Research in diabetes has accelerated in two areas, both of which are being reviewed in CTMI. The first is the use of a variety of animal models; the second is basic research in human investigation, islet cell antigens, and mapping of genes as sociated with susceptibility to disease. Dr. Thomas Dyrberg accepted editorial responsibility for this volume, which covers the first area. A second book, to be published later in the year, is edited by Drs. Brekkeskov and Hansen (CTMI 164, see page VI for contents). Although the contributors to both volumes represent the international scientific community, the editors are from the Hagedorn Research Laboratory in Denmark. Work at this institute and the Steno Memorial Hospital has been dedicated to research in diabetes for decades, and the insti tutions were appointed WHO Collaborating Centres for Re search and Training on the Pathogenesis of Diabetes Mellitus in 1983. It is worth noting that while addressing the hypothesis of the role of class II major histocompatibility glycoproteins in autoimmune diabetes (insulin-dependent diabetes, IDDM) a number of investigators established animal models in which class II molecules were expressed under the control of the rat insulin promoter. While generating interesting information on 100M, the finding of immunologic tolerance in such transgenic mice has attracted the attention of several basic immunologic laboratories for quite different reasons. Thus, we are reminded again of the Pasteur dictum that "chance favors the prepared mind. " Michael B. A. Oldstone, M. D."

The ADG held its first International Symposium at Churchill College, Cambridge, in July 1979. The second symposium was also held at Churchill College on 30-31 July, 1981, and this, the third, took place at the same college on 30-31 July, . 1983. The meeting was structured in a format which we hoped would appeal to the full range of our membership. The philosophy of the ADG is that medical microbiologists, veterinarians, toxicologists and dental bacteriologists have much to learn from each other and can best be achieved by bringing these various disciplines together frequently and in informal surroundings. Again the symposium was very generously sponsored by May and Baker Limited who met all costs of the meeting and entertained us splendidly. David Jackson and Donald Bedford were re sponsible for coordinating with the ADG on behalf of May and Baker and, as usual, gave us their full cooperation. This book contains the full-length papers, followed by the posters presented at the meeting. This book also serves as a vehicle for the abstracts of the first meeting of the Society for Intestinal Microbial Ecology and Disease, SIMED, held in Boston, Massachusetts. An introduction to this new society by its President, Sydney M. Finegold, M.D., precedes the abstracts. M.J. Hill VI CONTENTS Preface v List of contributors VIII Introduction to the Anaerobe Discussion Group M.J. Hill XI A guinea-pig model demonstrating synergy between Escherichia coli and Bacteroides fragilis in infected surgical wounds."

If tumor viruses did not exist in nature they might have been created by scientists interested in basic mechanisms of develop- ment, differentiation, and tumorigenesis. In contemporary euka- ryotic cell biology tumor viruses playa similar role to that which bacteriophages once had for the molecular biology of prokary- otes. Tumor viruses provide extremely useful probes for the above cellular processes since their life cycle is genetically pro- grammed and can be followed at DNA, RNA, and protein levels. The experimental systems reviewed in this volume utilize a wide variety of viruses. A comprehensive introduction to this field has recently been published in the volumes of Molecular Biology o/Tumor Viruses: DNA Tumor Viruses, 2nd edition, edited by J. Tooze; and Molecular Biology o/Thmor Viruses: RNA Tumor Viruses, 2nd edition, edited by R. Weiss, N. Teich, H. Varmus, and J. Coffm, by Cold Spring Harbor Laboratories in 1980 and 1982. Polyoma and SV40 viruses (see the chapter by A. Levine) and adenoviruses (see the chapter by W. Doerfler) are double- stranded DNA-containing viruses. Polyoma and SV40 are struc- turally related viruses which contain a genome of approximately 5 kilo basepairs, while the DNA of adenovirus is about 7 times more complex. These DNA tumor viruses are understood at a genetic and molecular level which is comparable to our know- ledge of A and T4 bacteriophages. Retroviruses, the subject of the remaining four chapters, con- tain a single-stranded RNA genome of 5-8 kilobases.

Human gene therapy holds great promise for the cure of many genetic diseases. In order to achieve such a cure there are two requirements. First, the affected gene must be cloned, its se quence determined and its regulation adequately characterized. Second, a suitable vector for the delivery of a good copy of the affected gene must be available. For a vector to be of use several attributes are highly desirable: these include ability to carry the intact gene (although this may be either the genomic or the cDNA form) in a stable form, ability to introduce the gene into the desired cell type, ability to express the introduced gene in an appropriately regulated manner for an extended period of time, and a lack of toxicity for the recipient. Also of concern is the frequency of cell transformation and, in some cases, the ability to introduce the gene into nondividing stem cells. Sev eral animal viruses have been tested as potential vectors, but none has proven to have all the desired properties described above. For example, retroviruses are difficult to propagate in sufficient titers, do not integrate into nondividing cells, and are of concern because of their oncogenic properties in some hosts and because they integrate at many sites in the genome and, thus, are potentially insertional mutagens. Additionally, genes introduced by retroviral vectors are frequently expressed for relatively short periods of time. A second virus used as a vector in model systems has been adenovirus (Ad)."

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."

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 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.

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 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.

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 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.

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.

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.

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.

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."

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.

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."

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.

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."