This volume forms part of a prestigious series and covers the latest advances in our understanding of the pathophysiology and treatment of asthma. Our understanding of asthma has changed dramatically in recent years, and much of this new information is brought together in this volume written by inter nationally recognised authorities. The aim of the book is to review in depth the changing concepts of inflammatory processes in asthma and to discuss the implications for research of this common chronic disease. Many of the advances in and future therapy our understanding of asthma have originated from a pharmacological approach, and this volume highlights the promising new options for pharma cological intervention. It is hoped this book will be invaluable for research scientists and clinic ians involved in asthma research and will be a major reference resource for chest physicians and those involved in the development of novel pharmaceu tical entities. Each chapter is extensively referenced, generously illustrated with clear diagrams and photographs, and represents a state-of-the-art review of this growing area. c.P. PAGE P.l. BARNES Contents CHAPTER 1 The Pathology of Asthma: An Overview L.A. LAmNEN and A. LAmNEN. With 10 Figures ...................... 1 A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 1 . . . . . . . . . . . . . . . B. Methods to Investigate the Pathology of Human Asthma ............ 1 C. Bronchial Epithelium and Inflammatory Cells in Asthmatic Patients Between Attacks ........................... 2 I. Mast Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 4 . . . . . . . . . . . . . . II. Eosinophils ............................................... 7 III. Neutrophils.............................................. 10 D. Bronchial Epithelial Inflammation During an Asthma Attack. . . . . .. . 10 E. Epithelial Regeneration .... . . . . . . . . . . . . . . . . . . . . . . .. . . 12 . . . . . . . . ."

This book is a collection of critical reviews about a diverse group of virus families with two features in common: the stable repository of genetic information in each virus is RNA, and each virus modifies and appropriates a particular patch of the eukaryotic cell membrane system to complete its structure. The reviews take the reader from the level of virus genome structure and expression through the quaternary interactions between virus-specified elements and cellular components that cooperate to produce virus particles. There are spectacular illustrations in this volume, but it is much more than a picture gallery. Reading widely in this book can be an effective antidote to overspecialization: in these pages, you are likely to learn much about viruses and about cells that you didn't know before; you'll discover illuminating parallels between diverse virus families; you'll come away with a sharpened awareness of important things that are still to be learned. Memphis, Tenn. , Summer 1984 David W. Kingsbury Preface This book was written at the suggestion of Dr. David W. Kingsbury made at a work shop on viruses organized by the Multiple Sclerosis Society in Aspen, Colorado, U. S. A. , three years ago. Originally, we had thought to focus on the morphological aspects of viral assembly. Later, during our discussions on the process of budding of enveloped RNA viruses, it became evident that we should include biochemical data in our review and correlate them with the structural aspects of virus maturation.

Postreplicative methylation of bacterial DNA has long been known to be the molecular basis of" modification," which protects DNA against destruction by restriction endonucleases. More recently, another function of DNA methylation was found in Escherichia coli, where methy- lation is involved during DNA replication in the recogni- tion of old and newly synthesized strands. The intensive search for new restriction enzymes during the 1970s yielded an enormous arsenal of such enzymes and re- vealed the ubiquitous distribution of restriction/modifi- cation systems in the bacterial kingdom without provid- ing much information on the corresponding modifica- tion methyltransferases. However, it is obvious that DNA methyltransferases represent an ideal class of en- zymes to those interested in protein/DNA interactions; these enzymes are at least as interesting as the restriction enzymes, with which they share the capacity to recognize and interact with specific sequences of DNA. In recent years the interest in DNA methylation has been greatly stimulated by two discoveries: the correla- tion between gene expression and hypomethylation in eukaryotes and the convertability of DNA into its Z form through cytosine methylation. In fact, studies on DNA methylation are now being intensively performed in many laboratories. A description of the state of the art of DNA methylation has been the topic of two con- gresses: The Cologne Spring Meeting in 1981 organized by WALTER DOERFLER and an EMBO Workshop at Nethybridge in 1982 organized by ROGER ADAMS.

Any professional concerned with immunology will be interested in this book dedicated to the memory of Milan Hasek, former director of the Prague Institute of Experimental Biology and Genetics. Prof. Hasek was a congenial scientist and most amiable person - a personal friend of almost all leading immunologists around the world. He was displaced from his post of director in 1970, yet had a lasting impact upon his students and the group known as the Prague School of Immunogenetics. The topics covered in the contributions range from tolerance, immune network, and immunogenetics to the immunology of bacterial and viral infections. They are written by 27 of Prof. Hasek's former co-workers who emigrated to western countries around or after 1968 and became well-known and distinguished scientists in the field. The papers include their personal reflections of the Prague Institute, their impressions upon arriving abroad and their interesting experimental work since then. The book also provides a complete bibliography of their publications after leaving Czechoslovakia.

Contents: Introduction and Overview Lymphopoietic Growth Factors: Pathophysiology of T-Cell Mediated Shock Induced by Bacterial Superantigens - Natural Killer Cells and Interleukin-2-Activated Killer Cells - TumourImmunogenicity Induced by Exogenous Interleukins - Cytokine Gene Therapy of Cancer - Analysis of T-Cell Receptor Variability in Tumour Infiltrating Lymphocytes - Clinical Studies with Interleukin-2: An Overview - Clinical Trials with Local Administration of Lymphopoietic Growth Factors - Clinical Trials with Interlaukin-2. The Rome Experience. Haematopoietic Growth Factors: Lymphohaematopoietic Growth Factor Use in Lung Cancer Patients - Clinical Trials with Haematopoietic Growth Factors and Peripheral Blood Stem Cells

Many bacteria, such as certain Neisseria and Haemophilus or Escherichia coli, are able to withstand the bactericidal activity of complement and phagocytes. This bacterial self protection is brought about by encapsulation. Bacterial capsules thus enable the pathogenic bacteria to survive in the host by counter action or evasion of the nonspecific host defense in the early pre immune phase of an infection. It is only in the late immune phase of the infection, when specific anticapsular antibodies are formed and enforce the host's defense system, that this protective action is overcome. Encapsulated bacteria are then killed and eliminated. Interestingly, some capsules can not or only inefficiently be handled by the immune system. The ensuing lack of antibody formation results in a prolonged susceptibility of the host to the pathogenic bacteria exhibiting such capsules. It was found that bacterial capsules consist of acidic poly saccharides. From this it followed that the role of the capsules in the interaction of encapsulated bacteria with the host may be due to the chemistry of the capsular polysaccharides. This led to intensive studies of capsular polysaccharides in many laboratories. Our increasing knowledge of the structural features of capsular polysaccharides prompted not only immuno chemical studies analyzing the interactions of these poly saccharide antigens and characterizing the epitopes, but also investigations into their biosynthesis. These studies were complemented and supported by genetic analyses. Today many interdisciplinary investigations of capsular polysaccharides are in progress.

The first few months of any pregnancy are of supreme importance to the success of that pregnancy. This statement is so obvious as to be almost a platitude, yet it must be said that no aspect of pregnancy has been more neglected in the human than the first three months. Little is known of the morphological changes that occur at that time and our knowledge of the mechanisms that control this vital stage of pregnancy is almost non-existent. The explanation for this neglect of what is an obvious area for study is the difficulty of obtaining normal material. It is rare to have material to study from a healthy first trimester pregnancy and the study by Hertig and Rock!l) of early conception found by chance in hysterectomy speci mens must be unique. The information that we do have about early pregnancy is mostly gained from animal studies or single miscarriages in humans. Chromosomal defects are common but are not an explanation for the majority of recurrent miscarriages. Obstetricians have hypothesised many causes for this condition and have deve loped numerous metQods for treating it, but the studies have been poorly con trolled so that our understanding of the cause(s) has not advanced. Treatment of women with a history of recurrent miscarriage by paternal leuco cyte infusion (immunotherapy) may be yet another form of treatment that is hailed as a new advance only to be rejected when subject to rigorous testing.

The cells of the immune system generate a large variety of binding sites which differ in their binding specificities and can therefore react specifically with a large variety of ligands. These binding sites are part of receptor molecules, enabling the system to react to the universe of antigens. The classical antigen receptor is the antibody molecule, and accord ingly the first session of this colloquium deals with a classical sub ject, namely antibody structure. Dramatic recent advances in this field make it possible to interrelate primary and three-dimensional struc ture both to each other and to function, i.e. the binding of antigen and possible reactions occurring in the antibody molecule upon antigen binding. The latter point is of particular interest since it may be relevant not only for effector functions of antibodies such as the binding of complement, but also for the triggering of a lymphocyte through its antibody receptor for antigen."

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.

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.

The Second International Symposium on "The Influence of Antibiotics on the Host Parasite Relationship" was held in Munich, F. R. G. , from March 28 to 30,1985. The topics of the meeting dealt with the aspects of changes in bacterial metabolism and structure which occur under the influence of antibiotics, and with the effects of such changes on the antibacterial host resistance. The influence on pathogenicity factors, changes in the outer membrane of bacteria, as well as the influence on the individual components of the defence system were analysed in detail. In addition, these studies showed that antibiotics proved to be an excellent tool for the examination of bacterial physiology, so that, 50 years after the introduction of antibiotics, additional important knowledge can be gained about the effect of these substances on bacteria. Considering the observations reported, it appears justifiable to postulate that new antibiotics should be routinely tested with respect to their possible effects on antiinfectious resistance. Of course, a consensus will have to be found on which to base methods and criteria employEUROd. The symposium documented an increasing interest of microbiologists and clini cians for this field of research. It would not have been possible to organize it without the substantial support of the Paul Ehrlich Society as well as of Squibb-Von Heyden Pharma, Inc. Particular help concerning the organization has been given by Werner Kremer of Squibb-Von Heyden Pharma.

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 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."

It is with great pleasure and, much interest that I accepted to write the foreword to this book by Paul Doury, Yves Dirheimer, and Serge Pattin on the subject of "algodystrophy." First, because I know the extent of their personal experience, from which they have selected the best for this book. Second, because it seemed to me that their detailed analysis of the numerous works on the subject, works which have been published all over the world and which provide diverse physiopathologic interpretations, would provide a comprehensive study meeting a real need. Algodystrophy, to adopt the term used by the authors, merits rheumatolog ists' careful attention. It is indeed a frequent condition and, as is now well known, occurs in the most varied etiologic circumstances; it is not solely posttraumatic, a notion on which diagnosis had long been based. This variable etiology suggests the complexity of algodystrophy's pathogenic mechanism."

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."

M. B. A. OLDSTONE Viruses are generally studied either because they cause significant human, animal or plant disease or for their utility as materials to probe a basic phenomenon in biology, chemistry, genetics or molecular biology. Arenaviruses are unusually interesting in that they occupy both of these categories. Arenaviruses cause severe human diseases known primarily as the hemor rhagic fevers occurring in South and Latin America (Bolivia: Machupo virus and Argentina: Junin virus) and in Africa (Lassa virus). Because such viruses produce profound disability and may kill the persons they infect, they are a source of economic hardship in the countries where they are prevalent. Further, they provide new problems for health care personnel owing to the narrowing of the world as visitors from many countries increasingly travel to and from these endemic areas. In addition, lymphocytic choriomeningitis virus (LCMV) can infect humans worldwide, although the illness is most often less disabling than those elicited by other arenaviruses. Yet LCMV is likely of greater concern to non-arena-virologists and experimentalists using tissue culture or animals, i. e. , workers in molecular biology, cancer research, virology, immunobiology, etc. , because normal appearing cultured cells or tissues and animals used for research may be persistently infected with LCMV without manifesting clinical disease or cytopathology and transmit that infection to laboratory workers (reviewed OLDSTONE and PETERS 1978). For example, HINMAN et al.

In 1976 the International Committee on Taxonomy of Vi ruses (ICTV) created the family Iridoviridae to encompass several different vertebrate and invertebrate viruses that did not fit into any of the other established groups. The unifying features of this new family were (1) polyhedral symmetry; (2) large (approximately 170 kilobase pairs), lin ear, double-stranded DNA genomes; and (37) a cytoplas mic site of replication. The name "iridovirus" was derived from the observa tion that larvae infected with many of the insect viruses, as well as purified pellets of these viruses, glowed with a blue or green iridescence - presumably due to the Bragg effect of the viral crystals. However, none of the vertebrate "iridoviruses" displayed this particular characteristic. An attempt was made to substitute the more descriptive name of "icosahedral cytoplasmic deoxyribovirus," but not only was this term too unwieldy, it also did not conform to the latinized nomenclature the ICTV wished to adopt. So, for both historical and esthetic reasons, "Iridoviridae" was adopted as a family name, with Iridovirus as the genus represented by the type 1 iridescent insect virus, Tipula iri descent virus. At the 1982 ICTV Meeting, enough biochem ical data had accumulated to permit the establishment of the following five genera in the family Iridoviridae: English vernacular International Type species name name 1. Small iridescent Iridovirus Tipula iridescent virus insect virus (Type 1) 2. Large iridescent Chloriridovirus Mosquito iridescent insect virus virus (Type 2) 3."

CURRENT TOPICS IN MEDICAL MYCOLOGY, VOLUME 4, like the pre- ceding three volumes in the series, is intended to summarize current research advances inmedical mycology. Topics ex- plored in this volume include skin kinetics of azole anti- fungal drugs; killer system interactions; fusarium-caused hyalohyphamycosis; molecular technique for epidemiologic ty- ping of Candida species; and the need for a mycoses-repor- ting system.

It has been a challenge for us to edit this volume of Endocrinology and Metabo lism: Progress in Research and Clinical Practice. The topic of the pathogenesis of insulin-dependent, type I diabetes mellitus is particularly appropriate for this series, since advances in this area have been made, to a large extent, by applying state-of-the-art laboratory techniques to clinical samples. Over the last several years, a number of lines of evidence have been gathered, suggesting that classic type I diabetes mellitus results from the autoimmune des truction of pancreatic beta-cells in genetically susceptible individuals. This hypothesis is particularly appealing because it offers a rational approach to the prevention of diabetes by immunosuppression. We have tried to present a balanced, authoritative summary of the information currently available to support the autoimmune hypothesis for the pathogenesis of human type I diabetes, to place this information in historical perspective, to include relevant information from animal models of type I diabetes in which more invasive experimentation is ethical, and, finally, to update the reader on the current status of attempts to intervene in the progression of diabetes with immunosuppressive drugs. New York, New York Fredda Ginsberg-Fellner Robert C. McEvoy Contents Preface.. . . .. .. .. . . . . . . . . . . . . ... . . . . . . . . . . . .. . . . . . . .. . . . . v Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Xl . . . . . . . . . . . . . 1. The Autoimmune Hypothesis of Insulin-Dependent Diabetes: 1965 to the Present . . . . . . . . . . . . ..................... . . . . . .

Vaccines have historically been considered to be the most cost-effective method for preventing communicable diseases. It was a vaccine hat enabled global eradication of the dreaded disease smallpox. Mass immunization of children forms the anchor of the strategy of the World Health Organization (WHO) to attain "health for all" status by the year 2000. Vaccinology is undergoing a dimensional change with the advances that have taken place in immunology and genetic engineering. Vaccines that confer short or inadequate immunity or that have side effects are being replaced by better vaccines. New vaccines are being developed for a variety of maladies. Monoclonal antibodies and T cell clones have been employed to delineate the immunodeterminants on microbes, an approach elegantly complemented by computer graphics and molecular imaging techniques. Possibilities have opened for obtaining hitherto scarce antigens of parasites by the DNA recombinant route. Better appreciation of the idiotypic network has aroused research on anti-idiotypic vaccines. Solid-phase synthesis of peptides is leading to an array of synthetic vaccines, an approach that is expected to attain its full potential once the sequences activating suppressor cells are discovered and the rules for presentation of antigens to T and B cells are better worked out. A new breed of vaccines is on the horizon that seeks to control fertility.

Irritant dermatitis is a common condition, accounting for a significant proportion of occupational skin disease. The recent advent of non-invasive skin bioengineering technology has accelerated dermatology research in this field. This book comprises an exhaustive reference text on irritant contact dermatitis, covering all aspects of the condition: clinical features, epidemiology, prevention and therapy, prognosis, mechanisms, pathology and regulatory issues. The book also presents novel in vitro and in vivo research techniques and findings. As irritant dermatitis affects multiple specialties, the audience for this book is wide, including clinical and investigative dermatologists, allergists, toxicologists, pharmaceutical scientists, occupational and environmental physicians, public health physicians, cosmetologists and skin bioengineers.

lnflammatory reactions are generated in response to extemal and intemal stimuli, such as infection, trauma, clinical insult or dysregulation of the umnune system. The int1ammatory responses may bc antigen-specific or non-specific, local or systemic, chronic or rapid and severe, characterized by a massive release of mediators, often lethal. The aim of this book is to review selectcd aspects associated with the mechanism of the pathology of int1ammatory processes of ditlerent origin and to evaluate therapeutic strategies aimed at combating various inflamma- tory diseases. The introductory article describcs the inmlllnological status of patients with severe sepsis, with particular attention paid to the roJe of circulating neutrophils. Intcgrin activation and chemokine receptor expression and the roles of IL-15, prostaglandins and leukotriens in inflmmnation and immunity are the subjects of next articles. Subsequent reviews are focused on allergic diseases involving mast cells and Th2 type cytokines, in particular the mech- anisms of atopic dennatitis and signaling hy IL-13. The intlmmnatory responscs elicited by Mycobacterium tuberculosis and Mvcobacferium nviwn are also analyzed with special interest paid to the mechanisms which allow the bacteria to escape the host' s immune reactions. The thcrapeutic potential of IL- I 0 in infection and inflammation and thc possible factors contributing to the devclopment of idiopathic pulmonary fibrosis are rcvicwed in the next articles. The final report demonstrates the advantages of bacteriophage ther- apy in thc context of the aggravating problem of hactcrial resistance to antibi- otics.