At this writing the decade of the 1980s is rapidly coming to a close, and it is an appropriate time to review the picornavirus field. During the past decade there has been a remarkable reemergence of interest in picornaviruses and a virtual explo- sion of experimentation. The renaissance of picorna viruses can be attributed to several developments near the beginning of the 1980s. In 1981 the nucleotide sequence of the first picornavirus genome, that of poliovirus, was determined, providing a genetic map that would be the basis for a number of experimental questions regarding gene function and expression (Kitamura et ai. , Nature 291: 547; Racaniello and Baltimore, Proc Natl Acad Sci USA 78: 4887). In the same year it was reported that a cloned eDNA copy of the poliovirus genome is infectious when transfected into cultured mammalian cells (Racaniello and Baltimore, Science 214: 916, 1981). This discovery, which enables construction of poliovirus mutants and recombinants, has since been used for the study of many picornaviruses. Furthermore, the availability of cloned copies of viral genomes permits manipulation of gene products apart from infected cells. Third, the use of hybridoma technology to generate anti- picornavirus neutralizing monoclonal antibodies permitted mapping of antigenic sites (for example, Evans et ai. , Nature 304: 459, 1983). Finally, at mid-decade the three-dimensional structures of poliovirus (Hogle et ai. , Science 229: 1358, 1985) and rhinovirus (Rossmann et ai. , Nature 317: 145, 1985) were solved.

Malignant melanoma is the focus of investigations which range from basic re search to clinical trials with conventional therapy and with biological response modifiers. The involvement of investigators with different backgrounds in combi nation with recent progress in biotechnology has facilitated the characterization of the antigenic profile of melanoma cells, the analysis of the structural and function al properties of melanoma-associated antigens, and the application of immuno diagnostic and immunotherapeutic approaches to melanoma. As a result, a large body of information about various aspects of melanoma has been rapidly accumu lated during the past few years. In organizing this book I aimed at providing a readily available source of infor mation on the current research in melanoma. To this end I invited investigators with active research programs to contribute chapters describing and discussing the significance of their most recent results. To facilitate the preparation of the manu scripts and to avoid duplicating other recently published books on melanoma, I discouraged the contributors from providing extensive reviews of the literature on the various topics. Although I made every effort to be as complete as possible in the selection of the contributors, while writing this preface I realized that I had overlooked at least three investigators whose work should have been included.

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.

It is fourteen years since insulin was last reviewed in The Handbook of Ex perimental Pharmacology, in volume 32. The present endeavor is more modest in scope. Volume 32 appeared in two separate parts, each having its own subeditors, and together the two parts covered nearly all areas of insulin pharmacology. Such comprehensiveness seemed impractical in a new volume. The amount of in formation related to insulin that is now available simply would not fit in a reasonable amount of space. Furthermore, for better or worse, scientists have be come so specialized that a volume providing such broad coverage seemed likely in its totality to be of interest or value to very few individuals. We therefore decided to limit the present volume to the following areas: insulin chemistry and structure, insulin biosynthesis and secretion, insulin receptor, and insulin action at the cellular level. We felt these areas formed a coherent unit. We also felt, perhaps as much because of our own interests and perspectives as any objective reality, that these were the areas in which recent progress has been most dramatic, and yet, paradoxically and tantalizingly, these were the areas in which most has yet to be learned. Even with this limited scope, there are some major gaps in coverage. Regrettably, two important areas, the beta cell ATP-sensitive potassium channel and the glucose transporter, were among these. Nevertheless, the authors who con tributed have done an excellent job, and we would like to thank them for their diligence.

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."

Immunopharmacology is defined as that part of pharmacology that deals with drugs acting on the immune system and, in addition, with the pharmacological actions of substances derived from the immune system. In order to lend sharper definition to the term immunopharmacology the subject matter has been divided according to clinical and pragmatic criteria. The division into immunosubstituion, immunosuppression, antiallergic substances and immunostimulation gives the heterogeneous material a tighter structure than would any classification according to origin, chemical structure or mechanism of action.

A host of environmental factors regulate the embryonic development of neurons. In adults, the survival of neurons, the regeneration of damaged axons, and plastic changes in axonal arborization are also controlled by a complex array of environmental cues. An important category of regulatory influences involves target-derived hormone-like peptides act ing on neuronal cell surface receptors. Nerve growth factor (NGF) was the first such factor to be characterized (LEVI MONTALCINI and HAMBURGER 1953) and has served as the model against which all similar factors are compared. A number of factors with properties similar to NGF have been described with activities toward differing populations of neurons. Many of these factors have been characterized only poorly at the biochemical level. However, several factors have been charac terized to the extent that molecular clones are available and complete amino acid sequences are known. These include: three structurally related factors, NGF itself (SCOTT et al. 1983), brain-derived neurotrophic factor (BDNF) (LEIBROCK et al. 1989), and neurotrophin-3 (NT-3) (MAISONPIERRE et al. 1990; HOHN et al. 1990); ciliary neurotrophic factor (CNTF) (LIN et al. 1989) and a second set of structural homologs; acidic and basic fibroblast growth factors (aFGF, bFGF) (ABRAHAM et al. 1986; JAYE et al. 1986). Investigators have cloned the receptors for NGF (JOHNSON et al. 1986; RADEKE et al. 1987) and FGF (LEE et al. 1989)."

Current Topics in Medical Mycology, which is a new annual series published by Springer-Verlag, is intended to summarize current topics in medical mycology for medical mycologists and other scientists who are work- ing in microbiology and immunology. Topics to be in- cluded in each year's volume will serve as contemporary reviews, summaries of current advancements and future directions, and mechanisms to enhance the interdiscipli- nary use of medically important fungi in the areas of pathogenesis, epidemiology, mycotoxins, taxonomy, and other areas where basic, applied, and clinical science are used. Michael R. McGinnis Contents ix Contributors 1 Pathology of the Mycoses in Patients with the Acquired Immunodeficiency Syndrome (AIDS) FRANCIS W. CHANDLER 1 Composition and Structure of Yeast Cell 2 Walls 24 GRAHAM H. FLEET 3 Animal Models for Candidiasis M. NEAL GUENTZEL, GARRY T. COLE, and 57 LEODOCIA M. POPE 4 Dermatophyte Antigens and Cell-Mediated Immunity in Dermatophytosis 117 TAAVIKAAMAN 5 Natural Cell-Mediated Resistance Against Cryptococcus neoformans: A Possible Role for Natural Killer (NK) Cells J UNEANN W. M URPHY 135 6 Biotyping of Medically Important Fungi FRANK C. ODDS 155 7 Characterization of Protein and Mannan Polysaccharide Antigens of Yeasts, Moulds, and Actinomycetes ERROL REISS, MILTON HUPPERT, and ROBERT CHERNIAK 172 Contents viii The Changing Epidemiology and Emerging 8 Patterns of Dermatophyte Species 208 JOHN WILLARD RIPPON 9 Paracoccidioides brasiliensis: Cell Wall Glucans, Pathogenicity, and Dimorphism GIOCONDA SAN-BLAS 235 10 The Role of Zinc in Candida Dimorphism 258 DAvID R. SOLL 11 Killer Yeasts REED B.

The findings of immunogenetic linkages, autoantibodies including autoislet cell and autoinsulin antibodies-and viruses in diabetes has attracted increasing interest among immunologists, virologists, geneticists and clinicians. To gather together the recent avalanche ef new and exciting information emerging in this area, Current Topics in Microbiology and Immunology has put together two volumes on this subject. The first volume, CTMI 156, (see page VI for contents) provided data on the animal models and experimental approaches currently employed to evaluate both the autoimmune and virologic factors contributing to the causation and patho genesis of diabetes. The second is this current volume. It is edited by Drs. BAEKKESKOV and HANSEN and focuses on current knowledge in human diabetes. This volume on human diabetes contains ten chapters from leading researchers. The book is arranged in two components. The first part critically analyzes the genes in man that playa role in susceptibility to insulin dependent diabetes mellitus (IDDM). The second segment analyzes the role(s) that various environ mental factors play in IDDM and provides data on the autoantigens, aberrant immune responses, and the role of cytokines and free radicals in the pathogenesis of diabetes. La Jolla, California MICHAEL B. A. OLDSTONE, M.D. This collection of studies was conceived as part of a two-volume review of the immunology of diabetes. The contents of Volume 156, which forms part 1, are listed below."

This second volume reports on the reaction patterns of lymph nodes in neoplastic and immunodeficient diseases. Based on the contents of volume 1, it presents a detailed survey of lymph node structures and their cellular components under these conditions. The patterns of nodal reactions to the development and spread of cancer have recently been investigated and discussed by several authors. Here, the immediate interactions between tumor tissue and the regional nodes have been assessed in experimental models and in human material. Using modern morphological methods such as im munohistochemistry on the light and electron microscopic level, new insights have been gained into the stepwise process of lymphogenous metastasis. Macrophages/reticulum cells were found to playa signifi cant role in this process, which is duly emphasized. Based on appro priate animal models, one chapter focuses on various subtypes of these cellular elements and their role in the two separate phases of tumor spread and the development of true metastases. The induction of fibronectin in lymph nodes is effected by tumor cells forming a special part of the extracellular matrix. The multifunctional fibronec tin molecule serves as a mediator between tumor cells and fibroblasts, furthering the formation of tumor stroma. This volume also contains a comprehensive survey of primary im munodeficiency syndromes and their nodal manifestations, reference being made to the most recent immunological knowledge."

The Second International Symposium on Narcolepsy was held at Fairchild Auditorium, Stanford University, on 6-7 July 1985 under the presidency of Drs. William C. Dement and Christian Guillemi nault. It succeeded the First International Symposium on Narco lepsy held in La Grande Motte, France, organized by Pierre Pas souant in July 1975 in commemoration of the 100th anniversary of the publication of Jean B. E. Gelineau's paper which proposed the naming of narcolepsy. At the second narcolepsy symposium, many important research reports on both basic and clinical aspects of narcolepsy were given by investigators from many countries of the world. Audience inter est was particularly attracted by the section on the relationship be tween HLA and narcolepsy, in which recent evidence that almost all narcoleptic patients are HLA-DR2 positive was reported by in vestigators from Japan, England, France, Canada, and the United States. The close relationship between the HLA antigens, hitherto considered as immune-related genetic markers encoded by genes on human chromosome 6, and narcolepsy appeared to open a new approach not only for the research of narcolepsy but also for the mechanism of sleep in general. Publication of all these new findings on the association of HLA and narcolepsy was considered; an outline was worked out and all the groups agreed to prepare a contribution covering the various aspects of this topic."

Biological response modifiers are increasingly used in viral and cancer therapy. Since alterations of the immune system are the primary symptoms of HIV infection, especially therapies directed towards the modulation of the immune response have been under intense evaluation. This volume summarizes current knowledge of the interferon-based natural antiviral protection system including 2',5'-oligoadenylate and double-stranded RNA. It will also help to develop further a solid scientific rationale for the practical use of heterologous immunomodulators in the clinics.

During routine genetic screening of several immunoglobulin heavy chain congenic mouse strains in 1980, one of us (MB) was surprised to find that several mice in the C.B-17IIcr strain, which was being maintained in a specific-pathogen-free facility of the Fox Chase Cancer Center (Philadelphia, PA), did not express serum immunoglobulin of the appropriate allotype. Fearing an error in the breeding of these mice, the sera of the suspect mice were screened for other allotypes. When these tests revealed a complete absence of serum immunoglobulin, it became apparent that a mutation had probably occurred in the C.B-17IIcr line. Further analysis revealed that a single breeding pair was respon sible for all of the immunoglobulin negative mice and that the defect showed recessive inheritance. Thus was the C.B-17/Icr scid or severe combined immune deficient (scid) mouse discovered. Although it has taken most animal facilities several years to breed scid mice of high quality for experimental purpose, it was clear by 1987 that many investigators were beginning to exploit the unique qualities of the scid mouse for studies in several areas.

Molecular recognition undoubtedly governs any aspect of cellular interaction. To understand tumor cell growth regulation and spread, analysisof protein carbohydrate interactions can contribute to lead to the establishment of rational methods for diagnosis and therapy. Chemically and biochemically optimized preparation of adequate tools, their application for localization of receptor (tissue lectin) and ligand (cellular glycoconjugate) pairs in tumor cells and tumor sections and the usefulness of a lectin from a plant extract as potent immunomodulator indicate the prospect for a place of such techniques in pathology and oncology.

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 decision, in 1975, to write alone a monograph on micro tubules was not without risks. While I was familiar from its start in Brussels in 1934 with the work on col chicine and other mitotic poisons, the literature on microtubules was, 8 years ago, already increasing at an impressive rate. However, this monograph, which, contrary to other works on microtubules, tried to cover the whole field of research, from the fundamentals of the tubulin molecule and the possible role of these organelles in some aspects of human pathology, to some medical applications of microtubule poisons, has been accepted as a useful tool for workers in these fields. Since 1976, (date of the last references mentioned in the monograph) until the middle of 1983, papers on microtubule research have literally been pouring in, at the rate of several hundred a year. This may justify a second edition, although the considerable difficulties in keeping the size of the book within the same limits while not forgetting to mention some important work, could not be overlooked. The need for an entirely revised and rewritten edition prompted this new venture and was possible with the help of the considerable amount of reprints kindly sent to me day after day over the years. This work would have been unthinkable if the author had not maintained the same enthusiasm for microtubule research, which has been disclosing new facts every day."

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]."

This book is dedicated to the memory of Walter Brendel, late Professor of Experimental Surgery and Chairman of the Institute for Surgical Research at the University of Munich, Germany. For 20 years Walter Brendel organized the renowned Round Table Symposium on Applied Immunology, first in Kitzbiihel and later in Axams, Austria. On the occasion of the 20th symposium in January 1989 he gathered together a number of scientists who have been leaders in the field of transplantation immunology and clinical transplantation for the past two decades. All of them had participated at previous meetings, some on a regular basis. Many of the new discoveries in applied immunology and transplantation medicine were first presented and vividly dis cussed at the Round Table Symposia. The annual Kitzbiihel! Axams meetings became well-known and invitations much sought after, not only for this reason but also because of the uniquely intimate atmosphere that promoted the free exchange of research findings and theoretical cut and thrust.

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 . . . . ."

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.

In June 1986 a symposium was held in Giessen on Modern Trends in Virology. It was initiated by the Deutsche Forschungsgemeinschaft, which had supported virus research for the past 18 years in the Sonderforschungsbereich 47 at the University of Giessen. The purpose of the meeting was to serve as a forum for the members of the Sonderforschungsbereich to discuss scientific topics of mutual interest with about 200 virologists that had come from various parts of Europe, the United States, and Japan. It was not by chance that the symposium took place shortly after the 60th birthday of Rudolf Rott, who had founded the Sonderforschungsbereich in 1968 and has been its speaker ever since. Without his vision and his never resting energy Giessen would not have gained the position in the field of virology that it has today. This Festschrift, which contains the contributions presented at the plenary sessions of the symposium, is therefore dedicated to Rudolf Rott. HEINZ BAuER HANS-DIETER KLENK CHRISTOPH SCHOLTISSEK Table of Contents A Genetic Approach to Determining Glycoprotein Topology: The Influenza B Virus NB Glycoprotein has an Extracellular NHz-Terminal Domain Containing two N-linked Carbohydrate Chains R. A. LAMB and M. A. WILLIAMS . . . . . . . . . . . . . . . . . . . . . . . . . 1 Paramyxovirus Metabolisms Associated with the Cytoskeletal Framework Y. NAGAI, T. ToYODA, and M. HAMAGUCHI . . . . . . . . . . . . . . . . . . . 15 Correlation of High Evolutionary Rate of Influenza A Viruses in Man with High Mutation Rate Measured in Tissue Culture: A Hypothesis P. PALESE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

th This volume contains selected lectures presented at the 12 International Conference on Advances in Prostaglandin, Leukotriene and Other Bioactive Lipid Research: Basic Science and Clinical Applications which was held in Istanbul, Turkey, on August 25-29, 2002. This meeting brought together basic and clinical scientists for the purpose of discussing advances in bioactive lipid research with.special attention to cancer, cardiovascular diseases, gastrointestinal diseases and respiratory diseases. Topics covered included: the role of leukotrienes and lipoxins in of inflammation, the cytochrome P450 pathway, the genetics and genomics bioactive lipids, lipid peroxidation, apoptosis, angiogenesis, isoprostanes, receptors and inhibitors, cyclooxygenase and lipoxygenase pathways and inhibitors, prostaglandin synthases and receptor signaling, phospholipases and inhibitors. Sessions included plenary lectures with expertise in particular areas, oral presentation on selected topics and general poster sessions. J.M. Drazen (Boston, USA) discussed anti-leukotriene treatment in asthma patients while C. Brink (paris, France) presented the recent advances in leukotriene receptors. The recent advances in cytochrome p450 pathway described in the session organized by J.C. McGiff (Valhalla, NY, USA). T. Shimizu (Tokyo, Japan) and M. Balazy (Valhalla, NY, USA) gave an update on phospholipases and arachidonic acid peroxydation. The editors are greatful to the Organizing, Programme and Advisory Committees for their valuable contributions. We greatfully acknowledge the generous financial support provided by PharmaciaIPfizer, Fako Pharmaceuticals Inc. and Novartis Pharmaceuticals Inc. ofthe contributors to this volume, in particular We are also greatful to all to those who delivered their manuscripts by or before the requested deadline.

Proceedings of the NATO Advanced Study Institute on Immunotoxicology held at Acadia University, Wolfville, Nova Scotia, Canada, 14-23 July 1982

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.

Radiation induces a variety of chemical processes in biological tissues. This volume is a synthesis of up-to-the-minute reviews on such photochemical and photobiological sensitized reactions with particular relevance to photomedicine. The first part gives a description of experimental techniques for the study of the primary processes after radiation absorption by biological systems. It is followed by chapters on singlet oxygen and photomedicine, considering both phototherapy and photochemotherapy. These sections also discuss the next generation of potential photosensitizing drugs.