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.

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."

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

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

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

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

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.

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

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.

The idea for this volume was conceived during a discussion in the hallway at a conference in early 1990. "What is the best way to detect and define pluripotent hematopoietic stem cells?" was the question posed by Dr. Fritz Melchers. After discussing the pros and cons of the available assays for quite some time, it became apparent that this topic required a wider expertise and merited a larger forum. Thus, we decided to extend the discussion and to compile the results in this volume. Much to our delight. many of the pioneers of recent experimental and theoretical developments in stem cell research agreed to contribute their expertise to answer the question. These authors review both past findings and present insights, thus providing an overview of the evolution that has been and is occurring in the field of stem cell research. In the light of recent trailblazing developments in both experimental models and in clinical application it is indeed time to reevaluate our knowledge about stem cells. Trans plantation of hematopoietic stem cells has become more and more prevalent as a curative therapy in a variety of acquired and genetic diseases, including cancer, radiation accident, as an agent for gene therapy, and perhaps even as treatment for autoimmune diseases. Stem cells are now derived not only from bone marrow but also from peripheral blood, cord blood, and fetal liver, greatly increasing their availability for human transplantation and in some cases (fetal tissues) obliterating the need to match donors and hosts."

The amazing world of the mononuclear phagocytes keeps expanding at a truly awesome pace. As a result, maintaining currency with the latest developments and controversies that pertain to this cell type is increasingly difficult. The aspects covered in this volume have been selected to provide an overview of subject areas that either have recently become much better understood or hold the promise of new levels of understanding as they are developed in the future. The scope of topics ranges from how these cells develop, through the means that are used to regulate them, to the roles that they have in different tissues and in a variety of infectious diseases.

Recent experimental and clinical progress in the evaluation of cytokines in treatment concepts for cancer patients is the central theme of this book in the ESO Monographs series. The discussion revolves on the experimental basis as well as current clinical experience with the use of human recombinant cytokines. It gives the state of the art and, as such, puts into perspective potential areas of growth and future research.

Rapid progress continues to be made in understanding the molecular and cellular events that comprise B-Iymphocyte differentiation. This is due in part to the high level of inter est shown by many investigators from diverse disciplines, who find this subject suitable for addressing some of the fundamental issues of immunobiology. B-cell developmen tal models are being extensively used to investigate cell-cell interactions, molecular mediators of differentiation and proliferation, differential onset of gene programs, and gene rearrangement and expression, as well as the generation of the immune response itself. Not surprisingly, increased understanding of B-cell differentiation sometimes results from the application of new techniques that permit greater insight into the cells comprising the system and the genetic mechanisms by which these cells express their differentiative potential. However, experimental strategies based upon the novel application of established technologies have also led to the clarification of many issues, as well as to the discov ery of previously unrecognized problems. One problem, well recognized by those active in the field, is how to keep up with significant developments as they appear. The purpose of this book, part of a series devoted to analysing current issues in biology, is to help overcome this problem. No attempt at comprehensive cov erage of all of the issues has been made. Rather, a more thorough analysis of a few topics is presented."

The publication of Bronchoalveolar Mast Cells and Asthma marks the emergence of The Bloomsbury Series in Clinical Science, an important and novel series that will highlight, review and record major areas of research, development and practice in the field of clinical science. A number of other monographs are now in an advanced state of preparation and their release will establish not only their individual significance but that of the series as a whole. My thanks are due to the Editorial Board who have provided the ideas and selected the authors and whose continuing enthu siasm is so vital to the success of the series. Michael Jackson of Springer-Verlag merits special thanks for initially realising the potential of such a series and then guiding us all through to the time of its launch. Marianne Williams has supported us all and has provided the important link between Editorial Board and pub lisher. The author of this first publication, Kevin Flint, was tragically killed during its preparation, and we hope that the book will serve as a tribute to the memory of Kevin for all who were lucky enough to know him. Barry Hudspith has been of enormous help in finalising the work and in shaping the form of the book."

To the entomologist all insects have six legs; the layman tends to use the term "insect" to include the eight-legged spiders and mites. All these creatures are correctly classified as arthropods. Many thousands of the hundreds of thousands of recognised species of arthropods are found in the human environment-domestic, occupational and rec reational. Those species which are obligate parasites of man, the human scabies mite and the head and body lice, produce familiar clinical syndromes. They remain important in medical practice and have been the subject of a great deal of recent research. This is beginning to throw much light on the immunological mechanisms which largely determine the reactions of the host. Dr. Alexander has provided a detailed survey of this work. The wasps, bees, ants and other Hymenoptera which may sting man in self-defence can cause painful, even fatal reactions. The recent work on this important subject has also been thoroughly reviewed. Every dermatologist of experience will admit that he sees many patients in whom he makes a diagnosis of "insect bites," if he has the confidence to do so, or of "papular urticaria" or "prurigo" when he lacks such confidence, mainly because he is at a loss to know which arthropod is likely to be implicated. In his survey of the enormous literature in the entomological, public health and dermatology journals Dr. Alexander has provided an invaluable guide in which the solutions to these clinical mysteries can be sought."

Over the last few years, many new observations have profoundly changed our concepts of the immune competence of the newborn. For the immune system, as for other systems and functions, the neonatal age represents a crucial transition period. In fact the immune characteristics of the fetus are likely to result fro- or be conditioned by - several often contradictory physiological requirements. On the one hand, it would certainly be an advantage for the fetus to acquire a complete immunocompetence as soon as possible in order to be able to cope with the eventual transplacental passage of pathogenic microorganisms and possibly also in order to reject maternal cells occasionally crossing the placental nd barrier. This is actually what occurs, at least in part, during the 2 and Jfd month of gestation when the fetus begins to acquire his biological individuality and at the same time the role of a "biological ego" resulting from the attain ment by the immune system of the capacity to discriminate between self and nonself."

Current Topics in Medical Mycology, is intended to summarize current research areas in medical mycology for medical my- cologists and other scientists who are working in microbiology and immunology. Topics to be included in each volume will serve as contemporary reviews, summaries of current advance- ments and future directions, and mechanisms to enhance the interdisciplinary use of medically important fungi in under- standing pathogenesis, epidemiology, mycotoxins, taxonomy, and other areas where basic, applied, and clinical sciences are used. Michael R. McGinnis v Contents Series Preface v Contributors ix Ultrastructural Correlates of Antimycotic Treatment MARCEL BORGERS 2 Soluble Polysaccharides of Cryptococcus neoformans ROBERT CHERNIAK 40 3 Tinea Imbricata RODERICK J. HAY 55 4 Adhesion and Association Mechanisms of Candida albicans MICHAEL J. KENNEDY 73 5 Peptide Transport in Candida albicans: Implications for the Development of Antifungal Agents FRED NAIDER and JEFFREY M. BECKER 170 6 Epidemiology of Coccidioidomycosis DEMOSTHENES PAPPAGIANIS 199 7 Immune Response to Paracoccidioides brasiliensis in Human and Animal Hosts ANGELA RESTREPO M. 239 vii Vlll Contents 8 Morphogenetic Transformation of Fungi MAXWELL G. SHEPHERD 278 9 Epidemiology of Nosocomial Fungal Infections DAVID J. WEBER and WILLIAM A. RUTALA 305 Melanins and Their Importance in 10 Pathogenic Fungi MICHAEL H. WHEELER and ALOIS A. BELL 338 11 Cytochrome P-450 of Fungi: Primary Target for Azole Antifungal Agents Yuzo YOSHIDA 388 Index 419 Contributors JEFFREY M. BECKER, Ph.D.

This volume deals with the structure and function of molecules that have, during the last decade, turned out to have a central role in immune responses. Trans plantation antigens were discovered and characterized by Gorer about 50 years ago, and the biological basis for the unequalled complexity of their variability between individuals within a species, in spite of extreme conservation between species, was the subject of intense research and discussion for many years. During the days of belief in "immune surveillance" against spontaneously developing tumors, it was suggested that histoincompatibility between members of one species would prevent cancer from being a contagious disease and thus a threat to the species. Immunologists involved in human transplantation had to learn and care about the complexity, especially after 1967, when it was found that HLA antigens were the products of the human MHC. Rejection of HLA-identical sib kidney grafts was so rare, even in those days, that cases of rejection were described in scientific papers."

During the past few decades we have witnessed an era of remarkable growth in the field of molecular biology. In 1950 very little was known of the chemical constitution of biological systems, the manner in which information was transmitted from one organism to another, or the extent to which the chemical basis of life is unified. The picture today is dramatically different. We have an almost bewildering variety of information detailing many different aspects oflife at the molecular level. These great advances have brought with them some breath-taking insights into the molecular mechanisms used by nature for replicating, distributing and modifying biological information. We have learned a great deal about the chemical and physical nature of the macro molecular nucleic acids and proteins, and the manner in which carbohydrates, lipids and smaller molecules work together to provide the molecular setting of living systems. It might be said that these few decades have replaced a near vacuum of informa tion with a very large surplus. It is in the context of this flood of information that this series of monographs on molecular biology has been organized. The idea is to bring together in one place, between the covers of one book, a concise assessment of the state of the subject in a well-defined field. This will enable the reader to get a sense of historical perspective what is known about the field today - and a description of the frontiers of research where our knowledge is increasing steadily."

The last decade has witnessed rapid progress in our under standing of the mechanisms of protein export and secretion in both prokaryotic and eukaryotic cells. Studies of protein secretion across the membranes of the rough endoplasmic reticulum have led to the formulation of the now-classic signal hypothesis, which has stimulated many discussions and new ideas, and the identification of the signal recogni tion particle as an organelle in the initiation of the export process. However, more recent work pertaining to intrage nic information related to targeting specific proteins for either secretion or membrane localization, the energetics of protein secretion, the timing of synthesis versus the initia tion of export, structural requirements for the processing of precursor proteins, and the identification of the proces sing enzymes (signal peptidases), has been the result of a combined biochemical and genetic approach to the study of protein localization in bacteria. While reviews on the biochemistry and genetics of pro tein secretion have appeared frequently in recent years, this book attempts to summarize the current status and the future perspectives of this rapidly moving field in a single volume. Topics covered in this book include the genetics of protein secretion in E. coli, biochemical analysis of pro tein export in vitro, signal peptidases, excretion of colicins and hemolysin in E. coli, protein secretion in Bacillus, and protein secretion cloning vectors."

Anergic reactions and anergic diseases are found in many fields of medicine. As wen as affecting the skin, allergic diseases occur in internal organs such as the lungs and the kidneys and in the vascular and nervous systems. Interdisciplinary understanding and cooperation thus seem necessary to get a better insight into allergic reactions in the different fields of medicine in order that we may give our patients the best diagnostic and therapeutic care. Allergic diseases are on the increase. Studies from Sweden show that 15% of the population there are atopic, and some people speculate that in Germany about 10%-15% of all adults suffer from one of the many different allergic conditions. We in our clinic also have the impression that the incidence of atopic reactions has increased in recent years. The figure of 15% would mean something like 200 000 people in Munich alone We all know that a wide variety of environmental factors can induce allergic reactions in the skin, the respiratory system, or internal organs. The most important anergens in our environment are pollen, molds, animal dander, housedust mite, food or food additives, various insects, industrial compounds and drugs. The direct costs of hospital and community medical care, other services, and drugs to help patients with asthma, hay fever, and skin allergies have in creased considerably in the last 10 years. The figures should make it clear to everybody that we are dealing with a health and environmental problem of great practical importance."

F. B. Michel Asthmology is the neologism I suggested for ideas which were acceptable at the begin the title of a book published in 1981 on ning of the 20th century, and in particular bronchial asthma [4,5]. to Pasteur's concept of "one cause, one ill ness", many syndromes like high blood Among a certain number of scientific pressure or asthma are the result of the publications on this subject, it is one of the overlapping of hereditary factors and ac few suggestions that I have the weakness to quired factors. This is one reason why asth feel somewhat proud of. In fact, this word has had the career I hoped it would and, ma is not really an illness in the real sense judging by the frequency with which it is of the word but, a clinical and functional respiratory syndrome [1]. used in both written and spoken language, it did answer a need. I had no intention of The innate, the "terrain", transmitted by suggesting one more neologism but it heredity, can possibly concern two factors: seemed to me that the word asthmology The bronchial hyperreactivity factor (BHR), had an element of novelty and, above all, is often present in early childhood and its produced the necessary awareness of the reality is a result of the studies of large need to bring together, within a kind of groups of homo- and heterozygotic twins.