Mucosal immunity encompasses a broad field of research that includes areas of epithelial cell and molecular biology, molecular and cellular immunology, microbiology, virology, and vaccinology. This volume presents up to date and concise discussions of concepts as well as recent advances. It provides an overview of the components of the mucosal immune system, and the basic science relevant to mucosal vaccination. The authors assess current research in critical areas including: Organization of mucosal lymphoid tissue; antigen sampling and presentation in mucosal tissues; mucosalimmune responses and tolerance; immune effectors at mucosal sites; microbial-host interactions at mucosal sites; mucosal vaccines and adjuvants. This multi-disciplinary effort will be a valuable resource for researchers, clinicians and students who need a clear understanding of concepts and a guide to the wide-ranging literature in this very active research area.

This volume contains papers presented at the international conference on "Transgenic Mice and Mutants in MHC Research", held in Bar Harbor, Maine, in June, 1989. The meeting brought together eighty researchers working in the field. While mouse H-2 mutants have been known for many years their studies continue to contribute a great deal to our understanding of structure/function relationships and evolution of MHC molecules. Recently a new direction of research has emerged on regulation, expression and function of MHC genes using transgenic animals carrying exogenous MHC genes from the same or other species or engineered MHC genes. With the introduction of transgenic mice more specific questions about the various functions of MHC genes can be answered as, for example, the role of soluble and membrane-bound MHC molecules in self tolerance and elimination of specific T cell clones, recognition of human MHC antigens by the mouse immune system, the role of individual human MHC genes in disease susceptibility. New approaches for evaluation of the role of MHC linked and unlinked genes in susceptibility of mice to malignant tumors and their metastases have been also reported. Our purpose has been to provide a forum for discussion of these new developments. Many questions remain to be answered but the necessary tools have become available. We thank the contributors and hope that the readers will benefit from this Pro ceedings. We wish to acknowledge the financial sponsorship for the meeting by The Pew Charitable Trust and Howard Hughes Medical Institute.

The newest volume in the Current Topics in Microbiology and Immunology series edited by Dr. Vogt and dealing with oncogenes and retroviruses contains four review articles by international authorities in the field. These articles presenting the latest research results continue the tradition of excellence for which the series is so well known.

Parasitic zoonoses, the parasitic diseases transmitted between humans and other vertebrate animals, are widespread. The increasing pace of internationalization changes in diet and easy movement from one part of the world to another has caused parasitic zoonoses to be more prevalent. Consequently, these diseases have become the focus of recent research by parasitologists and pathologists whose work is presented in this book. Included in addition to the pathology of parasitic zoonoses and recent trends in research of imported parasites are the classification of phenotypes of anisakid nematodes, the immunohistopathological diagnostic method, and molecular technology to detect and diagnose parasites. Also included are papers on parasitology and international health and the pathology of cerebral malaria. With 38 color illustrations, this book is an invaluable resource for parasitologists, pathologists, and clinicians.

Michael Potter, Fritz Melchers, Martin Weigert The second workshop on Mechanisms of B Cell Neoplasia was held in Bethesda, Maryland in Wilson Hall at the National Institutes of Health on March 5, 6, and 7, 1984. It followed a workshop on the same topic that was held at the Basel Institute for Immunology, March 15-17, 1983. That first meeting attempted to bring together cell biologists, experimental pathologists and molecular geneti- cists interested in B cells, to discuss pathogenetic processes in the development and maintenance of the neoplastic state. The impetus for this discussion emanated from two important developments: first, the discovery of the viral promoter insertion mechanism for acti- vating the myc oncogene in bursal lymphomatosis by Hayward, Neil, and Astrin;-second, the findings that the non-random chromosomal trans locations involving the immunoglobulin gene chromosomes occur- red in very high frequencies in murine plasmacytomas and human Burkitt's lymphomas. During the planning stages of that meeting Shen-Ong et al. discovered that non-random translocations activated the myc oncogene. Promoter insertions and non-random trans locations were-rwo mechanisms that caused transcription of the myc oncogene messages in three different kinds of well defined experimental and clinical B cell tumors. Unregulated myc gene transcription provided the first evidence of a specific bioChemical lesion in B cell neo- plasia.

Tuberculosis has plagued mankind since prehistoric times and is still an important source of morbidity and mortality, with particularly devastating effects in developing and tropical countries. Tuberculosis results from an infection with Myeo baeterium tubereu/osis, and the World Health Organization estimates that perhaps as much as one-third of the world's population or approximately 1. 9 billion persons are or have been infected with M. tubereu/osis. Each year, there are 8-10 million new cases of tuberculosis and about 3 million deaths due to it. Indeed, tuberculosis is the leading cause of death in adults due to a single infectious agent and accounts for ap proximately 26% of all preventable adult deaths in the world. In addition, tuberculosis is an enormous social and economic problem because approximately 95% of new cases occur in developing countries and because about 80% of tuberculosis cases affect persons of child-bearing age and du ring their most economically productive years (ages 15-59). Tuberculosis has also re-emerged as an important public health problem in many developed countries. For example, between 1985 and 1992, the number of tuberculosis cases reported to the United States Centers for Disease Control and Prevention increased by more than 20%. Similarly, Austria experienced a 5% increase in tuberculosis cases from 1987 to 1991, Ireland a 9% increase from 1988 to 1991, Denmark a 20% increase from 1987 to 1992, and Italy a 27% increase from 1988 to 1992."

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."

The fact that none of the known DNA polymerases is able to initiate DNA chains but only to elongate from a free 3' -OH group raises the problem of how replication is initiated, both at the replication origin and on Okazaki frag ments. It was first shown by A. KORNBERG et al. that a general mechanism to initiate replication is through the formation of an RNA primer catalyzed by RNA polymerases or by a new class of enzymes, the primases (KORNBERG 1980). This mechanism, which can be used in the case of circular DNA molecules or linear DNAs that circularize or form concatemers, cannot be used at the ends of linear DNAs since the RNA primer is removed from the DNA chain, and there is no way of filling the gap resulting at the 5' -ends of the newly synthesized DNA chain. In some cases linear DNA molecules contain a palin dromic nucleotide sequence at the 3' -end that allows the formation of a hairpin structure which provides the needed free 3'-OH group for elongation. This mechanism, first proposed by CAVALIER-SMITH (1974) for eukaryotic DNA repli cation, was shown to take place in several systems (KORNBERG 1980, 1982). Another mechanism to initiate replication consists in the specific nicking of one of the strands of a circular double-stranded DNA, producing a 3'-OH group available for elongation (KORNBERG 1980)."

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.

In the past ten years there has been enormous progress in the development of eukaryotic viral vectors. In general, these vectors have been developed for one of three reasons: to achieve high levels of expression of a particular gene product (poxvirus, baculovirus, and adenovirus), to clone eukaryotic genes in combination with functional assays (Epstein-Barr virus), of for use as delivery vehicles for the stable introduction of foreign genes into mammalian cells (retroviruses, Epstein-Barr virus, and adeno-associated virus). Each vector has its strengths and weaknesses that are rooted in the sometimes bewildering stra tegies that the parent viruses use for propagation. No one of these vectors is appropriate for all of the problems that a mole cular biology laboratory is likely to encounter, and few of us are knowledgeable in the molecular virology of all of these viruses. This volume represents an attempt by the authors to assem ble a review of these vectors in one place and in a form useful to laboratories that do not necessarily have experience with eukaryotic viruses. Clearly, any virus can be modified to serve as a vector for some purposes, and it was not possible to include a description of all of these. In addition, one eukaryotic vector, SV40 (the first one developed), has been reviewed so widely that we saw no reason to include it here."

Genetic / DNA immunization represents a novel approach to vaccine and immune therapeutic development. The direct injec tion of nucleic acid expression cassettes into a living host results in a limited number of its cells becoming factories for production of the introduced gene products. This host-inappropriate gene expression has important immunological consequences, resulting in the specific immune activation of the host against the gene delivered antigen. The recent demonstration by a number of laboratories that the induced immune responses are functional in experimental models against both specific infectious diseases and cancers is likely to have dramatic consequences for the develop ment of a new generation of experimental vaccines and immune therapies. This technology has the potential to enable the pro duction of vaccines and immune-based therapies that are not only effective immunologically but are accessible to the entire world (rather than just to the most developed nations). Vaccine Development Vaccination against pathogenic microorganisms represents one of the most important advances in the history of medicine. Vaccines, including those against polio, measles, mumps, rubella, hepatitis A, hepatitis B, pertussis and other diseases, have dramatically improved and protected more human lives than any other avenue of modern medicine. The vaccine against smallpox, for example, has been so successful that it is now widely believed that this malicious killer, responsible for more deaths in the twentieth century than World Wars I and II combined, has been removed from the face of the earth.

The great majority of bacterial infections are initiated by the adhesion of pathogenic bacteria to cells and mucosal surfaces of the host. The sequela of adhesion may range from the action of toxins outside target cells to their penetration into or through tissue. Besides the consequences of bacterial adhesion related in infection, the result may be colonization of mucosal surfaces with normally harmless bacteria, which in stress situations may become virulent, a phenomenon known as nosocomial infections. With very few exceptions, adhesion is carbohydrate speci fic. It is mediated by bacterial recognition proteins that are, according to the phenomenon studied, termed adhesins or hem agglutinins; the term "lectin" is sometimes also used. The chemical nature of the ad he sins and their organization on the bacterial surface have been studied intensively in many laboratories. The application of genetic and biochemical techniques has led to substantial progress in the molecular characterization of adhesins in recent years. We now know that adhesins may occur as structural subunits of fimbriae and that they may form fimbriae which can be considered as mono- or multifunctional linear adhesin polymers. Other adhesins do not form recognizable structures and are tenta tively called nonfimbrial. Adhesins may even be components of bacterial cell walls. Adhesin-receptor specificities have been unravelled. The study of the distribution of receptors in tissue has created implications about the possible susceptibility to infections.

When it comes to bacterial disease, we are living in a state of false security. Antibiotics have indeed brought unprecedented health benefits, protection from and cure of bacterial diseases during the past 50 years. But there are ominous signs that the fortress and the defenses built on antibiotics are crumbling. They are crum bling because we wittingly or unwittingly created selective con ditions for the emergence of superior pathogens that can no longer be controlled by antibiotics. There are numerous warnings. After a long period of eclipse tuberculosis has now emerged as a serious threat unchecked by antibiotic treatment. Recent years have seen reports of cholera epidemics, of anthrax infections, of serious problems with Salmonella and even with E. coli, just to name a few. Mankind is in a race with microbial invaders. The challenge is to anticipate and respond to developments that affect the precarious balance between man and microbe. This will re quire new knowledge and it will take time for an effective appli cation of that knowledge."

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)."

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.

The evolution ofdata about the HIV-Associated Lipodystrophy Syndrome has been rapid. The syndrome itself is complex and controversial. Although great progress has been made in understanding epidemiology and etiology of the syndrome, much about the syndrome remains mysterious. It was our intention to assist HIV providers with a framework for understanding the status and complexities ofthe field. Each author was requested to provide an evidence-based discussion of a topic for which they have expertise. While it is impossible that such a volume be completely comprehensive, we believe that the approach of this book will allow the reader to develop a relatively complete snapshot of the syndrome. We also believe that the reader of this volume will be able to confront the emerging literature on the HIV-associated lipodystrophy syndrome with a critical eye and that the volume will provide a context in which to place additional data as they are published.

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.

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."

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.

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."