A century ago the Italian pathologist Bizzozero described the relationships between spiral bacteria and the mammalian gastro intestinal tract. Since 1982, when Helicobacter pylori was discovered, gastroduodenal disease have been completely revised as a con sequence of the results of basic and clinical research in this field. Progress in understanding the pathogenesis of this bacterium has been made by studying H. pylori infection in animal models. More specific diagnostic tools have been developed using new molecular biology techniques. Future trends are directed towards preparing a specific H. pylori vaccine. A new classification for gastritis, the Sydney System, including H. pylori gastritis, was proposed in 1990. As concerns the clinical approach to peptic ulcer disease in the 1990's, the majority of authors agree on the importance of H. pylori eradication. Moreover, recent clinical studies suggest that H. pylori infection can be associated with other gastroduodenal diseases, such as non ulcer dyspepsia and gastric cancer. Multicenter trials to standardize serological methods and evaluate the efficacy of new antimicrobial therapy schedules are planned throughout different European countries. The fourth Workshop of the European Helicobacter Pylori Study Group was held in Bologna, Italy, in November 1991. Two years before Bologna University celebrated its ninth centennial, giving evidence of being the oldest University in the modern world. Thus the H. pylori story that has continued for more than a century has been discussed once again at the University with the oldest tradition in the world."

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."

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.

Many of the fundamental concepts of animal virology originated from the study of the variola-cowpox-vaccinia virus system with vaccinia virus serving as the type species (Fen- nerand Burnet 1957; Burnet 1959; Fenner 1976a, b). The importance of the Poxviridae(Fen- ner 1979) for the study of viruses as biologic entities and in defIning the events which occur in virus-infected cells are exemplifIed by investigations which: (a) described the epidemiology of a virus disease in an animal population (Fenner1949, 1959b); (b) em- ployed electron microscopy to study virion structure (Peters 1956, Nagington and Home 1962, Dales and Siminovitch 1961) and to derme the morphologic stages of virion develop- ment in infected cells (Morgan et al. 1954, Dales 1963); (c) dermed and elaborated on the mechanism of nongenetic reactivation for an animal virus (Joklik et al. 1960a, Fenner and Woodroofe 1960, Hanafusa 1960); (d) described the intracellular uncoating of a viral genome (Joklik 1964a, b); (e) studied the antigenic structure and complexity of poxvirions (Loh and Riggs 1961, Woodroofe and Fenner 1962, Appleyard et al. 1964, Appleyard and Westwood 1964); (1) described the use of chemotherapy to treat viral infec- tions (Bauer et al. 1963); (g) fIrst demonstrated the presence of virion-coded enzymes encapsulated within virions (Kates and McAuslan 1967, Munyon et al. 1967); and (h) established the H -2 restriction of cytotoxic T-cell killing of virus-infected cells in the murine system (Doherty et al. 1976).

Die Naturwissenschaften; Edward Arnold Co.; Research in Veterinary Science; Ltd.; Farm Mechanization and Buildings; Springer Verlag; The Ciba Foundation Ltd.; Journal of Agricultural Science; Journal of The Institute of Biology; The Lancet; The Reproduction and Fertility; Lea and Febiger; Physiological Society (G. B.); The Royal Masson et Cie, Paris; MacMillan Publishing Society; University of Chicago Press; Uni- Co., Inc.; National Academy of Science, versity of Rhodesia; Verhandlungen der U.S.; National Research Council of Canada; Deutschen Gesellschaft fur KreislautJorsch- Nature, London; North Holland Publishing ung; Waverly Press; and W. B. Saunders. Co.; Oxford University Press; Pergamon Press; Physiology and Behavior; Poultry D. L. INGRAM Science Association; Reinhold Publishing L. E. MOUNT Contents Preface Chapter 1 The Thermal Eml'ironment 1 Hot, Thermally Neutral, and Cold Environments 1 Development of Climatic Physiology 3 Physical Principles Chapter 2 Heat Exchange between Animal and Environment 5 Metabolic Heat and Its Dissipation 5 Body Temperature 6 Poikilotherm and Homeotherm 7 Heat Flow 8 Sensible Heat Transfer 9 Evaporative Heat Transfer 16 Calorimetry 21 Chapter 3 Metabolic Rate, Thermal Insolation, and the Assessment of Environment 24 Metabolic Rate and Heat Loss at High Temperatures 24 Thermal Conductance and Insulation 27 Evaporative Heat Loss 31 The Assessment of Thermal Environment 34 Responses of Different Species to High Temperatures 37 Physiological Mechanisms Chapter 4 Evaporative Heat Loss 39 Evaporative Loss from the Respiratory Tract 39 ix x Contents Conservation of Water Loss from the Respiratory 40 Tract in a Hot Dry Climate

The present volume contains 17 lectures of the 41 st Mosbach Colloquium of the Gesellschaft fiir Biologische Chemie, held from April 5-7, 1990 on the topic "The Molecular Basis of Bacterial Metabolism". From the beginning it was not the intention of the organizers to present a comprehensive account, but rather to select new, exciting progress on sometimes exotic reactions of specifically bacterial, mainly anaerobic metabolism. Members of our society had contributed to this progress to an extent that greatly stimulated the scientific exchange with international colleagues during the days in Mosbach. The editors hope that this stimulation will be conveyed to the readers of the articles, which reach from the biochemistry of methanogenesis, via anaerobic radical reactions, metal biochemistry in hydrogen and nitrogen metabolism, conversions of light - and redox energy, to the regulation of metabolic adaptation, and the attempts to bioengineer novel pathways for the degradation of xenobiotica. We believe that the book represents a highly progressive field of over lapping disciplines, comprising microbiology and molecular genetics, chemistry of biomimetic interest, and biophysics, and that it gives insight into the impact modern technologies have on microbiological research today. The colloquium was generously supported by the Deutsche Forschungsgemeinschaft, the Paul-Martini-Stiftung, and the Fonds fiir Biologische Chemie. A. Trebst, G. Schafer, and D. Oesterhelt were a great help in preparing the program and we wish to thank them for their advice.

The last decade has seen an explosion in our understanding of how bacterial pathogens trick, cajole, usurp and parasitize their various hosts. This renaissance is due to the convergence of molecular and cellular techniques with the power of microbial genetics. The purpose of this volume is to introduce recent advances in understanding selected systems chosen from both plant and animal hosts of bacterial pathogens. This somewhat nonobvious choice of topics was spurred by the recent findings, detailed by several conributors to this volume, of common systems used to secrete virulence factors from pathogens of both plants and animals. These serendipitous findings underscored the importance of basic research approaches to parallel problems in biology. More importantly, they brought together investigators who may not have otherwise become conversant with each other's experimental systems. I, for one, find the kinds of synergism reflected in a volume of this sort to be one of the most pleasant aspects of science and hope that the reader, whether a newcomer to the field or an expert, can find a new slant to old problems in the reviews contained h, E: lre. It was, however, necessary to limit volume length, and this has forced the exclusion of a number of fascinating bacterial pathosystems.

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."

An integrated retrovirus effectively becomes part of the cellular genome, but with the difference that the virus to a large extent retains control over its own expression through nontranslated sequences in the long terminal repeat (L TR). Some retroviruses also code for nonstructural proteins that further regulate proviral expression. Integration changes the cell genome; it adds viral genes, and in the case of transducing retroviruses also adds cell-derived oncogenes that have been incorporated into the viral genome. Integration can also have consequences for cellular genes. The transcriptional signals in a provirus can activate expression of neighboring cellular genes; the integration even can disrupt and thus inactivate cellular genes. These effects of retroviral genomes take place in cis; they are referred to as insertional mutagenesis and are the subject of this volume. Almost 10 years have passed since W. Hayward, S. Astrin, and their colleagues found that in B cell lymphomas of chickens, induced by avian leukosis virus, transcription of the cellular proto-oncogene myc was upregulated through the integration of a complete or partial provirus in its vicinity. This landmark discovery suggested a mechanism by which retro viruses that do not carry cellular oncogenes in their genome ("nonacute retroviruses") can cause cancer. It contributed the first evidence for the carcinogen potential of oncogenes that are not part of a viral genome."

Important progress in the elucidation of the mechanisms influencing bacterial pathogenicity has recently been made through the introduction of modem genetic techniques. Molecular cloning allows the isolation of genes for pheno- types that epidemiological surveys have suggested play an important role in pathogenesis. The structural analysis of determinants for pathogenic traits can lead to the identifica- tion not only of the primary sequence but also of the possi- ble secondary and tertiary structures for important viru- lence factors such as toxins and adhesins. From these data, the prediction of antigenic domains suitable for the devel- opment of new vaccines appears to be feasible. The regula- tion of virulence determinants by endogenous and exoge- nous factors can be more clearly understood through the functional analysis of the cloned virulence genes. This volume surveys representative virulence properties of gram-positive and gram-negative bacteria to which the genetic approach has been successfully applied. The exam- ples described here include important bacterial toxins (e.g., diphtheria toxin, cholera toxin, toxic shock syndrome toxin, hemolysins), adhesion structures from E. coli and Neisseria gonorrhoeae, and factors supporting iron uptake, serum resistance, and invasiveness in a variety of bacteria. Both the present state and the possible futural develop- ments of these systems are described.

A puzzling epidemiological problem was the driving force behind the discovery of human adenoviruses by Wallace Rowe and his colleagues 30 years ago. The de velopment of a plaque assay for poliomyelitis virus in 1953 led us to the threshold of quantitative virology, and in the same year the double-helical structure of DNA was discovered and became a cornerstone of mo lecular biology. The potential of adenoviruses as research tools in the molecular and cellular biology of eukaryotic cells was recognized as early as the late 1950s and early 1960s by several investigators. Structural and biochemical stu dies dominated the early years. In 1962, some of the adenoviruses were the first human viruses shown to be oncogenic in experimental animals. Thus adenovirology offered the investigator the entire gamut of host cell interactions, productive and abortive, as well as trans formed and tumor cell systems. The possibilities that adenoviruses afforded for the study of the molecular biology and genetics of eukaryotic cells were fully rea lized in the late 1960s and the 1970s."

Pioneering work on hepatitis B virus and hepatitis delta virus, and the discovery of hepatitis B-like virus in animals during the 1970's has been followed, over the past ten years, by an explosion of interest in how these viruses replicate, maintain chronic infections, and cause liver disease and hepatocellular carcinoma. The purpose of this book is two-fold. First, the authors of each chapter provide a summary of their specialty that will not only serve as an introduction, but will also provide the newcomer to hepatitis B virology with up-to-date information and insights into the goals and accomplishments of each area of investigation. Second, since the diversification of interests and increased specialization of hepadnaviruses researchers has reached a level where it is no longer possible for any one individual to read all the primary literature, this book will help to refocus interest on what is, after all, the major objective: to understand and ultimately treat or prevent chronic liver disease and liver cancer. Accordingly, chapters are included which span a range of interests, from the management of hepatitis B patients to new approaches to antiviral therapy, from the role of hepadnavirus gene expression in DNA replication to the role of ribozymes in the delta virus life cycle, from liver cancer in naturally infected woodchucks to liver disease in HBV transgenic mice to the use of hepatitis virus vectors to treat inherited enzyme deficiencies.

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.

Binding of various ligands (hormones, neurotransmitters, immunological stimuli) to membrane receptors induces the following changes: 1. Receptor redistribution (clustering, "capping") 2. Conformational changes that can be detected by fluorescent probes 3. Alteration in membrane fluidity (spin label and fluorescence polarization probes) 4. Changes in fluxes of ions and metabolites 5. Increased phospholipid turnover (especially of phosphatidyl inositol) 6. Activation of membrane-bound enzymes (adenyl cyclase, ATPase, transmethylases). Some of the early changes resulting from or associated with the binding (adsorption) of virions to the host cell membrane are of the same type. Adsorption of animal viruses to cells is the ftrst step in a chain of events resulting in the production of progeny virus on the one hand and in damage to cells and tissues on the other. In the classical studies of viral infection, cells are adsorbed with virus, usually for 60 min, and the changes induced by the virus in the host cell are recorded thereafter. In the past decade, more and more studies have been aimed at the events occurring in these ftrst 60 min of the so-called adsorption period. These studies deal with the nature of adsorption, e. g. , the ligand-receptor type of interaction between the virus and the cell membrane. Many receptors for viruses were identifted and so were the viral proteins which take part in adsorption.

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."

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.

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).

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.