Biomedical scientists widely acknowledge that individuals' immune respon siveness is important in resistance to infections by microorganisms, including fungi. Because of the devastating acquired immunodeficiency syndrome (AIDS) epidemic, caused by the human immunodeficiency retrovirus, it is now accepted that suppressed immune responses, especially cellular immu nity, are important contributors to increased individual susceptibility to opportunistic infections-including infections caused by fungi which were at one time thought to be very lowly or nonpathogenic. Within the last few years, there has been an almost explosive increase in interest and studies concerning the nature and mechanisms of the immune response to fungal infections. Many immunologists who are not well versed in mycology have begun to study the nature and mechanisms of antifungal immunity using a wide variety of newer as well as more conventional immunologic technologies, both in vivo and in vitro. Up to the 1980s, however, there was little interest among basic immunologists concerning fungal immunity. This situation has changed dramatically in the past half decade, mainly because of AIDS.

North American Parasitic Zoonoses provides a concise and useful review of essential information about parasitic zoonotic diseases. North American Parasitic Zoonoses, volume six of "World Class Parasites", is written for researchers, students, veterinarians, physicians and scholars who enjoy reading research that has a major impact on human health, or agricultural productivity, and against which we have no satisfactory defense. It is intended to supplement more formal texts that cover taxonomy, life cycles, morphology, vector distribution, symptoms and treatment. It integrates vector, pathogen and host biology and celebrates the diversity of approach that comprises modern parasitological research.

American trypanosomiasis, or Chagas disease, is caused by the protozoan parasite, Trypanosoma cruzi. Sixteen to eighteen million people are currently infected with this organism, and 45,000 deaths are attributed to the disease each year. Infection with T. cruzi is life-long, and 10-30% of persons who harbor the parasite chronically develop cardiac and gastrointestinal problems associated with the parasitosis. Although major progress has been made in recent years in reducing vector-borne and transfusion-associated transmission of T. cruzi, the burden of disability and death in persons chronically infected with the organism continues to be enormous. Eight to ten million persons born in countries in which Chagas disease is endemic currently reside in the United States, and epidemiologic and census data suggest that 50,000-100,000 are chronically infected with T. cruzi. The presence of these infected persons poses a risk of transmission of the parasite in the USA through blood transfusion and organ transplantation and several such cases have now been documented. American Trypanosomiasis, volume seven of World Class Parasites is written for students of tropical medicine, parasitology and public health, for researchers and practitioners alike who wish to bring themselves abreast of the status quo with respect to this disease. It is intended to supplement formal textbooks, in order to broaden and illuminate current areas of scientific and public health concern. Uniquely for T. cruzi, this book addresses parasite, vector and host biology, the pathogenesis of Chagas disease and current and prospective therapeutics and control strategies in a single volume.

Leishmania parasites cause a diverse group of diseases endemic to many tropical and subtropical regions of the world. This volume seeks to bring together recent research on cell and molecular biology of Leishmania with chapters on the host response to infection, the current epidemiology of leishmaniasis, explanations of the many different species, vector control, and strategies for vaccine development and drug treatment. Leishmania, volume four of World Class Parasites, is written for researchers, students and scholars who enjoy reading research that has a major impact on human health, or agricultural productivity, and against which we have no satisfactory defense. It is intended to supplement more formal texts that cover taxonomy, life cycles, morphology, vector distribution, symptoms and treatment. It integrates vector, pathogen and host biology and celebrates the diversity of approach that comprises modern parasitological research.

Fungal dimorphism is a topic that sounds inherently too rarified to attract more than a specialist audience. Yet some 230 individuals representing an eclectic mixture of interests, from basic science to medical practice, gathered in Churchill College, Cambridge in Semptember 1992 for a meeting devoted only to this subject. The symposium was the fourth in a series "Topics in Mycology" to be jointly organized by the Janssen Research Foundation and the International Society for Human and Animal Mycology. The participants enjoyed a rich and varied diet of oral presentations and poster displays in the field of fungal morphogenesis. This book sets down in print the material presented at the dimorphism symposium. We think that the high quality of these papers conveys very well the flavor of what was an excellent meeting. The selection of contributions in this volume covers very wide ground indeed. Chapters devoted to some non-pathogenic fungi are included, because the scientific basis of morphological development belongs to the fields of cellular and molecular biology: it does not recognize the boundary imposed by considerations of virulence of a fungus for a human host. Yet morphogenetic change in those fungi that do cause human disease frequently appears to be a component of the pathological process: many important pathogens change from a hyphal form in the external environment to a round form in infected tissues. This relationship between dimorphism and pathogenicity is the point of contact between pure biology and medicine.

The aberrant replication pathway of foamy viruses distinguishes them from all other retroviruses. Many details have been accumulated over the past ten or so years. Most of the findings on foamy viruses were obtained by research on a single virus isolate previously called "human foamy virus," which appeared to be the first to be investigated on a molecular level. However, to the editor's knowledge, genuine human foamy viruses do not exist, but several trans-species transmissions of different simian foamy viruses from monkeys and apes to human hosts.

P. Doherty...VB Introduction D. Dobbelaere and D. McKeever...IX Theileria Development and Host Cell Invasion Michael K. Shaw...1 Genomic Polymorphism, Sexual Recombination and Molecular Epidemiology af Theileria Parva R. Bishop, D. Geysen, R. Skilton, D. Odongo, V. Nene, B. Allsopp, S. Mbogo, P. Spooner and S. Morzaria...23 Epidemiological Significance of Strain-Specific Immunity to Theileria Parva D. J. McKeever and W. I. Morrison...41 Virulence and Attenuation in Theileria Annulata R. Adamson and R. Hall...55 Theileria Survival Strategies and Host Cell Transformation V. T. Heussler...69 Genomics of Theileria Parva V. Nene, R. Bishop, J. Quackenbush, M. Pertea, S. L. Salzberg, E. Taracha, S. Morzaria, C. M. Fraser and M. Gardner...85 Non-Transforming Theileria Parasites of Ruminants C. Sugimoto and K. Fujisaki 93 Index...107 FOREWORD The apicomplexan protozoal parasites continue to provide major challenges for human and animal health. While most of us have some familiarity with the ravages of malaria, there is relatively little awareness of diseases caused by parasites of the Theileria species. The reason is that these tick-borne organisms are problematic only in cattle and small ruminants. This does not mean, however, that the various manifestations of Theileriosis are of little interest to those concerned principally with human health. The economic loss and diminished food production associated with East Coast Fever (ECF, caused by T. parva) continues to be a major problem in East Africa.

The articles in this volume provide a comprehensive overview of our current understanding of the roles played by cellular factors in the early steps of retroviral replication. A better understanding of these functions will provide critical new insights into retrovirus-host cell interactions and is likely to prove useful for the future development of effective antiretroviral therapies.

The time seems ripe for a critical compendium of that segment of the biological universe we call viruses. Virology, as a science, having passed only recently through its descriptive phase of naming and num hering, has probably reached that stage at which relatively few new-truly new-viruses will be discovered. Triggered by the in tellectual probes and techniques of molecular biology, genetics, biochemical cytology, and high-resolution microscopy and spectroscopy, the field has experienced a genuine information explo sion. Few serious attempts have been made to chronicle these events. This comprehensive series, which will comprise some 6000 pages in a total of about 22 volumes, represents a commitment by a large group of active investigators to analyze, digest, and expostulate on the great mass of data relating to viruses, much of which is now amorphous and disjointed, and scattered throughout a wide literature. In this way, we hope to place the entire field in perspective, and to develop an in valuable reference a*nd sourcebook for researchers and students at all levels. This series is designed as a continuum that can be entered anywhere, but which also provides a logical progression of developing facts and integrated concepts.

The field of bacterial genetics has been restricted for many years to Escherichia coli and a few other genera of aerobic or facultatively anaerobic bacteria such as Pseudomonas, Bacillus, and Salmonella. The prevailing view up to recent times has been that anaerobic bacteria are interesting organisms but nothing is known about their genetics. To most microbiologists, anaerobic bacteria appeared as a sort of distant domain, reserved for occasional intrusions by taxonomists and medical microbiologists. By the mid-1970s, knowledge of the genetics and molecular biology of anaerobes began to emerge, and then developed rapidly. but also im This was the result of advances in molecular biology techniques, portantly because of improvements in basic techniques for culturing anaerobes and for understanding their biochemistry and other areas of in terest. Investigations in this field were also stimulated by a renewal of interest in their ecology, their role in pathology and in biotransformations, and in the search for alternative renewable sources of energy. The initial idea for this book came from Thomas D. Brock. When Dr. Brock requested my opinion about two years ago on the feasibility of publishing a book on the genetics of anaerobic bacteria, as a part of the Brock/Springer Series in Contemporary Bioscience, I answered positively but I was apprehen sive about assuming the role of editor. However, I was soon reassured by the enthusiastic commitment of those I approached to contribute. Eventually, thanks to the caring cooperation of the contributors, the task became relatively easy.

Salmonella infections of man and animals continue to be a distressing health problem worldwide. Far from disappearing, the incidence of typhoid fever in developing countries may be far higher than we had imagined. Salmonella food poisoning has increased to one of the major causes of gastroenteritis in the developed world, in itself also an indication that animal salmonellosis is still a major cause for concern. The situation requires a concerted multidisciplinary research effort in order to generate the new information and technology needed to assist in the control of these diseases. This concept was the driving force behind the NATO Advanced Research Workshop on "Biology of Salmonella" held at Portorosa, Messina, Italy, May 11-15, 1992. With additional support from the University of Messina, Medeva Group Research (UK) and the Swiss Serum and Vaccine Research Institute, the meeting brought together epidemiologists, microbiologists, molecular biologists, immunologists and clinicians. All the participants were actively working on different but related aspects of Salmonella and salmonellosis, with most of the leading laboratories worldwide being represented. The workshop provided an excellent opportunity for interdisciplinary consultation; it is not often that the topic of Salmonella and salmonellosis is covered to such breadth and depth in one extended meeting. Keynote addresses by invited speakers were interspersed with offered papers, many by younger members of the scientific community, and this volume presents the collated manuscripts of the lectures and extended summaries of the offered papers.

Although there are a number of excellent current reviews on one or another aspect of cytomegalovirus, the last comprehensive treatment of this subject was that of Krech et al. (1971a). In view of the amazing advances in the virological, epidemiologic, and clinical knowledge of cytomegaloviruses, an up-to-date book is needed. Such a work should cover many areas of expertise and a voluminous technical literature. Each area might have been reviewed and analyzed by workers more expert than myself. However, I have embarked on the entire venture alone in order to attain unity and continuity in this book, characteristics that are not easily achieved in the more popular multiauthored works. I have tried to review the literature and to provide a critical summary for each area discussed. To do this, I provide as much of the primary data of the relevant works as needed and not just the qualitative conclusions. Inevitably, the flow of the narrative may be interrupted by dry facts and figures. However, such information is essential to make this a meaningful reference work. But for those not interested in such details, I have provided at what I hope are crucial points critiques and summaries. This book is not an exhaustive review of all the literature. This is probably no longer possible or even desirable. By selection, however, one runs the risk of having missed or ignored important papers. I am keenly aware of this, and I wish to apologize for such oversight, if that is possible.

The papers assembled in this collection comprise a majority of the oral presentations as well as several poster presentations given at the 22nd Annual Symposium arranged by the Bastern Pennsylvania Branch of the American Society for MicrobioloS)'. The symposium would not be possible without the generous support of the many sponsors (see sponsor list) or without the concerted effort of a11 the Committee members. This Symposium series has evolved into an annual Bastern Pennsylvania Branch ASM event that attracts participants from a wide geographie area. It should be noted that one of the hallmarks of these symposia involves interaction between the presenters and those in attendance. Several authors have altered their by the participants. Therefore, the manuscript that manuscripts based on comments fo11ows should be viewed as a group effort of both the participants and presenters. J ames Poupard Lori Walsh Bruee Kleger ix CONTENTS 1 Introduction 1: CURRENT METHODS The Evolution of Antimicrobial Susceptibility Testing Methods . . . . . . . . . . . . . . . 3 James A. Poupard, Stephen F. Rittenhouse, and Lori R. Walsh Antimicrobial Susceptibility Tests: Testing Methods and Interpretive Problems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Patrick R. Murray Clinician Utilization of Rapid Antibiotic Susceptibility Data: A Prospective Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Franklin P. Koontz SESSION 2: CONTEMPORARY ISSUES IN SUSCEPTIBILITY TESTING When We Should Be Testing, How Often and What to Report . . . . . . . . . . . . . . . 35 Raymond C. Bartlett Areas of Recent Emphasis of the National Committee for Clinical Laboratory Standards Subcommittee on Antimicrobial Susceptibility Testing . . . . . . . . . . . . . . . . . . . . . . . 61 James H. Jorgensen Non-Traditional Approaches for Quality Control of Antimicrobial Susceptibility Tests . . . . . . . . . . . . . . . . . . . . . . . . .

This volume is based on a FEMS Symposium entitled "Bacterial Growth and Lysis: Metabolism and Structure of the Bacterial Sacculus" held at the Monastery of Lluc (Mallorca, Spain) on 5-10 April, 1992. The goals of the symposium were to assess the present state of knowledge on the structure and physiology of the bacterial murein sacculus, and to develop new hypotheses and strategies to promote further development of the field. Consequently, the contributions compiled in this volume include broadly different approaches, from the introduction of new analytical methods to the presentation of provocative models for cell wall growth and division. Structural, biochemical, and genetic aspects are widely covered with special emphasis on the enzymology and regulation of murein hydrolases (autolysins). Comprehensive reviews on bacterial S layers and yeast cell walls are included to stimulate conceptual cross-feeding with these closely related topics. We believe that this book will provide the reader with a useful and up-to-date review of the topic. We would feel deeply rewarded by any positive influence this book may have on the future progress of the field, whereby all the scientific credit for it should be given to the authors of the excellent contributions presented.

What justifies the size of this compendium of reviews on the paramyxoviruses? As intracellular parasites that reproduce with almost complete indifference to nuclear activities, paramyxoviruses have not been providing insights about genes that regulate cellular activities and development, topics that account for much of the excitement in modem biology. For contributions of virus research to those topics, we must look to the retroviruses, which have the propensity to steal developmentally important genes and subvert them to malignant pur poses, and to the nuclear DNA viruses, whose gene expression depends heavily upon cellular transcription machinery, making them exceptionally useful tools for identifying and characterizing components of that machinery. From this perspective, it may appear that purely lytic viruses like the paramyxoviruses are sitting on the sidelines of contemporary biology. But there is plenty of action on the sidelines. Paramyxoviruses remain unconquered, devastating agents of disease. Human deaths attributable to paramyxoviruses worldwide, especially in children, are numbered in the mil lions annually. There are many pathogenic paramyxoviruses and too few effec tive vaccines, and those vaccines (against measles and mumps) are affordable only by relatively affluent nations. Moreover, the paramyxoviruses are intrin sically interesting organisms, presenting the challenge of understanding the self-replication of RNA and many other challenges peculiar to the structures and functions of their proteins, not only as individual entities, but also as they act in concert during virus reproduction and interact with vital functions of the cells they infect and often (but not always) destroy."

Marek's disease virus (MDV) is a herpesvirus which causes a lymphoproliferative disorder of the domestic chicken worldwide. This serious economical problem caused by MDV was mostly solved by development of an effective vaccine against MDV. The development of live vaccines against the disease is remarkable as it has led to the first example of a commercially available vaccine against cancer as well as against diseases caused by herpesviruses.
This volume gives an overview on many aspects of MDV research and summarizes recent advances in the field. The topics include the history, biology, and molecular biology of MDV, pathogenesis, vaccinal immunity, immune response, genetic resistance and development of recombinant polyvalent vaccines. It is hoped that this volume will make an important contribution towards the control of infectious diseases.

Much research over the past 30 to 40 years has shown that the inflammatory response, while critical for host defense during microbial infection, may itself play a central role in the pathogenesis of sepsis. Although key mediators responsible for this injury have been identified, efforts clinically to augment our conventional antimicrobial and supportive therapies during sepsis with agents modulating the inflammatory response have been unsuccessful. As a result, the mortality associated with this lethal syndrome, especially when complicated by shock, has remained persistently high. Unfortunately, during this same period of time, the incidence of sepsis has accelerated as other fields of medicine have relied increasingly on therapies that predispose to infection. While frustrating, overall this experience in the field of sepsis has not been without value. Most importantly, it has helped define on several different levels the complexity of the septic patient. Recognizing and addressing this complexity as discussed by each of the contributors to Evolving Concepts in Sepsis and Septic Shock may now provide new inroads into the treatment of sepsis.

There is considerable interest in thermophile microorganisms, in their environments, their ability to survive at temperatures which normally denature proteins, but more importantly, as a valuable resource for bio technology. The first reported isolation of Thermus by Tom Brock was in 1969. This initiated the present era of thermophilic research with the realization that where liquid water is available, there may be no limits to the temper ature at which microorganisms can grow. Considerable research into the ecology, physiology, metabolism, and thermostable enzymes of thermo philes has led to their evaluation for a range of industrial and commercial processes. The past fifteen years have been an explosive period of dis covery of many new genera and species, including the descriptions of a new fundamental kingdom-the Archaea. Much of the current research has been focused on the Archaea; but it is significant that during this period, the original type strain YT-l of Thermus aquaticus described by Brock has provided a major step forward in molecular biology. DNA polymerase from strain YT-I has proved to be the major success in the commercialization of enzymes from thermophilic microorganisms to date. The ease with which Thermus strains can be handled in laboratories without specialized equipment, together with the large investment in de scribing their structure, metabolism, and genetics, should ensure a con tinuing effort in Thermus research.

This volume is based on the program of the Second International Conference on Drugs of Abuse, Immunity and AIDS, held in Clearwater Beach, FL in June 1992. The Conference was supported in part by the University of South Florida College of MediCine with financial assistance from the National Institute on Drug Abuse. The focus of this conference was the effects of drugs of abuse on immunity. It is now widely recognized that psychoactive drugs of abuse, including marijuana, cocaine, and opiates, as well as alcohol, have marked effects in an individual, including effects on their nervous system and behavior. In the past two decades, the scope of studies concerning the effects of some drugs of abuse have also involved investigations of alterations of various physiologic parameters including effects on the immune system. and the influence of such immune alterations on normal physiological responses. In this regard, participants in this Second International Conference provided newer information concerning both basic and clinical aspects of drugs of abuse and immunity, especially immunodeficiencies. In this regard, advances have been made in recent years concerning the nature and mechanisms whereby the immune system is regulated and the possible mechanisms by which drugs of abuse influence such immune systems. In particular, the emergence of psychoneuroimmunology as a new discipline the last decade has heightened interest in the immune responses influenced by psychoactive drugs. This has resulted in interdisciplinary investigations involving both clinical and basic scientists, including microbiologists, immunologists, physiologists, psychiatrists, oncologists, psychologists, etc.

In the past decade, the global efforts in the control of HIV disease were basically concentrated on the search for anti-retroviral agents. So far, anti-HIV therapies have been shown to be disappointing because of rapid development of drug-resistant mutant variants. Despite this drawback in the therapeutic fight against HIV infection, antiviral research should be actively pursued. However, failure of antiviral therapy indicates that other avenues of research should be rapidly explored with the same energy. In this setting, striking advances have been recently made in the dissection and understanding of the viro-immunological processes governing the progressive destruction of lymphoid organs associated with AIDS develop ment, and HIV-induced activation and apoptosis have been identified as key phenomena of the immune system destruction. This book assembles the most recent advances on basic and clinical aspects ofT-cell activationiapoptosis in HIV infection and their implications for immunotherapy. These data were presented at an international symposium held on July 11-12, 1994, in Paris. The book is partitioned into 21 chapters covering four comprehensive fields: 1) T-celllmacrophage activation and HIV infection; 2) Apoptosis and viropathogenesis of HI V disease; 3) Apop tosis and immunopathogenesis ofHIV disease; 4) Mediators ofT-cell activationiapoptosis and therapeutic applications. We hope that this book will assist the readers in understanding recent advances in the viro-immunopathogenesis of HI V disease as well as the rationales for potential immune cell-targeted therapeutic interventions.

In recent years, the area of pharmacotherapy of GI inflammation has witnessed important progress, with new drugs and therapeutic approaches being introduced. The volume reviews the pharmacotherapy of selected gastrointestinal inflammatory conditions chosen on the basis of their clinical importance and/or the areas where important and exciting progress has been made recently. Besides discussing current pharmacotherapy to treat the most important GI inflammation conditions, the book also indicates possible future therapeutic avenues likely to become available in a few years.
The book is of interest to various sectors of the scientific community ranging from clinicians to pharmacologists and from biochemists to microbiologists, who will find it a useful tool for their clinical practice and research activity.

In 1996 the International Committee for Taxonomy of Viruses (ICTV) recognized the name Nidovirales, as the formal name for Coronaviridae and A rteriviridae. In recognition of this change, and in response to the wishes of our colleagues we named this meeting for the first time "The International Symposium of Nidoviruses". The meeting in the wooded environment of Lake Harmony, Pennsylvania, provided a stimulating opportunity for assessing the progress made in the field since the last meeting in Segovia Spain in 1997. Over 150 scientists from academia and industry attended the meeting. The meeting hosted senior members of the Nidovirus community, some of whom have been studying the subject for over 20 years, as well as younger scientists, the next generation of Nidoviro10gists. The traditional informal format, the shared meals, the social activities and the relatively inexpensive venue made the meeting a popular adventure. In her opening remarks Susan Weiss showed pictures from previous meetings, reminding us how young we used to look. Neal Nathanson was our keynote speaker at the opening night, giving an overview on how viral pathogenesis studies helped in shaping the evolution of viral research and vaccine development. The scientific program of the meeting was divided into 9 sessions including lO keynote presentations. The meeting opened with a session on epidemiology, evolution and genome structure. Sasha Gorbalenya shared with us insights gained from comparative sequence analysis, emphasizing the unifying traits among nidovriuses, but also pointed out the remaining "black holes".

The genus Aspergillus has a worldwide distribution and is one of the most common of all groups of fungi. They are possibly the greatest contami nants of natural and man-made organic products, and a few species can cause infections in man and animals. The aspergilli are also one of the most important mycotoxin-producing groups of fungi when growing as contaminants of cereals, oil seeds, and other foods. Not all aspergilli are viewed as troublesome contaminants, however, as several species have had their metabolic capabilities harnessed for commercial use. The aspergilli have long been associated in the Far East with the koji stage of several food fermentations, particularly soy sauce and miso, and subsequently as a source of useful enzymes. The ability of these fungi to produce several organic acids, especially citric acid, has created major industrial complexes worldwide. Traditional methods of strain develop ment have been extensively studied with the industrial strains, while more recently, recombinant DNA technology has been applied to the aspergilli with emphasis on heterologous protein production. In compiling this book, I have been fortunate to have the full enthu siastic involvement of the authors, and to them I extend my very grateful thanks for mostly being on time and for producing such readable and authoritative chapters. Collectively, we hope that our efforts will strengthen the scientific understanding of this intriguing group of filamentous fungi and further their use in the field of biotechnology.

Heat shock proteins (HSP) have received ample interest by immunologists over recent years. Initially they were found to be dominantly immunogenic microbial antigens. The connection with inflammation was established when it was uncovered that T cells specific for these antigens have a crucial role in the induction and regulation of experimental arthritis. Since then, the raised presence of immunity to HSPs in virtually all conditions of inflammation, including autoimmune diseases, transplant rejection and atherosclerosis, has emphasised the critical significance of immunity to HSPs in inflammatory diseases.

The Annexins is focused on a specific family of calcium and membrane-binding proteins, annexins, ubiquitously spread within living organisms, including animals, plants and fungi. The volume covers important areas of annexinology. The characterization of structural-functional relationship within the annexin family of proteins, together with emerging transgenic animal models, provides an up-to-date overview of potential physiological roles of annexins. Growing evidence of participation of annexins in human diseases, called annexinopathies, related to disturbances in signal transduction, vesicular traffic, ion homeostasis and energy metabolism within the cell. The book will attract a broad scientific audience, not only scientists interested in annexins, but also others involved in multidisciplinary studies, as well as undergraduate and postgraduate students. It can be used in courses relating to special topics such as calcium homeostasis, calcium-binding proteins, membrane structure and transport properties, various signal transduction pathways, and membrane trafficking.