The traditional approach to diagnosis of virus infectians by isolation of the causative virus is usually both slow and expensive. More recently, the emphasis has been on the direct detection of viruses or viral antigens in clinical specimens. This can be done using established techniques such as immunofluorescence or electron microscopy, or by newly developed biochemical methods. The purpose of this meeting was to review these and other developments in the laboratory diagnosis of virus infections. We would like to thank all those who contributed to the success of this meeting. In particular, we are grateful to the CEC for financial sponsorship, to Professor C. Dow, Director of the Veterinary Research Laboratories, for help in organising the meeting, and to Miss B. Hamilton for her excellent typing of the manuscripts. M S McNulty J B McFerran VII CONTENTS Page Preface V VIRAL DIAGNOSIS BY TIMMUNOFLUORESCENCE P. S. Gardner APPLICATIONS OF IMMUNOFLUORESCENCE IN VETERINARY VIRAL DIAGNOSIS M. S. McNulty and G. M. Allan 15 TAGGING OF VIRAL ANTIGENS USING IMMUNOPEROXIDASE . AND IMMUNOOOLD TEGINlQUES R. Ducatelle, F. Castryck and J. Hoorens 27 DETECTION OF BVD VIRUS IN VlRAEMIC CATTLE BY AN INDIRECT IMMUNOPEROXIDASE TEGINIQUE A. Meyling 37 VIRAL DIAGNOSIS BY ELECTRON MICROSCOPY J. D. Almeida 47 CAPTURE ASSAYS FOR THE DETECTION OF VIRUS-SPECIFIC IgM ANTIBODY R. S. Tedder 60 DETECTION . AND IDENTIFICATION OF PAPILLOMAVIRUSES IN BENIGN . AND MALIGNANT 'TIlmJRS OF CATTLE M. S. Campo 72 DETECTION OF VIRAL NUCLEIC ACIDS IN CELL CULTURES .

Research on antiviral drugs and their mode of action in infected cells. in animals and in man. has led to a better understanding of the molecular pro cesses involved in virus replication. Screeninq of large numbers of natural and semisynthetic compounds resulted in the characterization of certain sub stances that had a limited efficiency as antiviral druqs. A few chemically synthesized compounds were also found to be effective as antiviral agents in the chemotherapy of human virus diseases. A major difficulty in the develop ment of effective antiviral agents has been the lack of selectivity. and toxicity for uninfected cells. of drugs that effectively inhibited virus replication in vitro. Further understanding of the molecular processes of virus replication in infected cells has resulted in the development of new antivirals directed at virus-coded enzymes or proteins. Recent studies on antivirals that are activated by the herpes simplex virus type l-coded thy midine kinase from a prod rug to an antiviral drug have opened new directions in the development of effective antiviral drugs. The present book deals with a number of antiviral drugs effective against herpes simplex viruses and provides some insight into the molecular aspects of virus replication. It also throws light on the new approaches to the development of antiviral drugs. The molecular basis of the antiviral activity of new and known drugs and their possible use in chemotherapy of viral disease are presented in this book."

The science ofparasitology is particularlyrelevantto the health ofhumans and animals throughout the world. As such, it provides the core of the Rockefeller Foundation program ofbiomedical research called The Great Neglected Diseases of Mankind. While some bacterial, viral, and fungal diseases are included in this program, the parasiticdiseases caused bypro- tozoa and helminths almost uniformly fit into this category. Many ofthem infect vast numbers of people and animals (of the order of hundreds of millions), but theyare greatlyneglected bythe scientific establishmentof the modern world. The principal reason for this neglect, both scientific and financial, is the fact that these diseases are primarily problems ofthe developing world. Hence, no vaccines exist for anyofthe human parasitic diseases; for many, treatment is either nonexistent or highly toxic; and diagnosis still relies largely on the visual examination ofbiopsies, blood, and excreta. In contrast, the discovery ofa spate ofantibiotics has revolu- tionized treatment of bacterial diseases, and vaccines have been devel- opedfor manybacterial andviral diseases. Furthermore, the field ofmicro- biology, which deals largely with bacteriology and virology, has sparked the scientific revolutions ofimmunology and molecular biology. In order to examine the present status of parasitology and the reasons for its putative neglect, as well as to develop means of remedying the sit- uation, aseries ofconferences has been convened, bringing together clas- sical parasitologists and a new and complementary breed of parasite-ori- ented immunologists, biochemists, molecular biologists, and population ecologists.

R. VANFURTH Infection is an inseparable part of communal life, and infections are more common and more severe in hospital communi ties because the sick are more easily infected than the healthy. However, even though progress in the medical sciences has meant that many more patients suftering from relatively severe diseases can be helped at present, the use of more sophisticated and complex treatment leads to impairment of the defence mechanisms in more patients than was the case ten to twenty years ago, and these patients are also more prone to develop an infection. Two questions are particularly relevant in this context. 1) Under what conditions do hospital infections occur? Defects of host defence mechanisms are of great importance in this respect. Such defects can be due to the disease or to the treatment given to the patient. 2) Which of the host defence mechanisms can be affected by a stay in the hospital? Among the factors involved in the host defence against infections (Table I), a number are especially important in this respect. For instance, venepuncture, indwelling catheters, and surgery all cause a breach in the surface structures. Anaesthesia causes temporary impairment of mechanical factors. Vascularization may be defective -- especial ly in the aged and patients with diabetes mellitus -- and this may complicate the healing of wounds in the skin and mucous membranes after surgery."

Aquatic microbial ecology, a growing interdisciplinary field, has become increasingly compartmentalized in recent years. The aim of this volume is to propose a framework for biochemical and molecular approaches, which are employed ever more widely in studies of aquatic microbial communities and ecosystem functioning. The book presents state of the art applications of modern molecular research techniques to a range of topics in ectoenzymes microbial carbon metabolism bacterial population dynamics RNA chemotaxonomy of microbial communities plasmids and adaptation to environmental conditions. Written for limnologists, marine biologists, and all researchers interested in environmental microbiology and molecular aspects of ecology, this volume will provide a stimulating introduction to this emerging field.

A comprehensive source of information on variations found in skin diseases throughout the world is offered here. By considering the overall problems of hereditary variables, climate fluctuations, and therapeutic differences, this volume provides an appraisal of the diverse factors that make up the composite picture of cutaneous medicine. Divided by continent and then further organized into countries or regions, each entry presents basic information on the disease indigenous to the area, including its definition and symptoms, etiology, clinical manifestations, histopathology, appropriate laboratory tests, differential diagnosis, management, prevention and references. Additional chapters discuss the influence of travel and migration as well as of variables such as climate. 38 full color plates superbly illustrate the many variations of major dermatologic diseases. As technology has made global travel far quicker and more commonplace, this book is a must for all dermatologists, infectious disease specialists, and for all family practitioners and general internists.

The very first international working discussion on slow infections of the nervous system was entitled "Slow, Latent, and Temperate Virus Infec tions" and was held at the National Institutes of Health (NIH) in December 1964. The primary impetus was the discovery and investigation of kuru in New Guinea by D. Carleton Gajdusek, M. D. This working discussion brought together investigators in human and veterinary medicine, virolo gists, microbiologists, and neuropathologists actively engaged in laboratory work with viruses that illustrated properties of latency, masking, slowness, or temperateness, with emphasis on subacute and chronic neurologic dis eases of unknown etiology. In the Preface to the monograph of published papers presented at the working discussion, Gajdusek and Gibbs wrote the following: After microbiology had given solution to the etiology of most acute infections of the central nervous system and after fungi and bacteria had been incriminated in impor tant chronic disorders of the nervous system such as torula and tuberculosis men ingitis, we have been left, in neurology, with a wide range of subacute and chronic affections of the central nervous systems of unknown etiology. Some of these diseases, still listed as idiopathic, are among the most prevalent afflictions of the central nervous system. Many others with familial patterns of occurrence do not yet have their basic pathogenesis or underlying metabolic defect elucidated, although we tend to think of them as genetically mediated."

The microbiology of drinking water remains an important worldwide concern despite modem progress in science and engineering. Countries that are more technologically advanced have experienced a significant reduction in water borne morbidity within the last 100 years: This reduction has been achieved through the application of effective technologies for the treatment, disinfec tion, and distribution of potable water. However, morbidity resulting from the ingestion of contaminated water persists globally, and the available ep idemiological evidence (Waterborne Diseases in the United States, G. F. Craun, ed. , 1986, CRC Press) demonstrates a dramatic increase in the number of waterborne outbreaks and individual cases within the United States since the mid-1960s. In addition, it should also be noted that the incidence of water borne outbreaks of unknown etiology and those caused by "new" pathogens, such as Campylobaeter sp. , is also increasing in the United States. Although it might be debated whether these increases are real or an artifact resulting from more efficient reporting, it is clear that waterborne morbidity cannot be ignored in the industrialized world. More significantly, it represents one of the most important causes of illness within developing countries. Approxi mately one-half the world's population experiences diseases that are the direct consequence of drinking polluted water. Such illnesses are the primary cause of infant mortality in many Third World countries.

Although there have been many books on HIV and AIDS, surprisingly little has been published that focuses on the immunology of retroviral infections in general, and HIV in particular. Retroviral Immunology: Immune Response and Restoration is the first book of its kind to address the most important aspects of the immunology of retroviruses, including not only the virus-specific immune responses, but also genetic and virologic factors modulating these responses. The book also deals directly with the emerging concept of immune restora tion in retroviral infections, a particularly important subject to the thousands of clinicians who deal with this problem on a daily basis. With the advent of highly effective antiviral drug regimens to slow down the replication of HIV and the progression of AIDS, new challenges and opportunities are arising. Restoration of general immune function has brought with it not only complica tions of immune restoration-mediated disease, but also the realistic hope for meaningful restoration of the ability to control HIV replication with the immune system. Leading scientists in the field have summarized the most current informa tion regarding experimental and clinical aspects of retroviral infections. Retroviral Immunology: Immune Response and Restoration should prove an impor tant point of reference for basic scientists and clinicians in this area of research. We are indebted to all of our authors for their excellent contributions."

This Community meeting has been organised, since over the past 15 years in different countries of Western Europe including Scandinavia, a lot of research has been directed to the summer mastitis problem. Summer mastitis in cattle is a well known disease which, because of its abruptness and the difficulties concerned in defining the predisposing factors and the pathogens involved, is hard to control. Moreover, as it is anticipated that in the transmission of the bacteria one or more dipterans are involved, the complexity in defining the disease and hence co-ordinating our scientific knowledge in relation to practical control was stimulus enough for this workshop to be organised. Our aims can be summarised in the following goals: 1. Exchange of information in the practical, technical and scientific field in order to stimulate a co-ordinated research approach at a time in which the cattle husbandry sector is under great economical stress. 2. Inform research workers from countries where the disease is or seems to be, not endemic, on aspects that might be of interest for them in the approach of comparable problems. 3. To draw up conclusions and recommendations with regard to future research activities in order to avoid needless duplication of effort.

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 . . . . . . . . . . . . ..................... . . . . . .

This volume includes contributions from the speakers of the Second IMD Congress (September 10-15, 2007; Moscow, Russia) who were eager to share some of the academic and clinical enthusiasm that defines the IMD meetings. The goal of the International Immune-Mediated Diseases: From Theory to Therapy (IMD) Congress is to bring the world 's best immunologists and clinicians to Moscow.

The papers published herein comprise the presentations given at the eighteenth of an annual series of clinical symposia arranged under the auspices of the Eastern Pennsylvania Branch of the American Society for Microbiology. This symposium allowed approximately 200 persons to gather and exchange ideas on the rapid laboratory diagnosis of infectious diseases. The institution of the Diagnosis Related Group (DRG) method for reimbursement by both government agencies and private insurance carriers has provided a financial aspect to the established clinical reasons for rapid laboratory diagnosis. Now the health of the institution, as well as the patient, is dependent on a timely diagnosis and, hopefully, cure. Accordingly, the goal of this symposium was to present the latest developments in "same-day microbiology." In the face of stable or diminishing resources, the laboratory director is presented with many choices. Do nucleic acid probes, non instrumental ELISA techniques, or time-resolved fluorometry have a place in his or her laboratory? Should the laboratory test for newly described human pathogens such as human immunodeficiency virus or human papilloma virus? Can rapid techniques supplant conventional methods? Or are they merely adjunctive? This symposium attempted to assist in the formulation of informed decisions. Bruce Kleger Donald Jungkind Eileen Rinks Linda A. Miller vii ACKNOWLEDGEMENTS We would like to thank the Eastern Pennsylvania Branch of t e American Society for Microbiology for sponsoring this symposium and for making this publication possible. We especially thank the Symposium Committee for their diligent work in organizing an informative and successful symposium."

Bacterial diarrheal diseases are a very important problem for human health, and many people, especially infants and children, die every year from diarrheal diseases, particularly in developing countries. Thus, in 1978 the World Health Organization initiated a Diarrhoeal Diseases Control Programme and is now working actively to control diarrheal diseases. The "International Symposium on Bacterial Diarrheal Diseases" which took place in Osaka from March 23rd to 25th, 1982, was organized by Osaka University with the support of the Ministry of Education, Science and Culture of the Japanese Government. The aim of this Symposium was to promote exchange of scientific information on bacterial diarrheal diseases, few years due since studies in this field have progressed rapidly during the last to work in many laboratories throughout the world. It seems appropriate that this Symposium was held in Osaka, since during the past century Japanese bacteriologists have made a number of important con tributions in the field of bacterial diarrheal diseases. Outstanding among these contributions are the recognition of Shigella as a causative agent of bacillary dysentery by Dr. Kiyoshi Shiga and the serotyping of Vibrio cholerae into the Ogawa, Inaba and Hikojima serotypes by Drs. Kabeshima and Nobechi. Moreover more recently, Dr. Tsunesaburo Fujino of Osaka University discovered Vibrio parahaemolyticus as the causative agent of an important diarrheal disease."

Vaccines have historically been considered to be the most cost-effective method for preventing communicable diseases. It was a vaccine that en abled global eradication of the dreaded disease smallpo. ."

The belief that energy might be a limiting factor for the development of humanity led twenty years ago to a great interest being'taken in research on anaerobic digestion. The first international symposium held in Cardiff in 1979 was followed by the meetings in Travenmund (1981), Boston (1983), Guangzhou (1985) and Bologna (1988). By now anaerobic digestion has come to be recognized as an appropriate technology for waste treatment. More recently, the increase in the carbon dioxide content of the atmosphere and (in developed countries, especially_ in the EEC) the* fact that more and more land is becoming available for purposes other than food production make biomass production economically and/or socially feasible for industrial purposes. The possibility of using renewable organic carbon resources in this way is of great potential interest for developing biological techniques and could considerably increase the use of anaerobic micro-organisms in cellulose biotransformation and energy production from crop residues. This FEMS Symposium is devoted to the interspecies hydrogen transfer phenomenon involved in the mineralization of organic matter in anaerobiosis. This process is carried out in Nature by consortia of anaerobic micro-organisms living syntrophically. Many industrial applications of these consortia as black boxes for biogas production and waste treatment have been described. Although these early approaches were fruitful, it seems likely that a better knowledge at the molecular level of the more characteristic anaerobic bacteria which constitute these consortia would greatly increase and improve the utilization of these organisms.

Mycoplasmas are placed in a separate class, Mollicutes, which removes them from bacteria. Their main characteristics are lack of a cellular wall and inability to synthesize the peptidoglycan polymer. The lack of a cell wall accounts for the pleomorphism, osmotic sensitivity, sensitivity to antibiotics that inhibit pep tidoglycan polymerization and synthesis, susceptibility to lysis by alcohol and detergents, and the ability to grow on agar gel. At present, three families are placed in the class Mollicutes: Mycotaceae, Acholetaceae, and Spiroplasmataceae. The first pathogenic mycoplasmas were discovered in Pasteur's laboratory nearly 90 years ago as the causative agents of a sheep disease. They were first named PPLO, pleuropneumonia-like organisms. In 1928, Nocard in France coined the name mycoplasma for PPLO, but his publication and the new name remained practically unnoticed until Leonard Hayflick and Robert Channock succeeded in culturing the "PPLO" of human "atypical virus pneumonia" in the United States in 1960. Hayflick resurrected the name given by Nocard and since then, the causative agent of human "atypical virus pneumonia" is known as Mycoplasma pneumoniae. Other mycoplasmas cause diseases in dogs, sheep, birds, cattle, pigs, etc."

Contrary to common belief, infectious diseases are not as well under control as we would like. We are now at a crossroads regarding the impact of the environment on infectious diseases. Renewed interest in biological weapons and the emergence of new pathogens, coupled with a better understanding of the impact of infectious agents on other conventional diseases, has led us to realise that we can no longer remain complacent about the impact of infectious agents on human, animal and crop health. The present book first discusses current and emerging military and civilian policies on the environment. In addition, the impact of environmental biology on the future of space exploration is discussed, especially in reference to the Mars mission. There follows a discussion of the state of bacteria in the environment, with a presentation of current and emerging techniques of microbial investigation. Finally, two case studies are presented on the impact of these techniques on both political and environmental problems.

The emergence of pathogens resistant to conventional antimicrobial agents has forced us to intensify the efforts in search for new approaches to prevent infectious diseases. Such a direction was indicated in studies over the last two decades showing that adhesion of pathogens, primarily via glycoconjugate or protein receptors of the host tissue, is crucial for the infectious process. Moreover, it was found that infection can be prevented by blocking adhesion of the pathogen to mucosal surfaces of the host. The various aspects of interference with the process of microbial adhesion as a way of preventing diseases were the subject of the Bat-Sheva Seminar, "Towards Anti-Adhesion Therapy of Microbial Infectious Diseases," held in Zichron Yaakov, Israel, February 25 to March I, 1996. A major aim of the Bat-Sheva de Rothschild Foundation for the Advancement of Science in Israel, which sponsors a series of seminars, ours among them, is to provide the necessary tools and settings for international forums and exposure of young scientists and promising students to the state of the art of the field. This goal has been achieved during the week's discussions, and its major aspects are presented in this compendium. The seminar's participants, as well as the readers of this book, thank the founder and Foundation for their support. This book includes the major themes of this rapidly growing area. However, by no means do we intend to cover every bit and piece in it. The book's first section deals with the lectin-sugar interactions and their inhibitors.

In metastasis, tumor cells disseminate from the primary lesion and home to secondary organs where they may remain dormant for a long time. Metastasis formation is still the most feared manifestation for tumor patients and clinicians. Although improvements have been made concerning earlier detection and specific therapy, most of the cancer patients still die ot distant metastases. The purpose of these three volumes is to review the recent progress in molecular metas- tasis research and to attempt to further understand the biol- ogy of this multifocal process. With respect to present day molecular biology, the pioneers of metastasis research established the basic concepts of metasta- sis formation in the 1970s and 1980s, namely, clonal selection of metastatic cells, heterogeneity of metastatic subpopulations, organ specificity of metastasis and the importance of angio- genesis (Fidler, Kripke, Nicolson, Folkman and others). In the 1980s and 1990s, several of the molecules involved were identified and their network interactions elucidated. These three volumes of Current Topics in Microbiology and Immuno- logy compile the most recent developments on these meta- stasis-related molecules; their interactions, regulation, and ways to interfere with their action. It became evident that metastasis-related molecules are confined to distinct cellular compartments, such as the extracellular space, the cell membrane, the cytoplasmic signalling network, and the nuclear regulatory system. For the complex tnetastatic cascade, proteolysis and alterations in adhesive functions are the most obvious and thus one of the most thoroughly investigated processes.

A series of remarkable discoveries in the past three decades have led to the molecular and genetic characterization of the transmissible pathogen causing scrapie in animals and a quartet of human illnesses: kuru, Jakob-Creutzfeld disease, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia. To distinguish this pathogen from viruses and viroids, the term "prion" was introduced to emphasize its proteinaceous and infectious nature.
Stanley B. Prusiner, editor of this volume, was awarded the 1997 Nobel Prize in Physiology and Medicine for his pioneering discovery of prions. The book reviews advances in studies of prions, which - as considereable evidence indicates - are novel pathogens composed only of protein."

The value of studies of monotypic populations is constantly argued in bacterial ecology. The controversy itself is evidenceofthe strong awareness that bacterial activities in natural sites are not determined by the bacteria alone. At the same time, the best evidence that bacteria are influenced by environmental factors is the contrast between their behavior in laboratory cultures and their relatively subdued influence when in the presence of com petitors, predators, and fluctuating-often stressful-environmental conditions. Monotypic populations are admittedly reductionist, but are not therefore irrelevant to bacterial ecology. Quite the contrary. Without pure culture studies, our understanding of important and applicable bacterial activities-N fixation, for example-would still be z limited to what we could discern from a comparison of events in steamed vis-a-vis un heated soil. As was evident throughout the previous volume in this treatise, practically any method of studying natural bacterial communities upsets them while permitting only limited assessment of the respective qualities and quantitative contributions to total com munity activity of each type of bacterium present. Total activity itself is difficult to assess and is not dependably accomplished by any single method. This third volume comprises information regarding the properties of bacteria as they have been learned largely from pure culture studies. Its purpose is twofold: to provide readers with fundamental information regarding the cellular organization, physiological capabilities, and genetic systems of bacteria; and to connect known bacterial properties with environmental influences on them and with their influences on natural processes."

G. Piekarski appears not to have been brought home to at Forty years have passed since Trussent pub- least some clinicians. Of special importance in lished an important book in the English lan- this connection are T. vaginalis and Pentatri- guage on Trichomonas vaginalis Donne and uro- chomonas hominis (Davaine), the intestinal tri- genital trichomoniasis. During the intervening chomonads of many mammalian species, in- four decades, much information has been accu- cluding humans. Some practitioners still tell mulated on trichomonads parasitic in humans their patients about the possibility of an intesti- and on the diseases they cause. In light of this, nal origin of trichomonal infection of the uro- many parasitologists and clinicians believe that the time has come for a complete review, in genital tract. book form, of various aspects of these parasites Trichomonas vaginalis infection of new- and of the trichomonad parasitemias. This need borns, infants, and young children constitutes has been further reinforced by the finding that, an interesting, although not extensively pur- despite the use of effective anti trichomonal sued, area of investigation. For hitherto incom- drugs during the past years, the prevalence of pletely understood reasons, the period of preg- human urogenital trichomoniasis, the world's nancy appears to favor the increase of most common sexually transmitted disease, has symptomatic trichomoniasis; there is, there- been increasing significantly. As might have fore, little doubt that infants can be infected been expected, therefore, discussion of various during birth.

In metastasis, tumor cells disseminate from the primary lesion and home to secondary organs where they may remain dormant for a long time. Metastasis formation is still the most feared manifestation for tumor patients and clinicians. Although improvements have been made concerning earlier detection and specific therapy, most of the cancer patients still die of distant metastases. The pu-rpose of these three volumes is to review the recent progress in molecular metas tasis research and to attempt to further understand the biol ogy of this multifocal process. With respect to present day molecular biology, the pioneers of metastasis research established the basic concepts of metasta sis formation in the 1970s and 1980s, namely, clonal selection of metastatic cells, heterogeneity of metastatic subpopulations, organ specificity of metastasis and the importance of angio genesis (Fidler, Kripke, Nicolson, Folkman and others). In the 1980s and 1990s, several of the molecules involved were identified and their network interactions elucidated. These three volumes of Current Topics in Microbiology and Immuno logy compile the most recent developments on these meta stasis-related molecules; their interactions, regulation, and ways to interfere with their action. It became evident that metastasis-related molecules are confined to distinct cellular compartments, such as the extracellular space, the cell membrane, the cytoplasmic signalling network, and the nuclear regulatory system. For the complex metastatic cascade, proteolysis and alterations in adhesive functions are the most obvious and thus one of the most thoroughly investigated processes.

In comparison with antibacterial chemotherapy the clinical use of specific antiviral drugs is a fairly recent development. By the 1950s a number had been discovered, but their clinical application was delayed until 1962, when methisazone was used for the treatment of infective complications of smallpox vaccination and idoxuridine in the treatment of herpetic keratitis. In retrospect the reasons for this slowness in development is now evident. It was due in large part to the prevailing view held at the time that virus infections could never be treated with specific agents, since the multiplica tion of virus is so closely integrated with the metabolic processes of the host cell that specificity of action seemed impossible of achievement. In contrast, bacteria were independent entities with metabolic systems differing widely from those of the mammalian host, which afforded points of attack by specific agents which had no action upon mammalian systems. Although the mode of action of the sulphonamides and penicillin was not known for some time, they afforded perfect examples of the success of this mode of attack."