African swine fever (ASF) is caused by a virus that is classified as a member of the Iridovirinae family. The disease in the warthog, the natural host, in Africa was described in 1921 by R. E. Montgomery. The reservoir of the vi rus is inti cks. The i ntroduct i on of domestic pi gs into territory occupied by warthogs i nf ected wi th ASF in the 1960's has endangered the pig industry around the world. The domestic pig is highly sensitive to ASF and develops a devastating disease that kills the pig without giving the immune system a chance to defend the animal against the virus infection. The ability of ASF virus to infect and destroy cells of the reticuloendothelial system leaves a defenseless host that succumbs to an infection which may be described as an acquired immune deficiency di sease of domestic pi gs. Introduction of the virus into Iberia in the 1960's led to a series of ASF epidemics in Spain and Portugal . . and later in France, that caused heavy economic losses. Between 1976 and 1960, ASF virus made its appearance in Malta and Sardinia . . as well as in Brazil, The Dominican Republic . . Haiti, and later in Cuba. In 1985-6 . . ASF appeared in Belgium and The Netherlands.

This volume, the last in this series on cancer growth and Moreover, the current status of plant-derived vinca alka progression, is a companion volume to Volume IX and loids and non-alkaloid natural products is summarized. further explores established and novel approaches for the Advances in hyperthermia and additional approaches for therapy of patients with malignant neoplasms. The stra the therapy of malignancies are also presented. tegies reflected in these volumes are direct extrapolations The volume continues with chapters on bone marrow from the basic science of cancer biology, growth and pro transplantation as well as hematologic and nutritional sup gression described in earlier volumes of this series. Some port for the cancer patient. Blood pressure in the cancer approaches are directed towards the eradication or modifi patient, therapy for nausea and vomiting as well as pain are cation of the properties of heterogeneous malignant tumor discussed. The last chapter is devoted to the problems of the cells at various stages of tumor progression, while other terminally ill, including evaluations of the burden relatives approaches are directed towards modification of the host and friends of the cancer patient have to bear. antitumor defense systems, e. g., enhancement of host anti It is clear that important advances in the basic science of tumor immune reactivity."

The outbreaks of myxomatosis among rabbits in Australia in 1950 and in Europe in 1952 provided scientists with opportunities of observing the course of the interaction of a very lethal virus disease with a large population of highly susceptible mammals, i.e. with a model system to study the evolution of an infectious disease, and the effects of an infectious disease on the evolution of a mammal. This scientific account of the spread of the disease in Australia and Europe, of its effects upon rabbit numbers, and of the genetic changes that occurred in parasite and host, is of great interest to ecologists, virologists, parasitologists, mammalian zoologists, geneticists, agriculturists, and public health workers, as well as to those directly concerned with rabbit raising or control.

G. Petursson and Rikke Hoff-J0rgensen The concept of slow viral infections was first put forward in 1954 by Dr. Bjorn Sigurdsson, an Icelandic physician who had been studying some sheep diseases which were introduced into Iceland with the importation of a foreign breed of sheep in 1933. Sigurdsson's main criteria for defining slow infec tions were a very long initial period without clinical signs lasting months or even years following infection and a rather regular protracted, progres sive course, once clinical symptoms had appeared, usually ending in serious disease or death. Sigurdsson included in this list of slow infections maedi -visna, infectious adenomatosis of sheep, scrapie in sheep, Bittner's mam mary carcinoma and Gross' leukemia in mice. All of these diseases, except scrapie, are caused by retroviruses. The characteristics of slow infections as described above are of prac tical importance for epidemiology, diagnosis and control of these diseases. For many years the slow infections remained primarily a veterinary problem, mainly affecting sheep and goats in certain countries. In recent years, how ever, the human immunodeficiency virus (HIV) causing acquired immunodefici ency syndrome (AIDS), has suddenly appeared in many countries of the world and brought the slow infection concept forcefully to the attention of the medical profession. The disease problems and the economic effects of slow infections of sheep and goats are increasingly recognized in various coun tries. For the reasons stated above we feel that this book should be useful for veterinarians and physicians alike."

Radiophannaceuticals labeled with short-lived radionuclides are utilized to unravel biochemical processes, and to diagnosis and treat diseases of the living body are-developed through extensive evaluation in ~iological models. 'fhC first attempt to compile information was a volume entitled ANIMAL MODELS IN RADIOTRACER DESIGN that was edited by William C. Eckelman and myself in 1983. The volume had a focus on the animal models that investigators were using in order to design radiotracers that displayed in vivo selectivity as measured by biodistribution and pharmacokinetic studies. A concern in the early days of nuclear medicine was species differences. Often a series of labeled compounds were evaluated in a several different animal models in order to gain confidence that the selected radiotracer would behave appropriately in humans. During the past 12 years there have been remarkable advances in molecular genetics, molecular biology, synthetic radiopharmaceutical chemistry, molecular modeling and visualization, and emission tomography. Biological models can now be selected that are better defined in terms of molecular aspects of the disease process. The development of high resolution PET and SPET for clinical applications facilitates the development of new radiopharmaceuticals by the use of models to quantitatively evaluate drug effects, and progression of disease, and hence to arrive at better diagnosis and treatments for animals and humans. With these advances there is an effective use of biological models, and the refinement of alternatives for the development of new radiophannaceuticals.

Interest in the coronaviruses has never been greater. Their economic impact is considerable as they infect humans, livestock, poultry and companion animals. Murine hepatitis virus (MHV) infection of the mouse and rat central nervous systems are the subject of intense study; these investigations are providing insights into the potential role of viruses in human neurological diseases and, more generally, into mechanisms causing neurological damage. The single-stranded, positive-sense RNA genomes of two species of these enveloped viruses (IBV and MHV) have been cloned completely and one of them (lBV) sequenced in its entirety, revealing a genome size of some 27000 nucleotides. This has made possible more incisive investigations into the nature of those polypeptides, encoded by more than half of the genome, which are likely to contribute, in the main, to RNA polymerase/replicase activity. Intriguingly, ribosomal frameshifting is exhibited within the mRNA coding for these polypeptides. The cloning/sequencing phase of coronavirology for which the 1980's will be partly remembered, has provided a sound framework for furthex: studies of the virus structural proteins and also some provocative insights relevant to these studies. The large spike glycoprotein(s), responsible for membrane fusion and bearing important antigenic sites, varies amazingly in length and composition both within as well as between coronavirus species. Receptors on host cells have been identified. The integral membrane glycoprotein (M) has been shown to use internal hydrophobic sequences to direct translocation within membranes.

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 .

The field of genetic toxicology is a relatively new one which grew out of the studies of chemical mutagenesis and modern toxicology. Considering that systematic practices to detect chemical mutagenesis are only a little over thirty years old, this field has evolved very rapidly with an abundance of methods for identifying chemical mutagens. To evalulate the usefulness of the methods and to select the assay which will yield the most important information under practical conditions requires the broad experience such as that which Dr. Brusick has acquired over the last decade. Since this field is expanding very rapidly and new test ing methods are being recognized, it should be kept in mind that revisions may have to be made during the next five to ten years. The need for such a book has been obvious to us, particularly since training courses and workshops on genetic toxicology are being organized which find it beneficial to utilize established guidelines and since the reports in the literature do not always describe in detail how the work was carried out during laboratory testing. In addition to his broad background in genetics, Dr. Brusick has had much practical experience, having organized and directed the most extensive laboratory for mutagen testing. I am most pleased to see this volume, for which there is an ever-increasing need. Alexander Hollaender Associated Universities, Inc. 1717 Massachusetts Avenue, N.W."

9. REFERENCES 90 CHAPTER 9: OPPORTUNITIES FOR REPLACEMENT, REDUCTION AND REFINEMENT: HUMAN VIRAL VACCINES 93 1. INTRODUCTION 93 2. TESTS FOR EXTRANEOUS MICROORGANISMS 94 3. MUMPS VACCINE . . . 94 4. HEPATITIS B VACCINE 95 4. 1. Test for freedom from live hepatitis virus 95 4. 2. Potency test 95 5. INFLUENZA VACCINE 96 5. 1. Potency test 96 5. 2. Abnormal-toxicity test 96 6. MEASLES VACCINE. . . . . 96 6. 1. Tests for extraneous agents 97 6. 1. 1. Test for Mycobacterium tuberculosis 97 6. 1. 2. Test for extraneous viruses 97 6. 2. Abnormal-toxicity test 98 7. POLIOMYELITIS VACCINE. . . 99 7. A. Inactivated poliomyelitis vaccine 99 7. A. l. Production. . . . . . 99 7. A. 2. Test for residual live virus 99 7. A. 3. Tests for extraneous agents 100 7. A. 3. l. Test for Mycobacterium tuberculosis . . . . . 100 7. A. 3. 2. Test for extraneous viruses 100 7. A. 4. Tumourigenicity test. . . . . 100 XII 7 . A. 5. Potency test . . . . . . . 101 7. A. 6. Test for abnormal toxicity 102 7. B. Live, oral poliomyelitis vaccine 103 7. B. l. Test for extraneous agents 103 7. B. 2. Test for neurovirulence 105 7. B. 3. Test for abnormal toxicity 106 8. RABIES VACCINE 106 8. 1. Production 106 8. 2. Test for residual live virus 107 8. 3. Tests for extraneous microorganisms 107 8. 3. 1. Test for Mycobacterium tuberculosis 107 8. 3. 2. Tests for extraneous viruses 108 8. 3. 2. 1. In dogs 108 8. 3. 2. 2.

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 23rd annual meeting of the International Society on Oxygen Transport to Tissue took place from August 23-27, 1995, at the Station Square Sheraton along the shores of the Monongahela River where it meets with the Allegheny and Ohio Rivers to form the "Point" of the city of Pittsburgh. Pittsburgh was a convenient location for the meeting be ing between both the East and West coasts of the United States and between the Asian and European continents. It is easily accessible by air via its large international airport. In ad dition, Pittsburgh has just recently undergone a transition from the steel mills and indus tries of old to an age of computers and biotechnology as evidenced by the new Biotechnology Center of the University of Pittsburgh where a lunch and tour were pro vided for interested participants. On the tour, the participants got to see the mix of projects ranging from molecular biology to clinical projects studying membrane oxygenators, ven tricular assist devices, oxygen carriers, and more, representing the forefront of research on oxygen delivery systems to tissue.

It is a great pleasure for me to introduce this great deal of information from various insti- manual for the diagnosis of parasites of domes- tutes and universities. tic animals. It is a unique publication in many The result is an impressively comprehen- respects. Books concerning parasitic anima I sive, beautifully illustrated and, above all high- diseases - comprehensive textbooks, but also ly serviceable manual. It is easy to consult. Its field manuals - abound. These generally deal systematic and colour-coded layout allows the with aetiology, c1inical signs and pathology, as user to steer swiftly and surely through a vast weil as control and treatment. However, while amount of information. Clinical pictures and methods for diagnosis are often mentioned, figures show the parasite stage of diagnostic these are rarely sufficiently practical and spe- interest, facilitating a rapid and accurate diag- cific to allow the person ne I in field laborato- nosis. The book has been designed to be used ries to reach a concise, rapid dia gnosis of the by veterinarians and technicians, by teachers parasite species involved in any particular case. and students - in fact, by anyone dealing with Parasitic Infections of Domestic Animals suc- the diagnosis of diseases in domestic animals. ceeds in redressing these shortcomings.

With the rapid spread of drug use and abuse in this country over the last decade, events relating to drugs have become increasingly prominent in the court of law as well as in society in general. It is anticipated that throughout the 1980s this problem will continue to be one of the major social problems in the United States. With the complexity of the Federal and state laws and their interrelationships, and with the increasing demand for the expert chemist or toxicologist, or both, in the courtroom, more education for these people relating to drugs must be implemented. The prosecuting and defense attorneys are also in need of accurate toxicological information to adequately handle cases in which drugs playa role. This book is intended to be a practical as well as an educational book-a resource tool for the active forensic chemist, as well as for the student. It is with the forensic chemist in mind that the material on controlled substances and substances found in cases of drug abuse has been arranged in a systematic order for quick and easy reference. This section includes synonyms, pharma ceutical preparations, biochemistry and/or pharmacognosy, toxicology and/or pharmacology, and how the substance is controlled under Federal law. Under the concept of scientific consideration as compared with the Federal law, this book enables one to deal with some of the major conflicts in the American legal system concerning scientific evidence and how it is presented in a court of law."

The articles published in this volume are based on the papers del ivered at a conference on the Role of Metal Ions in Biological Systems held November 20 and 21, 1972, at Argonne National Laboratory. The purpose of the conference was to present to an interdiscipl inary audience of physical scientists some recent developments illustrating the chemical and environ mental participation of the heavy metal ions in the biological system. The invited speakers at the conference are special ists in the fields they describe, and the articles presented here are at a level of interest to readers with backgrounds in physical sciences who are not necessari Iy doing research in the areas described. The articles are referenced through 1972, and in some cases early 1973, and thus should also be of value to research workers. It is hoped that the book wi II be of particular interest to chemists, biologists, workers in the fields of en vironmental science and publ ic health, as wei I as graduate and senior undergraduate students in these discipl ines. The conference was sponsored by the Central States Universities, Inc., a consortium of sixteen midwestern univer sities, the Center for Educational Affairs, Argonne National Laboratory, and the United States Atomic Energy Commission. It is my pleasure to thank the members of the conference committee for their ideas and active help in organizing the conference."

Tiselius demonstrated that the immunologically active components of immune sera migrated electrophoretically in the gamma globulin region. His findings illuminated the classic observations of Jenner regarding development of resistance to infection, and those of von Pirquet, Pasteur, and Arthus regarding the transfer and specificity of resistance. Conceptual integration of these observations provided the impetus for the present modern era of immunology. Subsequent to Tiselius's work, multiple, rapid advances have occurred in the study of congenital and acquired immune deficiency states in mice, chickens, and humans. These studies have readily demonstrated that the immunologic ability of an organ ism to protect itself from environmental influences is a prerequisite for survival. Indeed, this necessity for protection from microenvironmental influences has promoted the evolu tionary development of immunologic diversification, namely, host dependence upon a sophisticated, multifaceted network of cells and effector mechanisms responsible for the clearance and neutralization of toxins and potentially harmful pathogens. The obligate dependence of animals upon the functional integrity of their immunologic systems is illus trated by the ready invasion of ubiquitous organisms when the host is in a state of immune defense derangement. Nevertheless, derangements in immune function can range from par tial to complete and can be compatible with survival. The consequences of such derange ments run the gamut from subclinical disease to inevitable mortality."

The human-animal bond has evolved and diversi?ed down the ages. Dogs, cats and even horses, have long ful?lled the role of faithful companion and indeed, as exempli?ed by the introduction of seeing and hearing dogs, there may be a critical level of co-dependency between the species. In the twenty-?rst century, the animal types that are kept as pets in many parts of the world are extensive ranging from reptiles through rodents to ruminants and beyond. As would be predicted by the nature of the relationship, the approach to treatment of a companion animal is often closely aligned to that which would have been offered to their owner. However, an increasing awareness of welfare issues, such as the recognition that animals expe- ence pain and the proven bene?ts of disease prevention in intensive farming units, together with the growth in zoos and wildlife parks, has increased the likelihood of food producing and non-domesticated animals receiving medicinal products during their life-time. Although many of the individual drugs or classes of drugs administered to animals are the same as, or derived from, those given to man, the safe and effective use of drugs in animals often cannot be achieved by simply transposing knowledge of drug action on, or behaviour in, the body from one species to another. The impact of the anatomical, physiological and pathophysiological variability that spans the animal kingdom can often profoundly alter drug response.

Both a theoretical text and a practical handbook, Vaccines for Veterinarians is the first of its kind to bring the basic science of animal vaccination and the practical details of vaccine use together in one single volume. From the first chapter on the history of vaccination and the triumph of rinderpest eradication to the last chapter on the rapidly emerging field of cancer vaccines, this book offers a truly comprehensive grounding in established and emerging vaccines for both major and minor species. Specific topics include viral vectored vaccines, DNA-plasmid vaccines, RNA vaccines, reverse vaccinology, the complexities of adjuvant use, vaccine failures and adverse events, vaccine production and regulation, robotic vaccination machines, contraceptive and production-enhancing vaccines, and so much more. At a time when resistance to human vaccination is receiving much publicity, this evidence-based book is the ideal counter to ill-informed speculation - serving as a timely reminder that vaccination is essential for the control of infectious diseases in animals. Well-respected and experienced veterinary author, Ian Tizard, provides expert guidance on the topic of vaccinations and immunology in veterinary medicine. Expert Consult site offers an online version of the book, making it easy to search the entire book electronically. The latest information on viral vectored vaccines keeps you up-to-date on the topic as well as the properties and relative advantages of currently used vectors in animal vaccines. Survey of vaccine responses covers the different mechanisms by which the immune system responds to different types of vaccines. Inclusion of the latest vaccine technologies discusses the advantages and disadvantages of DNA-plasmid vaccines, RNA vaccines, and more. Coverage of adverse events and hypersensitivities includes the best ways to treat them and report them. Coverage of passive immunization discusses the growing use of therapeutic monoclonal antibodies in veterinary medicine. Coverage of immunotherapy includes recent improvements and new products in both active and passive immunotherapy against animal cancers.

Peste de Petits Ruminants (PPR) is a highly contagious viral disease of domestic and wild small ruminants that can significantly affect economies. The authors are experts in the field and provide an up-to-date and comprehensive review covering all aspects of the disease. The book is divided into seven chapters highlighting genome organization, virus replication and the determinants of virulence, pathophysiology and clinical disease, immunology and immunopathogenesis, epidemiology, diagnostic assays and vaccines, and the challenges concerning global eradication. It is an invaluable reference work, presenting the latest information for virologists, microbiologists, immunologists, veterinarians, and scientists working in PPR research.

The best protection against environmental mutagens is to identify them before they ever come into general use. But it is always possible that some substance will escape detection and affect a large number of persons without this being realized until later generations. This article considers ways in which such a genetic emergency might be promptly detected. A mutation-detecting system should be relevant in that it tests for effects that are as closely related as possible to those that are feared. It should be sensitive enough to detect a moderate increase in mutation rate, able to discover the increase promptly before more damage is done, responsive to various kinds of mutational events, and designed in such a way as to maxi- mize the probability that the Gause of an increase can be found. Methods based on germinal mutation necessarily involve enormous numbers of persons and tests. On the other hand, with somatic mutations the individual cell becomes the unit of measurement rather than the in- dividual person. For this reason, I think that somatic tests are preferable to germinal tests, despite the fact that it is germinal mutations which are feared.

As editor I want especially to thank Dr. Ernst Freese for helpful co operation in preparing these volumes, and to express my appreclatlOn to Drs. Kurt Hirschhorn and Marvin Legator, the other members of the editorial board. Alexander Hollaender January 1971 Preface The purpose of these volumes is to encourage the development and ap plication of testing and monitoring procedures to avert significant human exposure to mutagenic agents. The need for protection against exposure to possibly mutagenic chemicals is only now coming to be generally realized. The recently issued Report of the Secretary's Commission on Pesticides and Their Possible Effects on Health (the Mrak Report-U.S. Department of Health, Education and Welfare, December 1969) has made an important start. Its Panel on Mutagenicity recommends that all currently used pesticides be tested for mutagenicity in several recently developed and relatively simple systems. Whether recommendations such as these are actually put into effect will depend on convincing government, industry, and the public that the problem is important, that the proposed tests would be effective, and that they can be conducted at a cost that is not prohibitive. Why is it important to screen environmental agents for mutagenic activity? To those who will read this book, the answer is self-evident. The sine qua non of all that we value and all that we are is our genetic heritage.

The publication of the James Herriot books led to an upsurge in interest in the veterinary profession among the public and inspired many to study veterinary medicine. However, the veterinary profession has changed markedly since those Herriot days, with many more opportunities for people entering the veterinary field, including such as job prospects in bioscience research, government work, specialization in exotic animal medicine, animal welfare advisory work, international development work, and a whole host of other career options. The landscape of the veterinary curriculum has also broadened considerably, with topics like animal behavior, ethics, business management, client communication, veterinary public health, and clinical skills, alongside clinical veterinary medicine. Authored by a Royal Veterinary College instructor with extensive experience within the veterinary profession and with teaching new students, this book provides a thorough explanation of what prospective students can expect to study at veterinary school, and it discusses career options available to new graduates.Additionally, the book offers a useful overview of current issues in the wider veterinary profession, as well as an honest and thought-provoking discussion of what veterinary life is actually like. It will also be of benefit to qualified vets and agricultural students. [Subject: Veterinary Science, Medicine, Agriculture]

Elastic filaments refer mainly to titin, the largest of all known proteins. Titin was discovered initially in muscle cells, where it interconnects the thick filament with the Z-line. Titin forms a molecular spring that is responsible for maintaining the structural integrity of contracting muscle, ensuring efficient muscle contraction. More recently, it has become clear that titin is not restricted to muscle cells alone. For example, titin is found in chromosomes of neurons and also in blood platelets. This topic is fast becoming a focal point for research in understanding viscoelastic properties at the molecular, cellular, and tissue levels. In titin may lie a generic basis for biological viscoelasticity. It has become clear that titin may hold the key to certain clinical anomalies. For example, it is clear that titin-based ventricular stiffness is modulated by calcium and that titin is responsible for the altered stiffness in cardiomyopathies. It is also clear from evidence from a group of Finnish families that titin mutations may underlie some muscular dystrophies and that with other mutations chromatids fail to separate during mitosis. Thus, it is clear that this protein will have important clinical implications stemming from its biomechanical role. One aspect of this field is the bringing together of bioengineers with clinical researchers and biologists. Genetic and biochemical aspects of titin-related proteins are being studied together with front-line engineering approaches designed to measure the mechanics of titin either in small aggregates or in single molecules.