especially the Pseudomonas species. It is a 10% component of the antibiotic complex, nebramycin, produced by the same species. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU] Tonsillitis: Inflammation of the tonsils, especially the palatine tonsils. It is often caused by a bacterium. Tonsillitis may be acute, chronic, or recurrent. [NIH] Tonsils: Small masses of lymphoid tissue on either side of the throat. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures

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preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicokinetics: Study of the absorption, distribution, metabolism, and excretion of test substances. [NIH] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Toxoid: The material resulting from the treatment of toxin in such a way that the toxic properties are inactivated whilst the antigenic potency remains intact. [NIH] Toxoplasmosis: The acquired form of infection by Toxoplasma gondii in animals and man. [NIH]

Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH]

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Treatment Failure: A measure of the quality of health care by assessment of unsuccessful results of management and procedures used in combating disease, in individual cases or series. [NIH] Trees: Woody, usually tall, perennial higher plants (Angiosperms, Gymnosperms, and some Pterophyta) having usually a main stem and numerous branches. [NIH] Trichomoniasis: An infection with the protozoan parasite Trichomonas vaginalis. [NIH] Trimethoprim-sulfamethoxazole: An antibiotic drug used to treat infection and prevent pneumocystis carinii pneumonia. [NIH] Trismus: Spasmodic contraction of the masseter muscle resulting in forceful jaw closure. This may be seen with a variety of diseases, including tetanus, as a complication of radiation therapy, trauma, or in association with neoplastic conditions. [NIH] Trivalent: Having a valence of three. [EU] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tungsten: A metallic element with the atomic symbol W, atomic number 74, and atomic weight 183.85. It is used in many manufacturing applications, including increasing the hardness, toughness, and tensile strength of steel; manufacture of filaments for incandescent light bulbs; and in contact points for automotive and electrical apparatus. [NIH] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]

Tylosin: Macrolide antibiotic obtained from cultures of Streptomyces fradiae. The drug is effective against many microorganisms in animals but not in humans. [NIH] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Tyrothricin: A polypeptide antibiotic mixture obtained from Bacillus brevis. It consists of a mixture of three tyrocidines (60%) and several gramicidins (20%) and is very toxic to blood, liver, kidneys, meninges, and the olfactory apparatus. It is used topically. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ultrafiltration: The separation of particles from a suspension by passage through a filter with very fine pores. In ultrafiltration the separation is accomplished by convective transport; in dialysis separation relies instead upon differential diffusion. Ultrafiltration occurs naturally and is a laboratory procedure. Artificial ultrafiltration of the blood is referred to as hemofiltration or hemodiafiltration (if combined with hemodialysis). [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH]

Dictionary 271

Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urethritis: Inflammation of the urethra. [EU] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [NIH]

Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Urticaria: A vascular reaction of the skin characterized by erythema and wheal formation due to localized increase of vascular permeability. The causative mechanism may be allergy, infection, or stress. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Vaginal Discharge: A common gynecologic disorder characterized by an abnormal, nonbloody discharge from the genital tract. [NIH] Vaginitis: Inflammation of the vagina characterized by pain and a purulent discharge. [NIH] Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]

Vanadium: Vanadium. A metallic element with the atomic symbol V, atomic number 23, and atomic weight 50.94. It is used in the manufacture of vanadium steel. Prolonged exposure can lead to chronic intoxication caused by absorption usually via the lungs. [NIH] Vancomycin: Antibacterial obtained from Streptomyces orientalis. It is a glycopeptide related to ristocetin that inhibits bacterial cell wall assembly and is toxic to kidneys and the inner ear. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] VE: The total volume of gas either inspired or expired in one minute. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vegetative: 1. Concerned with growth and with nutrition. 2. Functioning involuntarily or unconsciously, as the vegetative nervous system. 3. Resting; denoting the portion of a cell

272 Penicillin

cycle during which the cell is not involved in replication. 4. Of, pertaining to, or characteristic of plants. [EU] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venereal: Pertaining or related to or transmitted by sexual contact. [EU] Venous: Of or pertaining to the veins. [EU] Ventricles: Fluid-filled cavities in the heart or brain. [NIH] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertigo: An illusion of movement; a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjective vertigo). The term is sometimes erroneously used to mean any form of dizziness. [EU] Vestibular: Pertaining to or toward a vestibule. In dental anatomy, used to refer to the tooth surface directed toward the vestibule of the mouth. [EU] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Vestibulocochlear Nerve: The 8th cranial nerve. The vestibulocochlear nerve has a cochlear part (cochlear nerve) which is concerned with hearing and a vestibular part (vestibular nerve) which mediates the sense of balance and head position. The fibers of the cochlear nerve originate from neurons of the spiral ganglion and project to the cochlear nuclei (cochlear nucleus). The fibers of the vestibular nerve arise from neurons of Scarpa's ganglion and project to the vestibular nuclei. [NIH] Vestibulocochlear Nerve Diseases: Diseases of the vestibular and/or cochlear (acoustic) nerves, which join to form the vestibulocochlear nerve. Vestibular neuritis, cochlear neuritis, and acoustic neuromas are relatively common conditions that affect these nerves. Clinical manifestations vary with which nerve is primarily affected, and include hearing loss, vertigo, and tinnitus. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vibrio: A genus of Vibrionaceae, made up of short, slightly curved, motile, gram-negative rods. Various species produce cholera and other gastrointestinal disorders as well as abortion in sheep and cattle. [NIH] Vibrio cholerae: The etiologic agent of cholera. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virulent: A virus or bacteriophage capable only of lytic growth, as opposed to temperate phages establishing the lysogenic response. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH]

Dictionary 273

War: Hostile conflict between organized groups of people. [NIH] Warts: Benign epidermal proliferations or tumors; some are viral in origin. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Wound Infection: Invasion of the site of trauma by pathogenic microorganisms. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] Xerostomia: Decreased salivary flow. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

275

INDEX A Abdominal, 199, 241, 249 Abdominal Pain, 199, 241 Aberrant, 24, 199 Abortion, 199, 255, 272 Abscess, 6, 68, 92, 160, 199 Acatalasia, 199, 210 Acceptor, 199, 249 ACE, 28, 199 Acetylcholine, 199, 246 Acetylgalactosamine, 199, 230 Acetylglucosamine, 28, 199, 230 Acidity, 199, 252 Acoustic, 8, 199, 272 Acquired Immunodeficiency Syndrome, 162, 199 Acremonium, 68, 128, 136, 147, 199, 211 Acrylonitrile, 199, 260 Acute renal, 7, 154, 200, 233 Acyl, 17, 48, 95, 124, 127, 128, 133, 200 Acylation, 33, 122, 126, 131, 132, 200 Adaptability, 200, 211 Adaptation, 43, 200 Adduct, 126, 200 Adenine, 129, 200, 257 Adenosine, 200, 253 Adipose Tissue, 200, 221 Adjustment, 153, 200 Adjuvant, 200, 228 Adrenal Medulla, 200, 223, 224, 247 Adrenergic, 200, 221, 224, 242, 266 Adsorption, 123, 200 Adsorptive, 200 Adverse Effect, 160, 200, 262 Aerobic, 16, 25, 64, 200, 210, 211, 235, 245 Aerosol, 200, 266 Affinity, 11, 13, 32, 34, 36, 40, 43, 60, 66, 104, 130, 142, 151, 200, 201, 240, 263 Agar, 201, 217, 253 Age of Onset, 201, 270 Agonist, 201, 221, 242 Alanine, 17, 29, 35, 43, 145, 201 Albumin, 150, 201, 253 Algorithms, 201, 207 Alimentary, 201, 250, 251 Alkaline, 201, 202, 209, 249, 252 Alkaloid, 201, 207, 244 Allergen, 201, 219, 261

Allergic Rhinitis, 142, 201, 231 Allylamine, 201, 202 Alpha Particles, 201, 258 Alternative medicine, 171, 201 Alveoli, 202, 219 Amber, 202, 236 Amebiasis, 202, 243 Amine, 131, 202, 233 Amino Acid Sequence, 18, 116, 127, 128, 202, 204, 216, 229 Amino Acid Substitution, 18, 55, 74, 145, 202 Ammonia, 202, 230, 270 Amphetamine, 96, 202, 219 Ampicillin, 8, 40, 55, 56, 58, 62, 65, 74, 94, 96, 107, 116, 127, 131, 132, 138, 147, 148, 149, 202 Ampicillin Resistance, 40, 62, 149, 202 Amplification, 44, 202 Amyloid, 202 Anaerobic, 16, 203, 210, 211, 231, 235, 264 Anaesthesia, 69, 83, 203, 236 Anal, 203, 227, 244 Analgesic, 203, 214, 244 Analog, 203, 214 Analogous, 49, 203, 221, 269 Anaphylatoxins, 203, 215 Anaphylaxis, 69, 160, 170, 203 Anemia, 73, 112, 203, 241 Anergy, 203, 266 Anesthesia, 160, 203, 217, 222, 223, 255 Anesthetics, 39, 203, 206, 224 Angioedema, 142, 203 Animal model, 36, 42, 165, 203 Anions, 42, 201, 203, 238, 266 Annealing, 203, 254 Anode, 203 Anthrax, 18, 52, 170, 186, 187, 203 Antibacterial, 22, 34, 47, 57, 61, 93, 101, 117, 123, 126, 136, 137, 140, 162, 204, 210, 214, 235, 244, 247, 263, 265, 271 Antibiotic Prophylaxis, 8, 16, 36, 204 Antibodies, 26, 27, 51, 73, 77, 165, 204, 231, 235, 240, 244, 253 Anticoagulant, 204, 256 Antidote, 204, 253 Antifungals, 162, 204

276 Penicillin

Antigen, 25, 142, 200, 203, 204, 215, 233, 234, 235, 236, 261 Antigen-Antibody Complex, 204, 215 Antihypertensive, 153, 204, 242 Anti-infective, 204, 234, 246 Anti-inflammatory, 10, 12, 204, 205, 219, 229, 255 Anti-Inflammatory Agents, 204, 205 Antimetabolite, 204, 242 Antineoplastic, 204, 221, 234, 242, 243 Antioxidant, 118, 204, 228, 249, 262 Antispasmodic, 204, 255 Anus, 203, 204, 208, 215, 251, 258 Apoptosis, 204, 218 Aqueous, 116, 122, 126, 130, 133, 144, 148, 205, 206, 218, 223, 234, 239, 240 Archaea, 205, 243 Arginine, 203, 205, 248, 270 Aromatic, 127, 205, 209, 252, 265 Arterial, 201, 205, 235, 256, 267 Arteries, 205, 208, 217, 243 Arterioles, 205, 208, 209 Aseptic, 205, 248, 264 Aspirin, 159, 163, 205 Assay, 11, 32, 33, 48, 66, 95, 102, 105, 141, 149, 205, 260 Astringents, 205, 242 Asymptomatic, 15, 199, 202, 205 Atmospheric Pressure, 205, 234 Atopic, 142, 205 Attenuation, 36, 205 Auditory, 8, 100, 205 Auscultation, 205, 232 Autolysis, 20, 22, 54, 63, 205 Azithromycin, 4, 56, 61, 66, 68, 70, 72, 76, 87, 205 B Bacillus, 18, 29, 35, 43, 48, 52, 54, 55, 60, 66, 70, 102, 203, 205, 270 Bacteremia, 16, 45, 84, 87, 88, 205 Bacterial Infections, 31, 35, 123, 133, 206, 239 Bacterial Physiology, 200, 206 Bactericidal, 4, 42, 49, 55, 56, 70, 120, 206, 225 Bacteriophage, 49, 206, 253, 269, 272 Bacteriostatic, 206, 225, 265 Bacterium, 22, 33, 52, 134, 163, 206, 221, 233, 267, 268 Barbiturate, 39, 206 Basal Ganglia, 206, 213 Basal Ganglia Diseases, 206, 213

Base, 15, 38, 80, 120, 129, 133, 135, 174, 200, 206, 218, 219, 229, 238, 252, 254, 267 Basophils, 142, 206, 231, 239 Benign, 10, 206, 231, 246, 260, 273 Benzene, 206 Benzodiazepines, 39, 206 Beta-Lactam Resistance, 13, 33, 74, 120, 206 Beta-Lactamases, 17, 21, 28, 47, 55, 100, 104, 140, 206, 210, 211, 212, 235, 265 Bicuculline, 39, 207 Bilateral, 8, 207, 250 Bile, 15, 207, 228, 234, 238, 240, 264 Bile Acids, 207, 264 Bile Acids and Salts, 207 Bile Pigments, 207, 238 Bilirubin, 201, 207, 234 Binding Sites, 17, 29, 39, 207 Bioassays, 150, 207 Bioavailability, 137, 154, 207 Biochemical, 18, 20, 28, 29, 31, 33, 34, 42, 48, 55, 102, 122, 134, 182, 204, 207, 239, 252, 261 Biofilms, 13, 22, 25, 207 Biological therapy, 207, 231 Biopsy, 7, 207, 225 Biopsy specimen, 7, 207 Biotechnology, 47, 54, 68, 71, 93, 95, 119, 121, 144, 146, 156, 157, 171, 181, 207 Bioterrorism, 18, 208 Biotransformation, 208 Bladder, 7, 208, 216, 218, 236, 257, 270, 271 Bloating, 208, 241 Blood Glucose, 208, 232, 237 Blood pressure, 204, 208, 235, 244, 263 Blood vessel, 199, 208, 210, 212, 226, 229, 233, 240, 251, 257, 263, 265, 268, 271 Blood Volume, 208, 210 Body Fluids, 208, 263, 265 Bone Marrow, 95, 104, 206, 208, 218, 229, 235, 240, 244, 263, 264 Bowel, 203, 208, 220, 224, 236, 238 Bowel Movement, 208, 220 Bradykinin, 208, 253 Branch, 195, 208, 240, 250, 257, 263, 267 Breakdown, 208, 220, 228 Breeding, 129, 140, 208 Broad Ligament, 208, 226 Broad-spectrum, 202, 208, 210, 211, 247, 250, 268 Bronchi, 208, 224, 269 Bronchitis, 30, 208

Index 277

Buccal, 124, 209 Buccal mucosa, 124, 209 C Calcium, 209, 215, 239, 262 Candidiasis, 9, 209 Candidosis, 209 Capillary, 30, 37, 43, 208, 209, 272 Capsular, 26, 27, 36, 42, 47, 51, 57, 73, 209 Capsules, 209, 221, 228 Carbapenems, 19, 86, 209 Carbohydrate, 15, 209, 230, 254, 261 Carboxy, 209 Carboxylic Acids, 35, 209 Carboxypeptidases, 17, 102, 209 Carcinogen, 200, 209, 243, 245 Carcinogenesis, 155, 158, 209 Carcinogenic, 137, 206, 209, 237, 250, 255, 264 Carcinoma, 209 Cardiac, 201, 209, 210, 223, 224, 228, 232, 245, 264 Cardiomegaly, 163, 210 Cardiovascular, 8, 154, 163, 202, 210, 262 Cardiovascular Agents, 154, 210 Cardiovascular System, 163, 210 Carrier Proteins, 210, 253 Case report, 6, 8, 9, 85, 182, 186, 210, 214 Case series, 210, 214 Catalase, 139, 199, 210 Catastrophic Illness, 20, 210 Cathode, 203, 210 Cations, 39, 42, 55, 210, 238 Caudal, 210, 254 Cause of Death, 32, 36, 210 Caustic, 133, 210 Cefaclor, 55, 58, 74, 138, 210 Cefadroxil, 127, 138, 145, 210 Cefixime, 55, 79, 117, 210 Cefotaxime, 55, 58, 59, 61, 62, 64, 210 Cefotetan, 73, 210 Ceftazidime, 99, 210 Ceftizoxime, 100, 210 Ceftriaxone, 58, 59, 61, 66, 71, 73, 88, 111, 211 Cefuroxime, 58, 61, 66, 69, 74, 78, 104, 139, 211 Cell Death, 49, 204, 211 Cell Differentiation, 211, 262 Cell Division, 45, 206, 211, 231, 243, 253, 261 Cell proliferation, 24, 162, 211, 262 Cell Size, 24, 211

Cell Survival, 211, 231 Cell Transplantation, 21, 211 Cellulitis, 160, 162, 211 Cellulose, 211, 228, 253 Central Nervous System, 21, 111, 163, 199, 201, 202, 206, 211, 219, 228, 230, 231, 244, 261 Cephalexin, 4, 127, 131, 138, 210, 211 Cephaloridine, 210, 211 Cephalothin, 70, 211 Cephamycins, 118, 121, 146, 211 Cephapirin, 147, 212 Cephradine, 131, 212 Cerebellar, 150, 212 Cerebellum, 212 Cerebral, 71, 100, 206, 212, 217, 224, 241 Cerebrospinal, 57, 65, 212, 245 Cerebrospinal fluid, 57, 212, 245 Cervical, 183, 212 Cervix, 199, 212, 227 Character, 37, 212, 218 Chelating Agents, 105, 212 Chelation, 123, 212 Chemical Warfare, 212, 218 Chemical Warfare Agents, 212, 218 Chemotactic Factors, 212, 215 Chin, 212, 242 Chloral Hydrate, 212 Chloralose, 101, 212 Chloroform, 42, 213 Chlorophyll, 212, 213, 228 Cholecystectomy, 7, 213 Cholecystitis, 7, 213 Cholera, 166, 213, 262, 272 Cholesterol, 207, 213, 240, 264 Chorea, 163, 213 Chromatin, 205, 213, 224, 246 Chromosomal, 25, 43, 116, 118, 202, 213, 253 Chromosome, 24, 45, 213, 231, 240, 254, 261 Chronic renal, 213, 228 Cilastatin, 92, 95, 213, 235 Ciprofloxacin, 48, 69, 99, 213 CIS, 24, 49, 60, 213 Clarithromycin, 5, 59, 62, 72, 92, 161, 213 Claviceps, 213, 260 Clavulanic Acid, 19, 28, 78, 214 Cleave, 17, 214 Clindamycin, 4, 6, 10, 61, 78, 161, 162, 214 Clinical Medicine, 214, 255 Clinical study, 16, 50, 214

278 Penicillin

Clinical trial, 11, 12, 38, 50, 111, 112, 181, 214, 218, 258 Clone, 34, 53, 58, 59, 74, 75, 214 Cloning, 23, 33, 44, 46, 56, 120, 207, 214, 239 Coagulation, 209, 214, 253, 259, 268 Cochlear, 214, 268, 272 Cochlear Diseases, 214, 268 Cod Liver Oil, 214, 223 Codeine, 96, 214 Codons, 214, 229, 248 Coenzymes, 214, 224 Cofactor, 214, 256, 268 Coliphages, 206, 214 Colitis, 214, 236 Collagen, 202, 214, 227, 228, 255 Collapse, 203, 208, 215 Colloidal, 201, 215, 222, 252, 266 Colon, 214, 215, 236, 239, 255 Combination Therapy, 10, 215 Combinatorial, 20, 23, 215 Commensal, 13, 53, 76, 215 Complement, 28, 50, 203, 215, 229, 244, 253, 261 Complementary and alternative medicine, 99, 108, 215 Complementary medicine, 99, 215 Complementation, 42, 57, 149, 216 Compliance, 5, 139, 216 Computational Biology, 181, 216 Computed tomography, 7, 71, 100, 216 Computerized tomography, 216 Conception, 199, 216, 255, 264 Concomitant, 93, 216 Congestion, 216, 225 Congestive heart failure, 163, 216 Conjunctiva, 216, 237 Connective Tissue, 6, 208, 211, 214, 216, 219, 228, 240 Connective Tissue Cells, 216 Consciousness, 203, 216, 218, 220, 257 Consensus Sequence, 216 Conserved Sequence, 16, 216 Consumption, 216, 219, 247, 259 Contamination, 36, 149, 216, 233 Continuum, 21, 217 Contracture, 217, 240 Contraindications, ii, 217 Convulsions, 206, 207, 217 Coordination, 212, 217 Coronary, 217, 243 Coronary Thrombosis, 217, 243

Cortex, 35, 110, 217, 225, 248, 255 Cortical, 100, 109, 217, 226 Corticosteroids, 10, 12, 217, 229, 255 Cortisol, 201, 217 Cortisone, 217, 219, 255 Craniocerebral Trauma, 206, 217, 231, 268 Crossing-over, 217, 258 Cryptosporidiosis, 205, 217 Crystallization, 33, 46, 93, 125, 148, 149, 217 Culture Media, 150, 201, 217 Curare, 217, 245 Curative, 21, 218, 267 Curettage, 218, 260 Cutaneous, 10, 75, 106, 142, 204, 209, 218, 238 Cyclin, 24, 218 Cyclosporine, 23, 218 Cysteinyl, 118, 121, 125, 143, 146, 218 Cystitis, 7, 218 Cytokine, 142, 218 Cytokinesis, 45, 218 Cytoplasm, 25, 150, 205, 206, 218, 224, 244, 246, 259 Cytosine, 129, 218, 257 Cytotoxic, 15, 149, 218, 262 Cytotoxicity, 15, 201, 218 D Daunorubicin, 218, 221 Decarboxylation, 218, 233, 242 Decision Making, 5, 30, 218 Decontamination, 29, 43, 218 Degenerative, 218, 233 Dehydration, 35, 213, 218 Deletion, 33, 42, 205, 218 Dementia, 135, 199, 218, 246 Denaturation, 218, 254 Dendrites, 218, 246 Density, 92, 141, 219, 240, 248, 254 Dental Care, 159, 219 Dental Caries, 219 Dental Materials, 159, 219 Dental Plaque, 45, 53, 219 Dental Records, 8, 219 Dentists, 5, 9, 160, 219 Dentition, 6, 219 Depolarization, 219, 262 Dermatitis, 9, 10, 142, 219 Dermatology, 82, 83, 86, 101, 219 Dermis, 203, 219, 243 Desensitization, 39, 88, 219 Detergents, 15, 219

Index 279

Deuterium, 219, 234 Developing Countries, 38, 219 Dexamethasone, 11, 219 Dextroamphetamine, 202, 219 Diabetes Mellitus, 8, 220, 230, 232 Diagnostic procedure, 4, 115, 171, 220 Diarrhea, 161, 202, 217, 220, 241 Diarrhoea, 220, 257 Diastolic, 220, 235 Dietary Proteins, 135, 220 Digestion, 201, 207, 208, 220, 222, 238, 240, 251, 264 Digestive system, 113, 220, 228 Digestive tract, 220, 263 Dilatation, 199, 203, 220, 255 Dimerization, 16, 220 Diploid, 216, 220, 253 Direct, iii, 14, 39, 46, 50, 58, 173, 214, 220, 221, 229, 234, 258 Disaccharides, 130, 220 Discrimination, 160, 220 Disease Progression, 165, 220 Disinfectant, 220, 225 Dissociation, 200, 220 Distal, 142, 220, 256 Dizziness, 160, 220, 272 Domesticated, 221, 231 Dominance, 103, 221 Dopamine, 202, 220, 221, 244, 246, 252 Dormancy, 29, 43, 221 Dorsal, 221, 254 Dosage Forms, 139, 221 Dosimetry, 154, 221 Doxorubicin, 93, 221 Doxycycline, 10, 23, 48, 57, 170, 187, 221 Drug Design, 31, 37, 175, 221 Drug Interactions, 160, 174, 221 Drug Monitoring, 154, 221 Drug Residues, 117, 221 Drug Resistance, 18, 41, 57, 103, 221, 222 Drug Tolerance, 221, 222, 268 Duodenum, 207, 222, 264 Dura mater, 222, 242, 249 Dyes, 203, 206, 222, 246, 266 Dyspepsia, 27, 222 E Ectopic, 15, 222 Ectopic Pregnancy, 15, 222 Edema, 203, 222, 228, 238, 239, 245 Effector, 199, 215, 222 Efficacy, 4, 5, 12, 15, 30, 50, 51, 56, 58, 59, 61, 75, 137, 166, 210, 221, 222, 235

Elastic, 222, 266 Electroacupuncture, 100, 222 Electrolysis, 203, 210, 222 Electrolyte, 163, 222, 232, 254, 263 Electrophoresis, 30, 43, 222 Electroplating, 222, 266 Emaciation, 199, 222 Embryo, 199, 211, 222, 236, 255, 263 Embryo Transfer, 222, 255 Emollient, 222, 230, 247 Emphysema, 7, 223 Empiric, 4, 223 Empirical, 41, 137, 223 Empyema, 57, 73, 223 Emulsion, 119, 223, 227 Encapsulated, 28, 223 Encephalopathy, 8, 223 Endemic, 213, 223, 241 Endocarditis, 5, 8, 45, 58, 60, 70, 74, 76, 79, 90, 209, 223 Endocardium, 223 Endocrine Glands, 223 Endogenous, 22, 221, 223, 249 Endorphins, 223, 246 Endoscopy, 27, 223 Endotoxin, 28, 99, 223 End-stage renal, 153, 213, 223 Enflurane, 101, 223 Enkephalins, 223, 246 Enteritis, 183, 224 Enterocolitis, 224 Environmental Exposure, 224 Environmental Health, 96, 180, 182, 224 Environmental Monitoring, 37, 224 Enzyme Activation, 16, 224 Enzyme Inhibitors, 224, 253 Eosinophilia, 224, 226 Eosinophils, 142, 224, 231, 239 Epidemic, 10, 63, 166, 224 Epidemiological, 84, 224 Epidermis, 219, 224, 257, 264 Epinephrine, 93, 200, 221, 224, 246, 247, 270 Epithelial, 28, 224, 233, 251 Epithelial Cells, 28, 224, 233 Epitope, 51, 224 Ergot, 225, 260 Erysipelas, 63, 81, 162, 225 Erythema, 10, 72, 87, 106, 163, 225, 271 Erythema Chronicum Migrans, 10, 225 Erythrasma, 162, 225 Erythroblasts, 21, 225

280 Penicillin

Erythrocytes, 203, 208, 225, 258, 259, 261 Erythroid Progenitor Cells, 225 Erythromycin, 3, 6, 9, 55, 58, 61, 62, 66, 79, 107, 116, 120, 161, 205, 213, 225 Erythropoiesis, 225 Esophagus, 220, 225, 228, 252, 264 Estradiol, 11, 225 Estrogen, 11, 182, 225 Ethanol, 149, 225, 226 Eukaryotic Cells, 45, 150, 225, 248 Excisional, 58, 225 Excitation, 225, 246 Excitatory, 226, 230 Exhaustion, 226, 241 Exogenous, 13, 134, 135, 200, 208, 223, 226, 270 Exotoxin, 46, 61, 78, 162, 226, 264 Extensor, 226, 256 Extracellular, 20, 39, 100, 142, 202, 207, 216, 226, 227, 263 Extracellular Matrix, 216, 226, 227 Extraction, 16, 42, 105, 119, 122, 148, 226 Extremity, 226, 250 Exudate, 226, 231 F Fallopian tube, 15, 226 Family Planning, 181, 226 Fasciitis, 7, 161, 226 Fat, 7, 117, 200, 207, 208, 226, 240, 263, 266 Fatigue, 225, 226, 232 Fatty acids, 201, 209, 226 Fermentation, 19, 42, 94, 128, 133, 143, 144, 148, 157, 226 Fertilization in Vitro, 226, 255 Fertilizers, 226, 266 Fibrin, 61, 226, 267 Fibrinogen, 226, 227, 253, 267 Fibroblasts, 216, 226, 227 Fibrosarcoma, 226, 227 Filtration, 122, 133, 148, 227 Fixation, 64, 227, 261 Flatus, 227, 228 Flexion, 227, 257 Fluorescence, 149, 227 Fold, 46, 53, 208, 227 Follicles, 162, 227 Folliculitis, 162, 227 Food Technology, 227, 243 Forearm, 10, 208, 226, 227 Fosfomycin, 61, 227 Fractionation, 100, 227 Free Radicals, 204, 220, 227

Fungi, 62, 65, 128, 136, 158, 162, 204, 213, 228, 243, 260, 263, 268, 273 Fungus, 209, 211, 225, 228, 260 Furosemide, 39, 228 G Gallate, 61, 93, 101, 228 Gallbladder, 92, 199, 213, 220, 228 Gamma irradiation, 100, 228 Ganglia, 199, 206, 228, 246, 251 Gangrenous, 228, 262 Gas, 7, 12, 21, 202, 227, 228, 234, 241, 245, 247, 265, 266, 271 Gastric, 137, 202, 221, 228, 233, 248, 251 Gastric Juices, 228, 251 Gastric Mucosa, 228, 251 Gastritis, 137, 228 Gastroenterologist, 26, 228 Gastroenterology, 5, 26, 163, 228 Gastrointestinal, 27, 163, 208, 213, 224, 225, 228, 241, 262, 265, 272 Gastrointestinal tract, 163, 225, 228, 262 Gavage, 155, 228 Gelatin, 131, 217, 228, 230, 266, 267 Gels, 228, 243 Gene Expression, 18, 24, 51, 52, 150, 229 Gene Therapy, 21, 229 Genetic Code, 229, 247 Genetic Engineering, 140, 207, 214, 229 Genetic testing, 229, 254 Genetics, 24, 52, 221, 229 Genital, 14, 183, 213, 229, 271 Genomics, 46, 55, 229 Genotype, 14, 20, 229, 252 Giardiasis, 229, 243 Gingivitis, 219, 229 Gland, 126, 200, 217, 229, 240, 241, 249, 261, 264, 265, 268 Glomerular, 229, 259 Glomeruli, 229, 257 Glomerulus, 229, 246 Glucocorticoid, 219, 229, 255 Glucose, 124, 150, 208, 211, 220, 230, 232, 237, 260 Glucose Intolerance, 220, 230 Glutamate, 230 Glutamic Acid, 52, 230, 246, 255 Glutamine, 124, 150, 230 Glutathione Peroxidase, 230, 261 Glycerol, 139, 230, 252 Glycine, 29, 43, 145, 202, 207, 230, 240, 246, 261 Glycoprotein, 227, 230, 239, 268

Index 281

Glycosaminoglycans, 15, 230 Glycoside, 220, 230, 234, 260 Glycosidic, 230, 246, 248 Goats, 116, 230 Gonadal, 230, 264 Gonorrhea, 15, 31, 158, 211, 230 Governing Board, 230, 254 Graft, 85, 230, 233, 236 Grafting, 124, 230 Gram-negative, 33, 116, 133, 150, 210, 211, 212, 230, 231, 235, 245, 246, 247, 250, 268, 272 Gram-Negative Bacteria, 116, 231, 268 Gram-Positive Bacteria, 231, 247, 250 Granule, 39, 150, 231, 259 Granulocyte, 72, 231 Granulocytopenia, 84, 231 Growth factors, 150, 231 Guanine, 129, 231, 257 Guinea Pigs, 58, 231 Gutta-Percha, 9, 231 H Habitual, 212, 231 Haemophilus, 55, 74, 110, 117, 211, 231 Hair follicles, 162, 219, 227, 231, 264 Half-Life, 153, 211, 231 Haploid, 24, 231, 253 Haptens, 201, 231 Hay Fever, 201, 231 Headache, 225, 231, 237 Heart failure, 232 Heart Murmurs, 163, 232 Heart Sounds, 232 Helminths, 232, 236 Hematology, 49, 88, 232 Heme, 25, 207, 232 Hemin, 26, 232 Hemodiafiltration, 232, 270 Hemodialysis, 232, 239, 270 Hemofiltration, 232, 270 Hemoglobin, 26, 203, 212, 225, 232, 238, 239 Hemoglobin A, 212, 232 Hemoglobinopathies, 112, 229, 232 Hemolytic, 9, 56, 73, 75, 87, 226, 233, 236 Hemorrhage, 217, 231, 233, 265 Hepatic, 201, 233 Hepatitis, 6, 160, 182, 233 Hepatitis A, 182, 233 Hepatocytes, 233 Hepatovirus, 233 Heredity, 229, 233

Herpes, 183, 233 Herpes Zoster, 233 Heterogeneity, 28, 201, 233 Heterotrophic, 228, 233 Heterozygotes, 221, 233 Histamine, 203, 233, 235 Histidine, 22, 145, 233 Homogeneous, 130, 217, 233, 252 Homologous, 46, 49, 217, 229, 233, 261, 266 Hormone, 207, 217, 224, 225, 233, 237, 242, 255, 262, 268 Human papillomavirus, 183, 233 Humoral, 4, 233 Humour, 233, 234 Hybrid, 11, 24, 214, 234, 260 Hybridization, 14, 23, 234 Hydrogel, 146, 234 Hydrogen, 129, 130, 143, 199, 202, 206, 209, 210, 218, 219, 230, 234, 243, 244, 246, 247, 249, 252, 256, 266 Hydrogen Peroxide, 129, 130, 210, 230, 234, 266 Hydrogenation, 206, 234 Hydrolases, 22, 49, 116, 234, 252 Hydrophilic, 126, 219, 234 Hydrophobic, 34, 95, 126, 127, 219, 234, 240 Hydroxylation, 19, 234 Hydroxyproline, 202, 215, 234 Hydroxyurea, 21, 234 Hyperbaric, 100, 101, 234 Hyperbaric oxygen, 100, 101, 234 Hyperbilirubinemia, 234, 238 Hypersensitivity, 5, 10, 160, 161, 201, 203, 219, 234, 235, 261 Hypersensitivity, Immediate, 235 Hypertension, 182, 235, 238 Hypnotic, 206, 212, 235 Hypospadias, 124, 235 Hypotension, 161, 217, 235 Hypoxic, 235, 243 I Id, 49, 96, 106, 141, 187, 194, 196, 235 Imipenem, 56, 65, 92, 95, 99, 213, 235 Immune response, 200, 203, 204, 217, 231, 235, 236, 244, 261, 262, 265, 271, 272 Immune Sera, 235 Immune system, 6, 27, 47, 142, 159, 162, 207, 235, 236, 240, 245, 252, 271, 273 Immunity, 4, 50, 199, 201, 235, 240, 269 Immunization, 27, 81, 235, 236, 261

282 Penicillin

Immunocompromised, 51, 160, 235 Immunocompromised Host, 51, 235 Immunodeficiency, 4, 8, 10, 166, 182, 199, 235 Immunodeficiency syndrome, 166, 235 Immunogenic, 36, 51, 235 Immunoglobulin, 51, 142, 204, 235, 244 Immunologic, 158, 212, 235 Immunology, 17, 20, 70, 72, 73, 77, 81, 84, 89, 93, 200, 235 Immunosuppressant, 23, 236, 242 Immunosuppressive, 165, 229, 235, 236 Immunotherapy, 207, 219, 236 Impairment, 236, 242 Impetigo, 105, 162, 236 In situ, 144, 236 In vivo, 21, 23, 25, 27, 34, 37, 41, 59, 61, 73, 78, 125, 136, 137, 143, 149, 229, 236, 249 Incision, 7, 236, 238 Incontinence, 236, 255 Indicative, 154, 236, 250, 271 Induction, 33, 44, 67, 142, 236 Infarction, 217, 236, 243 Infertility, 15, 236 Infestation, 9, 236, 243 Infiltration, 236, 255 Inflammatory bowel disease, 9, 236 Influenza, 161, 166, 237 Information Systems, 38, 50, 237 Informed Consent, 50, 237 Infusion, 126, 237, 269 Ingestion, 142, 203, 237, 242, 254 Inhalation, 52, 142, 170, 200, 223, 237, 242, 254 Initiation, 28, 163, 237, 262, 265 Initiator, 53, 237 Inlay, 237, 259 Inner ear, 211, 214, 237, 271 Inoculum, 162, 237 Inorganic, 133, 138, 237, 265 Inpatients, 86, 237 Insight, 12, 26, 31, 34, 48, 156, 237 Insulator, 231, 237 Insulin, 150, 237, 270 Insulin-dependent diabetes mellitus, 237 Intensive Care, 68, 237 Intermittent, 8, 81, 237 Internal Medicine, 43, 79, 89, 90, 228, 232, 237 Interstitial, 8, 237, 238, 246, 259 Intestinal, 135, 217, 224, 237, 241 Intestine, 161, 207, 208, 224, 237, 239, 264

Intoxication, 238, 271, 273 Intracellular, 14, 33, 236, 238, 242, 254, 261, 262 Intracranial Hypertension, 231, 238, 250, 268 Intramuscular, 8, 78, 117, 238, 250 Intramuscular injection, 8, 117, 238 Intravenous, 7, 90, 160, 162, 163, 186, 237, 238, 250 Intrinsic, 21, 105, 201, 238 Invasive, 12, 16, 26, 27, 30, 38, 58, 69, 75, 84, 85, 86, 235, 238, 241 Ion Exchange, 129, 211, 238 Ion Exchange Resins, 129, 238 Ions, 95, 199, 206, 212, 220, 222, 224, 234, 238, 243 Irradiation, 238, 259 Irritants, 42, 238 Isoleucine, 145, 238 Ixodid, 225, 238 J Jaundice, 182, 234, 238 Joint, 26, 81, 213, 238 K Kb, 44, 46, 53, 180, 238 Kidney Failure, 223, 238 Kinetic, 16, 32, 39, 64, 66, 125, 239 L Labile, 137, 215, 239 Labyrinth, 237, 239, 251, 272 Laceration, 9, 239, 267 Lanthanum, 39, 239 Large Intestine, 220, 238, 239, 258, 263 Latent, 90, 166, 182, 239 Lectins, 142, 239 Lens, 209, 239 Leptospirosis, 10, 71, 82, 86, 169, 239 Lethal, 22, 31, 32, 42, 50, 52, 206, 239, 245 Leucine, 145, 239, 251 Leukemia, 221, 229, 239 Leukocytes, 142, 206, 208, 212, 224, 239, 244, 246 Levofloxacin, 70, 75, 99, 239 Library Services, 194, 239 Life cycle, 228, 239 Ligands, 11, 19, 239 Ligase, 134, 239 Ligation, 239, 256 Lincomycin, 214, 239 Linkage, 128, 240, 251 Lipid, 28, 230, 237, 240 Lipophilic, 37, 240

Index 283

Lipopolysaccharide, 231, 240 Lipoprotein, 231, 240 Liposome, 93, 240 Liver, 101, 117, 182, 199, 201, 207, 220, 223, 228, 233, 240, 243, 255, 270 Localized, 7, 33, 203, 219, 223, 227, 236, 240, 248, 253, 261, 267, 270, 271 Lockjaw, 6, 240 Locomotion, 240, 253 Lymph, 163, 212, 234, 240, 265 Lymph node, 163, 212, 240 Lymphatic, 236, 240, 263, 268 Lymphatic system, 240, 263, 268 Lymphocyte, 72, 92, 199, 204, 240 Lymphocyte Count, 199, 240 Lymphoid, 44, 204, 217, 240, 268 Lymphokines, 162, 240 Lymphoma, 95, 104, 240 Lysine, 95, 150, 240, 270 Lysostaphin, 126, 240 Lytic, 22, 31, 241, 261, 272 M Macrolides, 56, 60, 137, 241 Maculopapular, 10, 241 Magnetic Resonance Imaging, 7, 241 Malabsorption, 163, 241 Malabsorption syndrome, 163, 241 Malaise, 225, 241 Malaria, 101, 241 Malaria, Falciparum, 241 Malaria, Vivax, 241 Malignant, 7, 199, 204, 226, 241, 246, 260 Malnutrition, 201, 241 Mammary, 126, 241 Manifest, 161, 241 Mass Media, 30, 241 Masseter Muscle, 241, 270 Mastitis, 92, 126, 147, 241, 262 Meat, 117, 241 Mediate, 24, 28, 33, 34, 142, 221, 241 MEDLINE, 181, 241 Melanin, 242, 252, 270 Membrane Proteins, 242, 256 Memory, 50, 218, 242 Meninges, 211, 217, 222, 242, 270 Meningitis, 26, 41, 47, 53, 54, 62, 65, 67, 76, 79, 81, 84, 85, 88, 94, 95, 141, 170, 242, 245 Meningococcal Infections, 28, 242 Meningococcal Vaccines, 28, 242 Mental, iv, 11, 113, 180, 182, 183, 212, 218, 220, 226, 242, 257, 260, 270

Mental Disorders, 113, 242, 257 Mental Health, iv, 11, 113, 180, 183, 242, 257 Mercury, 62, 101, 242 Metabolite, 157, 208, 242, 255 Methanol, 21, 149, 242 Methicillin Resistance, 32, 36, 43, 65, 242 Methionine, 145, 242, 266 Methotrexate, 11, 242 Methyldopa, 96, 242 Methylene Chloride, 137, 242 Metronidazole, 4, 5, 14, 23, 161, 243 MI, 116, 197, 243 Microbe, 202, 242, 243, 267, 269 Microbicide, 15, 243 Microbiological, 19, 243 Microorganism, 132, 148, 214, 243, 250, 272 Micro-organism, 118, 146, 219, 243, 261 Microscopy, 13, 243 Migrans, 72, 87, 243 Migration, 37, 243, 251 Milk Thistle, 108, 243, 262 Mitomycin, 49, 243 Mitosis, 205, 239, 243 Modeling, 37, 93, 221, 243 Modification, 18, 24, 29, 35, 43, 62, 120, 143, 202, 229, 243, 257 Molecular mass, 26, 243 Molecular Structure, 51, 243 Monitor, 8, 244, 247 Monoamine, 202, 220, 244 Monobactams, 19, 244 Monoclonal, 60, 238, 244, 258 Monoclonal antibodies, 60, 244 Monocytes, 142, 162, 239, 244 Monokines, 162, 244 Mononuclear, 226, 244 Morphine, 214, 244, 245 Morphogenesis, 20, 66, 244 Morphological, 20, 62, 222, 228, 244 Morphology, 10, 46, 55, 57, 92, 205, 232, 244 Motor nerve, 244, 245 Mucins, 219, 244, 260 Mucociliary, 244, 262 Mucosa, 14, 27, 224, 228, 244 Multivariate Analysis, 37, 244 Muramidase, 29, 43, 244 Muscle relaxant, 160, 245 Muscle tension, 245 Mustard Gas, 238, 245

284 Penicillin

Mutate, 36, 245 Myalgia, 161, 237, 245 Myocardium, 243, 245 Myositis, 100, 101, 245 N Naive, 33, 245 Narcotic, 242, 244, 245 Nasal Mucosa, 237, 245 Nasopharynx, 61, 78, 245 Nausea, 221, 225, 245, 270 NCI, 1, 112, 179, 213, 245 Nebramycin, 245, 268 Neisseria, 15, 31, 34, 56, 62, 63, 67, 69, 76, 79, 80, 81, 84, 85, 89, 90, 102, 103, 109, 230, 242, 245 Neisseria meningitidis, 56, 63, 67, 80, 85, 90, 242, 245 Neonatal, 41, 245 Neoplasms, 199, 204, 218, 246 Neoplastic, 240, 246, 270 Nephritis, 8, 246 Nephrotoxic, 8, 246 Nerve, 200, 203, 212, 218, 244, 246, 249, 254, 255, 260, 264, 269, 272 Nervous System, 21, 150, 163, 202, 211, 246, 251, 266, 267, 271 Netilmicin, 63, 246 Neural, 203, 233, 246 Neuraminidase, 25, 246 Neuromuscular, 199, 246, 255 Neuronal, 150, 246 Neurons, 150, 218, 226, 228, 245, 246, 266, 272 Neurosyphilis, 111, 186, 246, 250 Neurotoxicity, 92, 246 Neurotransmitter, 39, 199, 200, 202, 208, 221, 230, 233, 246, 247, 262, 265, 267 Neutralization, 148, 246 Neutrons, 201, 238, 246, 258 Neutrophils, 58, 231, 239, 246 Nitrofurantoin, 161, 246 Nitrogen, 64, 140, 144, 201, 202, 227, 230, 243, 247 Norepinephrine, 200, 221, 242, 246, 247 Nosocomial, 36, 40, 247 Nuclear, 206, 225, 247 Nuclei, 144, 201, 229, 241, 243, 246, 247, 256, 272 Nucleic acid, 120, 129, 135, 149, 218, 229, 234, 247, 257 Nucleic Acid Hybridization, 234, 247 Nucleotidases, 234, 247

Nutritional Status, 21, 247 O Observational study, 68, 247 Obstetrics, 79, 158, 247 Ocular, 103, 247 Odour, 130, 205, 247 Ofloxacin, 61, 247 Ointments, 221, 247 Oligosaccharides, 25, 246, 248 Omeprazole, 137, 248, 256 Opacity, 219, 248 Open Reading Frames, 40, 46, 53, 248 Operon, 25, 28, 49, 52, 67, 141, 248, 259 Opportunistic Infections, 199, 248 Oral Health, 159, 160, 248 Organ Culture, 15, 248, 268 Organelles, 218, 244, 248, 259 Orgasm, 151, 248 Ornithine, 135, 248 Orofacial, 160, 248 Orthopedics, 231, 248 Osmosis, 248 Osmotic, 147, 201, 248 Osteomyelitis, 161, 248 Otitis, 4, 6, 7, 12, 26, 53, 59, 61, 63, 65, 70, 80, 81, 107, 157, 248, 249 Otitis Media, 4, 6, 12, 26, 59, 61, 63, 65, 70, 80, 81, 107, 157, 248, 249 Otitis Media with Effusion, 6, 12, 249 Otolaryngologist, 159, 249 Otolaryngology, 8, 159, 249 Outpatient, 38, 41, 89, 111, 249 Ovary, 225, 249 Oxidants, 150, 249 Oxidation, 129, 130, 135, 199, 204, 208, 230, 249 Oxidation-Reduction, 135, 208, 249 Oxides, 129, 249 P Pachymeningitis, 242, 249 Palate, 245, 249 Palliative, 249, 267 Pancreas, 199, 220, 228, 237, 249, 270 Papillomavirus, 249 Papule, 225, 241, 249 Paralysis, 217, 249, 250 Paranasal Sinuses, 249, 262 Paraparesis, 250 Parasitic, 213, 217, 232, 236, 250 Parenteral, 54, 142, 158, 250 Paresis, 71, 100, 250 Parietal, 248, 250

Index 285

Paronychia, 162, 250 Parturition, 247, 250 Pathogen, 4, 15, 25, 34, 36, 40, 41, 46, 53, 237, 250 Pathogenesis, 12, 15, 21, 28, 36, 42, 47, 163, 250 Pathologic, 163, 205, 207, 209, 217, 234, 250, 256, 259, 271 Pathophysiology, 10, 109, 159, 160, 250 Patient Education, 30, 186, 192, 194, 197, 250 Pelvic, 15, 183, 250 Pelvic inflammatory disease, 15, 183, 250 Pelvis, 208, 250, 257, 271 Penicillic Acid, 147, 250 Penicillin Amidase, 132, 138, 250 Penicillin G, 59, 65, 71, 109, 111, 120, 124, 128, 131, 132, 158, 186, 187, 250 Penicillin Resistance, 13, 34, 41, 45, 50, 53, 55, 62, 63, 69, 73, 74, 76, 81, 87, 88, 89, 110, 250 Penicillin V, 75, 108, 155, 250 Penicillinase, 7, 56, 60, 61, 80, 84, 93, 101, 105, 147, 251 Penis, 235, 251 Pepsin, 251 Pepsin A, 251 Peptic, 137, 251 Peptic Ulcer, 137, 251 Peptide, 17, 19, 23, 29, 35, 43, 44, 48, 51, 102, 130, 141, 150, 202, 213, 234, 240, 251, 256, 266 Peptide Chain Elongation, 213, 251 Peptide Hydrolases, 234, 251 Perfusion, 89, 95, 251 Perianal, 9, 251 Pericarditis, 163, 251 Pericardium, 251 Pericoronitis, 161, 251 Perilymph, 158, 251 Perineum, 235, 251, 264 Periodontal disease, 25, 45, 53, 251 Periodontal Pocket, 77, 251 Periodontitis, 13, 23, 229, 251 Peripheral Nervous System, 223, 242, 246, 250, 251, 260, 265 Periplasm, 25, 252 Peroxide, 130, 252 Petechiae, 10, 252 Petrolatum, 223, 252 PH, 50, 57, 71, 100, 252 Phagocyte, 249, 252

Pharmaceutical Preparations, 211, 225, 228, 252 Pharmaceutical Solutions, 221, 252 Pharmacodynamics, 61, 64, 75, 252 Pharmacokinetic, 252 Pharmacologic, 203, 231, 252, 269 Pharyngitis, 30, 56, 57, 70, 75, 84, 92, 94, 107, 163, 252, 260 Pharynx, 53, 237, 245, 252 Phenolphthalein, 223, 252 Phenotype, 14, 20, 22, 24, 43, 76, 109, 216, 252 Phenyl, 126, 129, 134, 140, 252 Phenylalanine, 251, 252, 270 Phospholipases, 252, 262 Phospholipids, 226, 240, 252 Phosphoric Monoester Hydrolases, 234, 252 Phosphorus, 129, 209, 253 Physical Examination, 6, 7, 10, 253 Physicochemical, 37, 134, 253 Physiologic, 201, 231, 253, 258, 259 Physiology, 16, 22, 92, 93, 228, 232, 239, 253 Picrotoxin, 39, 253 Pilot study, 68, 253 Placenta, 225, 253, 255, 257 Plants, 158, 201, 207, 208, 212, 230, 244, 247, 253, 260, 263, 269, 270, 272 Plaque, 13, 14, 45, 253 Plasma, 153, 201, 204, 208, 212, 227, 228, 230, 232, 238, 253 Plasma cells, 204, 253 Plasma protein, 153, 201, 253 Plasmid, 48, 253, 271 Platelet Activation, 253, 262 Platelets, 142, 253, 262, 268 Pneumococcal Infections, 26, 83, 253 Pneumococcal Vaccines, 51, 253 Pneumonia, 6, 26, 27, 41, 47, 54, 57, 58, 59, 63, 67, 71, 75, 83, 84, 112, 217, 254, 270 Point Mutation, 14, 40, 149, 254 Poisoning, 36, 46, 212, 225, 238, 242, 245, 253, 254, 261 Polyethylene, 131, 254, 266 Polymerase, 80, 254, 259, 262 Polymerase Chain Reaction, 80, 254 Polymers, 122, 207, 238, 254, 256, 265 Polyploid, 24, 254 Polysaccharide, 26, 42, 51, 130, 204, 211, 254 Posterior, 10, 117, 203, 212, 221, 249, 254

286 Penicillin

Postoperative, 5, 7, 93, 254 Postsynaptic, 254, 262, 267 Post-synaptic, 39, 254 Potassium, 94, 133, 144, 148, 250, 254 Potentiation, 254, 262 Practice Guidelines, 30, 183, 186, 254 Precipitation, 149, 254 Precursor, 15, 19, 128, 130, 144, 148, 221, 222, 223, 224, 247, 252, 254, 255, 256, 270, 271 Prednisolone, 255 Prednisone, 160, 163, 182, 255 Pregnancy Outcome, 88, 255 Presynaptic, 246, 255, 267 Prevalence, 4, 29, 31, 38, 40, 47, 59, 74, 77, 85, 103, 159, 255 Probe, 45, 52, 255 Procaine, 116, 144, 163, 170, 187, 255 Proctocolitis, 183, 255 Prodrug, 93, 255 Proenzyme, 15, 224, 255 Progesterone, 255, 264 Progression, 166, 203, 255 Progressive, 6, 8, 161, 211, 213, 218, 221, 222, 231, 253, 255, 259 Proline, 36, 215, 234, 255 Promoter, 24, 46, 62, 255 Prone, 140, 255 Propantheline, 96, 255 Prophylaxis, 5, 8, 16, 21, 26, 50, 69, 70, 81, 88, 90, 112, 158, 161, 163, 247, 255, 271 Propofol, 39, 255 Proportional, 30, 255 Prospective study, 50, 90, 255 Prosthesis, 81, 256 Protease, 35, 53, 215, 256 Protein C, 16, 39, 46, 50, 149, 201, 202, 206, 240, 256, 270 Protein Conformation, 202, 256 Protein S, 11, 16, 20, 149, 157, 207, 213, 216, 225, 229, 256, 259, 265, 267 Protein Splicing, 16, 256 Proteolytic, 215, 227, 256 Proton Pump, 5, 137, 248, 256 Proton Pump Inhibitors, 137, 256 Protons, 201, 234, 256, 258 Protozoa, 243, 256, 263 Protozoan, 217, 229, 241, 256, 270 Proximal, 220, 255, 256 Psoriasis, 9, 245, 256 Psychiatry, 71, 100, 154, 227, 256 Psychic, 242, 257

Psychoactive, 257, 273 Psychotomimetic, 202, 220, 257 Public Health, 10, 27, 30, 32, 34, 38, 50, 53, 123, 158, 167, 183, 257 Public Policy, 181, 257 Puerperium, 247, 257 Pulmonary, 208, 216, 232, 239, 257, 266 Pulse, 223, 244, 257 Purines, 257, 261 Purulent, 199, 257, 271 Pustular, 236, 257 Pyelitis, 7, 257 Pyelonephritis, 7, 257 Pyogenic, 248, 257, 261 Pyrazinamide, 182, 257 Pyrimidines, 257, 261 Pyrogenic, 46, 61, 78, 162, 257 Q Quality of Life, 257, 266 R Race, 124, 243, 257 Racemic, 124, 257 Radiation, 159, 224, 227, 228, 234, 235, 238, 243, 257, 258, 270, 273 Radiation therapy, 227, 228, 234, 238, 258, 270 Radioactive, 218, 231, 234, 238, 244, 247, 258 Radiological, 7, 258 Radiology, 258 Randomized, 12, 16, 27, 68, 82, 86, 94, 222, 258 Reactive Oxygen Species, 25, 258 Receptor, 11, 35, 82, 142, 200, 204, 221, 258, 262, 266 Recombinant, 39, 92, 118, 120, 121, 125, 136, 145, 146, 258, 271 Recombination, 13, 229, 258 Rectal, 9, 89, 95, 258, 266 Rectum, 204, 208, 215, 220, 227, 228, 236, 239, 255, 258, 266 Recur, 12, 258 Recurrence, 12, 258 Red blood cells, 225, 233, 258, 260 Reductase, 242, 258 Refer, 1, 209, 215, 220, 223, 227, 228, 233, 240, 245, 246, 247, 258, 269, 272 Refraction, 258, 263 Refractory, 6, 12, 95, 104, 258 Regimen, 36, 63, 81, 163, 182, 186, 222, 258 Regulon, 33, 258 Relapse, 163, 259

Index 287

Relaxant, 259 Remission, 258, 259 Renal failure, 153, 259 Repopulation, 23, 259 Repressor, 33, 40, 248, 259 Reproduction Techniques, 255, 259 Resorption, 251, 259 Respiration, 217, 244, 259 Restoration, 12, 61, 93, 101, 259 Reticulocytes, 225, 259 Retroviral vector, 229, 259 Rheumatoid, 249, 259 Rhinitis, 255, 259, 262 Ribonucleoside Diphosphate Reductase, 234, 259 Ribosome, 259, 269 Rigidity, 31, 253, 259 Risk factor, 8, 25, 30, 41, 78, 87, 182, 256, 259 Ristocetin, 259, 271 Rod, 205, 206, 231, 260 Root Planing, 13, 14, 23, 260 Rubber, 159, 199, 231, 260 Ruminants, 230, 260 Rye, 100, 213, 225, 260 S Saccharomyces, 24, 260, 273 Saccharomyces cerevisiae, 24, 260, 273 Saccharomycetales, 260 Saliva, 244, 260 Salivary, 219, 220, 260, 265, 273 Salivary glands, 219, 220, 260 Saponins, 260, 264 Scarlet Fever, 260 Schizoid, 260, 273 Schizophrenia, 103, 260, 273 Schizotypal Personality Disorder, 260, 273 Schwannoma, 8, 260 Scleroderma, 226, 261 Screening, 11, 20, 48, 65, 67, 88, 182, 214, 261 Sebaceous, 219, 238, 261 Sebaceous gland, 219, 238, 261 Secretion, 137, 233, 234, 237, 244, 248, 261 Secretory, 150, 248, 261, 267 Sedative, 206, 212, 214, 261 Segregation, 258, 261 Selenium, 150, 261 Semisynthetic, 82, 127, 128, 131, 202, 210, 211, 213, 214, 235, 244, 246, 261 Sensitization, 73, 261 Sensor, 147, 261

Sepsis, 36, 41, 46, 88, 95, 104, 261 Septic, 61, 85, 205, 261 Septicaemia, 261, 262 Septicemia, 26, 53, 261 Sequela, 163, 261 Sequence Analysis, 16, 261 Sequence Homology, 17, 42, 261 Sequencing, 14, 44, 46, 53, 126, 254, 261 Serine, 15, 17, 116, 209, 261, 270 Serologic, 36, 261 Serotonin, 246, 261 Serotypes, 26, 51, 63, 83, 262 Serum, 6, 8, 28, 42, 69, 72, 107, 139, 150, 201, 202, 203, 215, 235, 261, 262 Sexually Transmitted Diseases, 68, 69, 76, 103, 182, 262 Shock, 46, 69, 85, 139, 147, 161, 203, 262, 269 Side effect, 4, 87, 160, 161, 173, 175, 200, 207, 210, 211, 262, 266, 269 Sigma Factor, 49, 262 Signal Transduction, 44, 142, 262 Signs and Symptoms, 159, 161, 259, 262 Silymarin, 101, 243, 262 Sinusitis, 6, 262 Skeletal, 7, 217, 248, 262 Skeleton, 6, 238, 262, 263 Skin test, 68, 73, 77, 80, 84, 89, 262 Skull, 217, 263, 267 Small intestine, 93, 222, 224, 229, 233, 238, 263, 270 Sodium, 8, 71, 102, 124, 139, 150, 250, 263 Sodium Bicarbonate, 124, 263 Soft tissue, 7, 159, 161, 208, 226, 227, 262, 263 Solid tumor, 221, 263 Solvent, 119, 122, 133, 137, 140, 148, 206, 213, 225, 230, 242, 248, 252, 263 Somatic, 233, 243, 251, 263 Spatial disorientation, 220, 263 Specialist, 188, 263 Specificity, 16, 18, 32, 48, 51, 110, 127, 148, 201, 263 Spectroscopic, 19, 29, 263 Spectrum, 4, 19, 58, 77, 117, 128, 136, 161, 210, 211, 235, 263, 265 Sperm, 139, 140, 213, 263 Spinal cord, 211, 212, 213, 222, 242, 246, 249, 250, 251, 263 Spirochete, 263, 267 Spontaneous Abortion, 255, 263 Spores, 35, 52, 237, 263

288 Penicillin

Staphylococcal Infections, 7, 32, 126, 264 Staphylococcal Scalded Skin Syndrome, 162, 264 Steady state, 29, 264 Steel, 264, 270, 271 Stem cell transplantation, 21, 264 Stem Cells, 225, 264 Sterile, 117, 118, 120, 205, 264 Sterility, 236, 264 Steroid, 12, 150, 207, 217, 260, 264 Stillbirth, 255, 264 Stimulant, 202, 219, 233, 253, 264, 271 Stimulus, 225, 264, 267 Stomach, 199, 220, 225, 228, 233, 245, 251, 252, 256, 260, 263, 264 Strand, 35, 130, 254, 264 Streptococcal Infections, 44, 186, 264 Streptococci, 4, 9, 13, 25, 41, 44, 45, 53, 58, 59, 85, 90, 94, 163, 236, 260, 264 Streptomycin, 95, 124, 139, 150, 158, 163, 265 Stress, 7, 49, 217, 245, 260, 265, 271 Stroke, 113, 180, 265 Styrene, 260, 265 Subacute, 236, 262, 265 Subclinical, 236, 265 Subcutaneous, 7, 10, 117, 163, 203, 211, 222, 228, 250, 265 Subcutaneous Emphysema, 10, 265 Submandibular, 6, 265 Subspecies, 263, 265 Substance P, 225, 242, 259, 261, 265 Substrate Specificity, 17, 32, 48, 95, 102, 145, 265 Suction, 227, 265 Sulbactam, 60, 64, 265 Sulfates, 182, 265 Sulfisoxazole, 6, 265 Sulfur, 143, 209, 242, 266 Sulfuric acid, 138, 265, 266 Superantigens, 46, 162, 266 Superoxide, 25, 266 Superoxide Dismutase, 25, 266 Supplementation, 100, 103, 266 Supportive care, 21, 266 Suppositories, 228, 243, 266 Suppository, 211, 266 Suppression, 23, 247, 266 Suppressive, 10, 266 Surfactant, 126, 266 Suspensions, 116, 144, 266

Sympathomimetic, 202, 219, 221, 224, 247, 266 Symptomatic, 4, 93, 266 Synaptic, 246, 250, 262, 266, 267 Synaptic Transmission, 250, 267 Synergistic, 126, 137, 267 Syphilis, 8, 10, 68, 75, 88, 90, 101, 111, 158, 159, 166, 183, 186, 246, 267 Systolic, 235, 267 T Tachycardia, 206, 267 Tachypnea, 206, 267 Tear Gases, 238, 267 Teichoic Acids, 231, 267 Temporal, 160, 267 Testis, 225, 267 Tetanus, 267, 270 Tetracycline, 10, 13, 14, 15, 31, 34, 58, 76, 161, 221, 267 Tetracycline Resistance, 34, 267 Therapeutics, 11, 23, 46, 100, 175, 267 Thermal, 220, 246, 254, 267 Thigh, 257, 267 Threonine, 15, 145, 261, 267 Threshold, 92, 147, 235, 267 Thrombin, 226, 227, 256, 267, 268 Thrombocytes, 253, 268 Thrombomodulin, 256, 268 Thrombosis, 256, 265, 268 Thrush, 209, 268 Thymus, 235, 240, 268 Thyroid, 268, 270 Thyroxine, 201, 252, 268 Ticks, 236, 268 Tinnitus, 8, 160, 248, 268, 272 Tissue Culture, 150, 268 Tissue Preservation, 124, 268 Tobramycin, 104, 268 Tolerance, 19, 21, 22, 25, 49, 54, 67, 84, 90, 94, 141, 200, 230, 268 Tomography, 216, 268 Tonic, 240, 268 Tonsillitis, 75, 260, 268 Tonsils, 268 Tooth Preparation, 200, 268 Topical, 15, 58, 205, 225, 234, 252, 263, 269 Toxicity, 7, 8, 96, 138, 221, 242, 246, 259, 269 Toxicokinetics, 269 Toxicology, 37, 96, 101, 155, 158, 182, 269 Toxin, 46, 52, 223, 267, 268, 269 Toxoid, 10, 269

Index 289

Toxoplasmosis, 205, 269 Trace element, 269 Trachea, 208, 252, 268, 269 Transduction, 141, 262, 269 Transfection, 207, 229, 269 Transfer Factor, 235, 269 Transfusion, 21, 269 Translation, 40, 202, 225, 256, 269 Translational, 21, 269 Translocation, 213, 225, 269 Transmitter, 199, 221, 242, 247, 269 Transplantation, 95, 104, 124, 213, 222, 235, 269 Trauma, 9, 269, 270, 273 Treatment Failure, 4, 34, 111, 270 Trees, 202, 260, 270 Trichomoniasis, 243, 270 Trimethoprim-sulfamethoxazole, 74, 270 Trismus, 6, 270 Trivalent, 129, 270 Trypsin, 255, 270, 273 Tungsten, 129, 210, 270 Tunica, 244, 270 Tylosin, 116, 270 Type 2 diabetes, 7, 270 Tyrosine, 142, 145, 221, 270 Tyrothricin, 158, 270 U Ulcer, 183, 211, 251, 270 Ultrafiltration, 133, 232, 270 Unconscious, 203, 235, 270 Urea, 248, 270 Uremia, 239, 259, 270 Ureters, 270, 271 Urethra, 235, 251, 271 Urethritis, 183, 271 Urinary, 7, 124, 161, 211, 213, 218, 236, 246, 255, 270, 271 Urinary tract, 7, 124, 161, 211, 247, 271 Urinary tract infection, 7, 161, 247, 271 Urine, 161, 208, 236, 257, 270, 271 Urogenital, 230, 271 Urticaria, 142, 203, 271 Uterus, 199, 208, 212, 222, 227, 255, 271 V Vaccination, 26, 50, 51, 142, 271 Vaccine, 26, 36, 38, 44, 47, 50, 51, 166, 183, 200, 271 Vagina, 140, 161, 209, 212, 271 Vaginal, 183, 266, 271 Vaginal Discharge, 183, 271 Vaginitis, 209, 271

Valine, 118, 121, 125, 143, 145, 146, 271 Vanadium, 129, 271 Vancomycin, 23, 36, 40, 53, 56, 59, 63, 66, 67, 120, 141, 174, 271 Vascular, 124, 201, 203, 219, 235, 236, 253, 271 Vasoconstriction, 224, 271 Vasodilator, 58, 208, 221, 233, 271 VE, 138, 271 Vector, 269, 271 Vegetative, 254, 271 Vein, 238, 247, 272 Venereal, 167, 245, 267, 272 Venous, 256, 272 Ventricles, 212, 272 Venules, 208, 209, 272 Vertigo, 248, 272 Vestibular, 8, 272 Vestibule, 237, 272 Vestibulocochlear Nerve, 268, 272 Vestibulocochlear Nerve Diseases, 268, 272 Veterinary Medicine, 181, 272 Vibrio, 213, 272 Vibrio cholerae, 213, 272 Viral, 165, 237, 269, 272, 273 Virulence, 25, 36, 42, 44, 45, 46, 47, 52, 53, 56, 63, 83, 269, 272 Virulent, 53, 272 Virus, 4, 8, 10, 166, 182, 199, 206, 221, 229, 233, 253, 259, 269, 272 Vitro, 15, 18, 23, 25, 29, 34, 36, 41, 42, 43, 51, 52, 54, 55, 59, 60, 61, 63, 64, 65, 66, 67, 72, 77, 78, 92, 93, 99, 102, 125, 134, 137, 149, 165, 222, 229, 236, 254, 260, 268, 272 Vivo, 25, 42, 61, 89, 95, 272 W War, 89, 156, 212, 245, 273 Warts, 233, 273 White blood cell, 204, 231, 239, 240, 253, 273 Windpipe, 252, 268, 273 Withdrawal, 23, 273 Wound Infection, 36, 161, 273 X Xenograft, 203, 273 Xerostomia, 160, 273 X-ray, 16, 48, 210, 216, 227, 228, 238, 247, 258, 273 Y Yeasts, 209, 228, 252, 260, 273

290 Penicillin

Z

Zymogen, 224, 255, 256, 273

Index 291

292 Penicillin

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