The construction of this volume has been guided by two personal convictions. Experience in the field of experimental chemotherapy, both in the pharmaceutical industry and academia, has convinced us that recent quantum technological advances in biochemistry, molecular biology, and immunology will permit and, indeed, necessitate an increasingly greater use of rational drug development in the future than has been the custom up to now. In Part l, therefore, we asked our contributors to provide detailed reviews covering the biology of the malaria parasites and their relation with their hosts, the experimental procedures including culture techniques that are necessary to take a drug from primary screening to clinical trial, and an account of antimalarial drug resistance. Our second conviction is that many research workers are all too loath to learn from the lessons of the past. For this reason we asked the contributors to Part 2 of this volume to review very thoroughly the widely scattered but voluminous literature on those few chemical groups that have provided the antimalarial drugs in clinical use at the present time. Much can be learned from the history of their development and the problems that have arisen with them in man. Some indeed may still have much to offer if they can be deployed in better ways than they are at present. This question has been taken up by several authors.

Named for the enlarged, inclusion-bearing cells characteristic of infection by these viruses, cytomegaloviruses present a significant challenge to both microbiologist and immunologist. Although most primary infections in humans are subclinical, cytomegalovirus can be associated with a wide spectrum of disease, particularly when infection occurs in the immuno compromised individual or as a result of congenital or perinatal infection. Although reinfection with cytomegalovirus has been demonstrated, most recurrent and persistent infections result from the reactivation of latent virus. Cytomegaloviruses, like other members of the Herpesviridae family, have the capacity to establish latency after a primary infection but the mechanisms for establishing the nonreplicating but reactivat able state have not been defined. The factors responsible for the spectrum of manifestations of cytomegalovirus infection are largely undetermined but host immunological function, route of infection, and size of inoculum all contribute to the extent and severity of disease. Cytomegaloviruses have the largest genomes in the herpes virus family, approximately 240 kilo base pairs, providing a potential coding capacity for more than 200 proteins of which less than one-fourth have been mapped and described. There are many similarities to other herpes viruses in genome structure and gene expression; for example, three temporal classes of genes can be identified as rx (immediate-early), f3 (early), and y (late) products. The first five chapters of this volume review and describe recent developments in understanding the trans cription and regulation of these gene classes.

Understanding neutralization is particularly relevant to an appreciation of the interaction between a virus and its antibody-synthesizing host since it is likely that viruses and the antibody system have evolved in response to reciprocally imposed selective pressures. Neutralization of viruses which only infect non-antibody-synthesizing hosts, while of considerable interest from of points of view is de facto without any such evolutionary signifi a number cance. In this second category are viruses of plants, invertebrates, vertebrates below fish in the evolutionary scale which do not synthesize antibody and most bacteria. Viruses of organisms parasitic on or commensal with antibody synthesizing vertebrates, such as enteric bacteria, protozoa or metazoan parasites, will be in contac, with antibody at some stage of their existence, and arthropod-borne viruses which have a higher vertebrate as second host are obviously bona fide members of the first category. There is an urgent need to understand the principles by which antibodies inactivate virus infectivity since, at present, we are unable to rationally construct effective vaccines against new agents like the human immuno deficiency viruses or to improve existing vaccines. The intention of this volume is to comprehensively review neutralization and where possible to construct a unifying theory which can be tested by experimentation."

Many RNA viruses have been known for decades to be genetically and biologically quite variable. Some well-known examples are influenza viruses, foot and mouth disease viruses, and Newcastle disease virus. During the past decade, it has become clear that most, it not all. , RNA viruses (riboviruses and retroviruses) are much more mutable than was recognized previously, and that this great mutability generates extremely complex populations consisting of indeterminate mixtures of related variants (Le. , "mutant swarms" or "quasispecies" populations). This is also true of DNA viruses (such as hepatitis DNA genomes via RNA transcripts B virus) which replicate their that are reverse-transcribed back to DNA. This hypermutability of RNA replicons provides great biological adaptability for RNA virus genomes. It also allows (but does not necessitate) RNA viruses, so that they can extremely rapid evolution of evolve over a million times more quickly than their eukaryotic DNA-based hosts. The genetics of RNA replicons is so unusual (and often counterintuitive) that it has many important biological conse quences which are neither readily apparent nor widely under stood. Failure to understand the distinctive aspects of RNA genetics frequently generates confusion and controversy and can adversely impact vaccine and antiviral drug programs and other applications of medical virology. The 14 chapters in this volume describe advances in a number of significant areas of RNA virus genetics and evolution.

Medical Parasitology is primarily intended to be an illustrated textbook which provides a review ofthe most important species ofparasite which occur in man; their areas ofdistribution, morphology and development, the typical disease symptoms resulting from infection, epidemiology and also methods of detection and indications for therapy. The main emphasis is on the protozoan and helmin thic diseases; medical entomology has only been covered in connection with the epidemiology of the diseases described here. Parasites sometimes occur exclusively in man (anthropoparasites) and sometimes also in animals (anthropozoonotic parasites). The monoxenous species complete theirdevelopmentinmanorinoneanimalalone (Scheme I). Heteroxenousspecies, which include most of the medically important parasites, develop partly in man and partly in animals in the course of their life cycle. They may even be forced to infect different species so that they can continue their development. This may sometimes be associated with a digenesis, the larval development taking place in one intermediate (Scheme II (R)) or in two different intermediate hosts (Scheme III (R), (c)), andthesexuallymaturestagedevelopinginanotherhost, the so-called definitive host (Scheme III (R)). The importance of the intermediate hosts can vary considerably (see below).

The humoral response of the immune system to a foreign antigen usually requires the recognition of two antigenic determinants. The one, called the carrier, is recognized by T-Iymphocytes, the other, called the hapten, by B-Iympho cytes. As a consequence, T - and B-Iymphocytes proliferate, B-Iymphocytes produce hapten-specific antibodies, and the system develops memory to the antigens. It was long thought that antigens would form a bridge to mediate the cooperation of T - and B-Iymphocytes. However, it now appears that antigens are broken down to fragments which then act as carrier determinants for T -lymphocytes. The cells which originally process antigen are called an tigen-presenting cells. They have phagocytic properties. They can take up and degrade antigens, in the case of pro teins to peptides. The peptides of protein antigens reappear on the surface of the antigen-presenting cells, where they must become associated with membrane proteins encoded by genes of the major histocompatibility complex (MHC) in order to be recognized by T-Iymphocytes. To activate helper T-Iym phocytes which cooperate in antibody responses, MHC class II molecules have to be expressed on the surface of the antigen-presenting cells. Once T -lymphocytes have be come activated, they are ready to cooperate with B cells."

Understanding the mechanisms involved in intracellular movement and localization of proteins is a central issue in cell biology. This volume is concerned with the events involved in the transport of membrane proteins, and the contents of vesicular compartments, to their ultimate destinations. In several chapters, particular attention is given to studies with viruses that are assembled by budding at specific membrane sites within the cell or at the cell surface; studies with such viral systems have provided significant insights into membrane biogenesis.

Parasitic diseases are the most widespread of all the major diseases, currently 9 affecting about 3 x 10 people and innumerable domestic animals. There is no doubt that among these parasitic diseases, the helminthic infections of the gastrointestinal tract are about the most important because of their global distribution, their high prevalence, their effects on the nutritional status of men and animals, their effects on the physical and mental development of children, and their economic effects on the production of animals. Anthelmintics are important elements in the control of these gastrointestinal helminthic infections. In this volume the editors and authors have tried to find a way through the immense amount of information on anthelmintic drugs that is scattered throughout the literature. Different authors have critically examined this information from different angles. However, the aim of all has been to provide the information needed by veterinarians, physicians, and public health workers to select the most suitable drug for a given situation.

Prostatitis continues to be a major clinical enigma. In this book, all modern aspects of etiology, pathogenesis, diagnosis and therapy are critically evaluated. Of special interest to the readers will be the modern diagnostic management of chronic prostatitis and the debatable therapeutic approach to chronic nonbacterial prostatitis. From the contents: Radical Transurethral Prostatectomy for Chronic Bacterial Prostatitis; Etiology, Pathogenesis, and Inflammatory Reactions in Chronic Bacterial Prostatitis; Therapy of Nonbacterial Prostatitis; Ultrasonographic Features of Prostatitis.

The mouse was first used in immunological research by Paul Ehrlich in 1891 in an extraordinary series of experiments on the maternal transfer of antitoxic immunity. A short 22 years later in 1913 Halsey Bagg acquired a stock of albino mice from a commercial dealer and used them in a series of experiments on learning. Because he was interested in the genetics of intelligence, Halsey Bagg began breeding a pedigreed line of these mice that were subsequently named for him - Bagg Albino. Though Halsey Bagg is not credited with initiating the inbred strains of mice, his stock curiously has played an indisputably important role. Bagg Albinos were progenitors of the present day BALB/c family of sublines - the subject of this book. They were also used as one of the parents in the development of inbred strains A, CBA and C3H, three other very famous strains. Today the BALB/c mouse is among the five most widely used inbred strains in biomedical research and a particular favorite in immunology and infectious disease research. The hallmark of the BALB/c response to so many kinds of infections is susceptibility and sometimes an exaggerated susceptibility, but this paradoxically is not associated with immunodeficiency as BALB/c is an excellent responder to immuni zation. These characteristics have made the BALB/c mouse a model for identifying genes that determine susceptibility to infectious and neoplastic diseases. In 1985 the laboratory BALB/c mouse became 72 years old. The current filial generations are somewhere around 350 generations MURPHY]."

Rapid progress in molecular biology, genetic engineering, and basic research in immunology has opened up new possibilities for application to diagnostic procedures and to clinical research. In a short period a new era of diagnosis dawned, covering nearly all fields of microbiology, immunology, and food technology. In consequence of this rapid development, scientists of many disciplines are involved studying infections of humans, animals, and plants or working in technical microbiology. The application of the newest findings of basic research to diagnostic work and to clinical research covers nearly all fields of microbiology and immunology. Moreover, it underlines the close relationship between diagnosis, therapy, and epidemiology. An outstanding example of these connections is given by the recent development of hepatitis B vaccine. The discovery and identification of a non cultivable agent by physicochemical and immunological methods were the heralds of a new era in the prevention of infectious diseases. This book provides an up-to-date, comprehensive review of developments and future aspects in various fields. I am convinced that the authors have succeeded in furnishing a large variety of new ideas and possibilities. K.-O. HABERMEHL Contents Time Realities in the Evaluation of Vaccines for Safety and Efficacy The Evaluation of Vaccines M. R. HILLEMAN . . . . ."

Almost 30 years ago RITOSSA described a new puffing pattern in salivary gland chromosomes of Drosophila following heat shock. This was the first description of a heat shock response. For years, development in this field remained modest and it took another decade before the relevant gene products-the heat shock proteins (hsp's)-were made visible by TISSIERES and co-workers. Subsequently, progress advanced more rapidly and we can now state that studies on the heat shock response have contributed much to our understanding of various principles in molecular and cellular biology such as control of gene expression and regulation of protein translocation. More recently, the study of hsp's has converged with immunology. There are several reasons for this: The chaperone function of certain hsp's makes them particularly apt for central functions of immunity, including antigen presentation and immunoglobulin synthesis. Furthermore, an effective immune response is often caused or followed by stress situations as they arise during trauma, inflammation, transformation, infection, or autoimmune disease. Due to their abundance during stress, hsp's can provide prominent antigens in many of these situations. This volume contains 11 chapters written by well-known experts dealing with various facets of the fascinating liaison between hsp's and immunity. The particular relation of hsp's to the immune system may be best illustrated by their intimate association with the major histocompatibility gene complex. Still, as discussed by GONTHER, the relevance of this fact to our understanding of hsp functions in immunity remaif)s speculative.

Once again the Current Topics in Microbiology and Immunology series presents a volume with up-to-date review articles on oncogenes. The well-known authority and editor of previous volumes in the series, Dr. Vogt, has accepted five contributions which critically evaluate recent research in the field.

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 bering, has probably reached that stage at which relatively few new truly new-viruses will be discovered. Triggered by the intellectual probes and techniques of molecular biology, genetics, biochemical cytology, and high resolution microscopy and spectroscopy, the field has experienced a genuine information explosion. Few serious attempts have been made to chronicle these events. This comprehensive series, which will comprise some 6000 pages in a total of about 18 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 invalua ble reference and 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."

A sample of the most exciting developments in the cloning, manipulation, expression and application of genetically-engineered monoclonal antibodies. This rapidly-evolving field has witnessed the PCR combinatorial cloning of vast immunological diversity, in vitro mutagenesis of MAbs, MAbs created by transgenic animals, novel expression systems in plants, animals and lower systems, as well as a rich variety of genetically modified MAbs as potential therapeutic agents. Leading scientists from academia and industry present their own findings as well as short reviews of these research areas.

We are most gratified by the response to the initiation of this series of volumes presenting recent developments and new concepts in microbial ecology. Favorable reactions have been expressed in both oral and written communication, and Ad vances in Microbial Ecology thus seems to be providing a worthwhile outlet in a rapidly growing field of microbiology and environmental sciences. The growing importance of microbial ecology is evident in many ways. Uni versity personnel are expanding their programs and increasing the number of research topics and publications. Substantial numbers of industrial scientists have likewise entered this field as they consider the microbial transformation of chemicals in waters and soils and the effects of synthetic compounds on natural microbial communities. Agricultural, medical, dental, and veterinary practitioners and scientists have also been increasing their activity in microbial ecology because of the importance of the discipline to their own professions. In addition, govern mental agencies have expanded regulatory and research activities concerned with microbial ecology owing to the importance of information and regulations fo cused on the interactions between microorganisms in nature and particular en vironmental stresses."

The complement system is a group of proteins which plays a major role in the processing and removal of microorganisms and tissue breakdown products from the circulation and extracellular spaces. The system is activated by a wide range of targets, and activation leads to the production of opsonins, chemotaxis of granulocytes, cell lysis and other biological activities. Inappropriate overactivation of the system contributes to inflammatory tissue damage in the host, while inadequate activation leads to accumulation of immune complexes and other debris in the circulation, and susceptibility to infection. The biology and biochemistry of the system is now adequately understood, and attempts can be made to manipulate the activation and activities of the system for potential therapeutic purposes. The reviews in this volume summarise what is known of the ways in which the complement system can be activated, by interaction with antibodies, microorganisms, cell debris, and complex carbohydrates and how the activities and activation of the system have been modified, accidentally or by design, in vitro or in vivo by drugs, venoms, particulate carbohydrates, specific antibodies, synthetic peptides and other reagents.

Blastomycosis remains the most enigmatic of human mycotic infections. The enigmas encompass the natural habitat of the etiologic agent, extent of exposure and subclinical infections in endemic areas, distribution of en demic foci throughout the world, inconsistency of serologic evaluation of infected patients, and varying response of such patients to standard treat ment regimens. In spite of diligent investigations by many competent investigators, we still do not know the ecological niche inhabited by the etiologic agent. We have many tantalizing clues but no definite answers. Nor do we know the extent of the endemic areas in the world for this disease. Skin testing, so useful in defining the distribution of histoplasmosis and coccidioidomycosis, has been of no value in mapping endemic areas for blastomycosis. Even the serologic evaluation of known cases of the disease has been too erratic in results to be useful as a diagnostic or prognostic procedure. The enigmas of blastomycosis go straight to the disease itself. There is an extensive literature on the debate concerning the presence and extent of subclinical infections. Case report series demonstrate that such transient infections do occur but, unlike other mycoses, the extent to which this phe nomenon is common in the general population still cannot be assessed. Even the diagnosis of established disease is a major clinical problem.

The 8th volume in the Proteases in Biology and Disease series focuses on the role of proteases in virus function and their potential as anti-viral targets. Viral infections are still difficult to threat and some remained life-threatening diseases in spite of antiviral drug research over decades. Proteases are still regarded as an Achilles heel of the pathogens and, thus, protease inhibitors may help to handle the known and the emerging viral threads. The book discusses viral proteases of the most important pathogenic viruses, responsible for severe diseases: AIDS, SARS, Hepatitis, Cytomegalovirus, T-cell lymphotropic virus, Picornavirus. This book focuses specifically on the viral proteases, crucial prerequisites for viral entry into cells and viral replication. Viral proteases represent an important pharmaceutical target. The current stage of protease inhibitor development and therapy are summarised and discussed by experts in the field. This volume represents a timely and valuable continuation of the Proteases in Biology and Disease series. The reader will learn the potential for proteases as targets for effective anti-virals. This book will be a valuable source of information on viral proteases and provoke further research in this important field."

The 12th Workshop on ""Mechanisms in B-Cell Neoplasia"" continues this series of meetings on intriguing new developments in human and experimental B-cell tumors. The integration of knowledge from basic B-cell biology to the clinical problems of multiple myelomas, follicular lymphoma, mantle cell lymphoma and B-CLL present the challenges that were discussed in the meeting.
The discussion focusses on:
- Cellular components of the "myeloma clone"
- Genomic instability in B-cells and B-cell tumors
- The CD5 antigen and B1 cells
- Regulation of cell cycle and apoptosis
- Role of IL-6, BCL-2, BCL-1, myc in B-cell development

ADP-ribosylating toxins have been the focus of intensive research for more than 30 years. Researchers from diverse fields of science have taken an interest in these bacterial toxins; they are studied, for example, by microbiologists, biochemists, cell biologists, and pharmacologists. There are two principal reasons for the broad and still growing interest in ADP ribosylating toxins. First, insights into the structure and functions of the toxins might be the key to prevention and treatment of diseases caused by the toxin-producing infectious micro organisms. Second, the ADP-ribosylating toxins provide potent and often unique pharmacological tools for the study of the physiological functions of their target proteins. The latter is especially the case with cholera and pertussis toxins, which both modify the IX-subunits of heterotrimeric G-proteins involved in signal transduction pathways. These toxins have proved invaluable in extending our basic understanding of the regulation of hormone-controlled signal transduction. This volume provides a review and an update of recent studies on the basic properties of bacterial ADP-ribosylating tbxins and/or exoenzymes. Our current knowledge of the cel lular entry mechanisms of ADP-ribosylating toxins is reviewed by MADSHUS and STENMARK. WILSON and COLLIER then deal with recent insights into the enzyme mechanism and active site structure of diphtheria toxin and Pseudomonas aeruginosa exotoxin A, which modify elongation factor 2. Toxins which ADP-ribosylate heterotrimeric G-proteins involved in trans membrane signal transduction are the subject of the next two chapters."

Peritrophic membranes are secretion products of the midgut. For long they have been related only to insects, but they occur widely in the animal kingdom. They effect a part of the gut lumen and function not only as a mechanical protection barrier, but also as an ultrafilter, a barrier to parasites, and as envelopes for fecal pellets. Such peritrophic envelopes are of great ecological importance in marine environments. The book is divided into the following themes: - Occurrence - Formation and Structure - Degradation - Chemical Composition - Functions. It is the first comprehensive compilation of all data concerning peritrophic membranes and will provide a basis for future researches in this up to now often neglected field.

Since the discovery of Australia antigen and its association with type B hepatitis, molecular characterization of the components making up hepatitis B virus (RBV) have been pursued with worldwide interest. Over the past two decades, such characterization has led to the development of sensitive assays to screen and exclude contaminated units from blood banks and has recently resulted in the licensing of several RBV vaccines. That more than 200 million people worldwide are chronically infected with RBV, and that they are at a high risk for the development of chronic hepatitis and hepatocellular carcinoma, still represent formidable problems in our understanding of host-virus relationships on the molecular level. In the absence of a suitable tissue culture system, and with a very limited host range of infection, characterization of RBV on the molecular level has made remarkable progress recently with the advent of genome cloning, sequencing and expression of individual virus genes by recombinant DNA technology. The presence of hepatitis B-like viruses in an expanding number of animal hosts, and the possibility of virus replication in cells other than hepatocytes, provide great promise that future work will elucidate the molecular mechanisms operative in the various outcomes of RBV infection.

The Brescia division of the Italian Association of Blood donors (AVIS Brescia) celebrated its 50th anniversary in 1985. The idea of organizing a Postgraduate Course on Viral Hepatitis on this occasion developed for ob vious reasons. Viral hepatitis is a major concern in blood transfusion and Brescia is located in the region of Lombardy characterized by a high HBsAg carrier rate in its population. Thus it seemed timely to convene a scientific forum in which the present state of knowledge on viral hepatitis would be summarized. This would allow us to review the tremendous progress achieved over the last 15 years, and also to focus on latest developments which pave the way for future investigation. The publication of the proceedings of this meeting was considered use ful, since it provides a tangible reminder of a comprehensive overview of the broad topic of viral hepatitis, its complications, and its connections with the practice of blood transfusion. The organizers were fortunate in obtaining the active participation of recognized experts in a variety of hepatological diSCiplines. Their contri butions summarized the more mature areas of knowledge in the field, in cluding clinical aspects, epidemiology and morphology, as well as newer developments in the forefront of hepatitis research, like new diagnostic techniques, oncogenesis, treatment, and vaccination."