This volume is not intended as review of the large literature on tumor antigenicity and efforts at tumor immunotherapy. Its pur pose, rather, is to present discursively an outline of the likely approaches to immunological intervention in neoplastic diseases which present themselves today, in light ofthe probable antigenic properties of cancer cells. References are cited only selectively, in illustration of some of the major considerations to which allusion is made and of some of the supportive evidence. No attempt is made at inclusiveness in the citation of concepts and fmdings. If undue emphasis appears to be given to some aspects of the litera ture and only sparse documentation to others, the grounds do not lie necessarily with a critical estimation of the extent or quality of reported work, but rather with the bias of the writer who consi ders stress on some facets of the field more appropriate than on others for elaboration of his arguments. The references brought in support of a given point are often intentionally varied, including both reports of original work and reviews, very recent observa tions and contributions that gave initial impetus to investigations, in an attempt to exemplify the pertinent literature; and reference is made both to data presented and to concepts advanced."

The technique of microinjection along with viral genetics and molecular biology has proven useful in the correlation of retroviral polynucleotide structure with function. The advantage of this technique is the involvement of living cells where rare activities may be observed and where properties of living cells can be assayed. Future studies involving recombinant DNA molecules and the asso- ciation of proteins with nucleic acids promise to yield additional insight into the nucleotide sequences involved in the expression of viral activities. References Anderson SM, Chen JH (1981) In vitro translation of avian myeloblastosis virus RNA. J Virol 40: 107-117 Berget SM, Moore C, Sharp PA (1977) Spliced segments of the 5' terminus of adenovirus 2 late mRNA. Proc Nat! Acad Sci USA 74:3171-3175 Bishop JM (1978) Retroviruses. Annu Rev Biochem 47:35-88 Capecchi MR (1980) High efficiency transformation by direct microinjection of DNA into cultured mammalian cells. Cell 22:479-488 Chien, Y-H, Junghans RP, Davidson W (1980) Electron microscopic analysis of the structure of RNA tumor virus nucleic acids. In: Stephenson JR (ed) Molecular biology of RNA tumor viruses.

Our current understanding of a/~ T cell receptor (TCR) ex pressing T cells advanced from function and specificity to the molecular organization ofthe TCR.We now know that the TCR a and ~ chains together express specificity for (antigenic) peptides presented by the "responder" M H C allele, thus explain ing the phenomenon of MHC restriction at a molecular level. Surprisingly even though our perception of the molecular organization of the y5 TCR is well advanced, current knowledge of function and specificity of the y5 T cell subset is poor. There fore it appeared rather timely to bring together scientists pioneering research on y5 T cells forthe International Workshop on Function and Specificity ofy5 Tcells,held October11-14, 1990 at Schloss Elmau/Bavaria, FRG. Besides offering a scientific forum for open discussions, it was also hoped that such a workshop would be seminal for collaborative interactions and personal relationships among scientists "addicted" to y 15 T cells.

Profound progress has been made in the fields of chronobiology and psychobiology within the past decade, in theory, experiment and clinical application. This volume integrates these new developments on all levels from the molecular, genetic and cellular to the psycho social processes of everyday life. We present a balanced variety of research from workers around the globe, who discuss the funda mental significance of their approach for a new understanding of the central role of ultradian rhythms in the self-organizing and adaptive dynamics of all life processes. The years since the publication of Ultra dian rhythms in physiology and behavior by Schultz and Lavie in 1985 have seen a burgeoning realization of the ubiquity and importance of ultradian rhythms within and between every level of the psychobiological hierarchy. The experimental evidence lies scattered through a disparate litera ture, and this volume attempts, albeit in a highly selective manner, to bring together some of the different strands. The editors are very conscious of the omission of many important current aspects; e.g. we have not included any of the fascinating and indeed long and well-established experiments with plants (Bunning 1971, 1977; Guillaume and Koukkari 1987; Millet et al. 1988; 10hnsson et al. 1990) that are widely regarded as having initiated the whole field of chronobiology (De Mairan 1729). Neither have we reviewed recent developments on glycolytic oscillations, since a great deal of the seminal work was already completed by 1973 (Chance et al. 1973).

Of all the parasitic diseases that beset man in the warmer parts of the world, malaria is still the major cause of morbidity and mortality. In spite of intensive efforts to interrrupt its transmission malaria still threatens over 800 million people, more than one-fifth of the world's population. Malignant tertian malaria caused by Plasmodium Jalciparum probably kills a million every year. Vivax malaria temporarily incapacitates millions more. The search for antimalarial drugs, both natural and syn. thetic, has been and continues to be one of the most challenging and, at times, rewarding exercises ever undertaken by ;:;hemists and biologists. The magnitude of the effort is reflected by the fact that, in the last 15 years, well over 250000 compounds have been screened for antimalarial activity in just one programme, that carried out under the auspices of the Walter Reed Army Institute of Research, not to mention sporadic studies undertaken by other research workers and organisations. While most people engaged in the search for new drugs agree that a rational approach based on knowledge of the intimate biochemical pathways of the target cells would be ideal as well as intellectually satisfying, most are reluctantly obliged to concede that, up to the present time, the chances of success following a more or less empirical search have been far greater. Spectacular advances in molecular biology and biochemistry in recent years, however, are rapidly changing this situation.

Diagnostic cytology has recently enjoyed increased attention and significance in modern research. Essential information on latest developments in methods and applications in cytology is provided by this book. Chapters review methodological advances, such as in cancer detection, and explore potential relationships to molecular biology. Also discussed are: viral infection, fundamentals of quantitative methods, and the revolutionary role of immunocytochemistry in diagnostic cell typing. The new insights offered by transmission and scanning electron microscopy into cellular structure and function are discussed, and the connections between cytology and histology are highlighted. Epidemiology in connection with cytology is incorporated in special reports. The current developments described here will become routine methods of the cytology of tomorrow.

The intention of the series Developments in Veterinary Virology is to provide monographs dealing with the major animal viral diseases. Each volume will include the latest achievements in fundamental research and practical applications and should be readable for people from various disciplines and different backgrounds. The multi-author approach provides the best opportunity to keep each chapter at the highest level and makes the composition of the volumes manageable to the editors. This monograph on Avian Leukosis presents comprehensive reviews on the recent history of avian retrovirus research, on epizootiological, virological, pathological aspects, on tumor induction, the immune response to avian retro viruses, virus-cell interactions and on techniques for diagnosis. The volume deals mainly with exogenous avian leukosis virus (ALV) infections, but one chapter is entirely devoted to endogenous avian leukemia virus. Molecular biology aspects are confined to various oncogenes and to lymphoma induction since retroviruses, including those specific for avian species, have recently been described in detail in the Cold Spring Harbor Laboratory series "Molecular Biology of Tumor Viruses." Two chapters are devoted to the practical application of insights obtained from avian leukosis research: influences of AL V infection on production performance and eradication procedures."

Venezuelan equine encephalitis (VEE) virus was first isolated in 1938 by Kubes and Rios (1) from the brain of a horse which died during an epizootic of a previously unrecognized disease in Venezuela. VEE-related viruses were subsequently isolated during t~e period of 1943-1963 in Venezuela, Colombia, Peru, Trinidad, Brazil, Surinam, Argentina, Panama, Mexico, and the United States (2) * Shope et ~. (3) fi rst defi ned the vi ru ses in the VEE comp 1 ex t-y showing serological relationships between classical VEE, ~lucambo, and Pixuna viruses. Young and Johnson (2) serologically characterized a variety of VEE isolates and proposed that the complex t>e divided into four subtypes (I, II, III, and IV). Viruses in subtype I were divided into five variants designated IA through IE. During 1069-1~71 a VEE epizootic-epidemic occurred in South America, Central America, and the United States involving a subtype lAB virus which caused high mortality among equines and human d i sea se (4). Venezuelan equine encephalitis viruses are alpha-togaviruses w~ic~ contain a positive strand rit>onucleic acid genome enclosed in an icosa~edral nucleocapsid. The virion has an envelope which contains blO glycoproteins: E2 of 5F,000 daltons (gp56) and E1 of ~O,OOO daltons (gp50) (5,6). Viral neutralization (N) and hemagglutiration (HA) sites have been placed on E2 by the use of monospecific rabtdt antisera and monoclonal antibodies specific for purified viral structural proteins (7-10). Only anti-E2 antisera neutralized virus infectivity or blocked virus hemagglutination.

Influenza virus is an important human pathogen, frequently causing widespread disease and a significant loss of life. Much has been learned about the structure of the virus, its genetic variation, its mode of gene expression and replication, and its interaction with the host immu nologic system. This knowledge has the potential of leading to ap proaches for the control of influenza virus. In addition, research on influ enza virus has led to important advances in eukaryotic molecular and cellular biology and in immunology. A major focus of this book is the molecular biology of influenza virus. The first chapter, which serves as an introduction, describes the structure of each of the genomic RNA segments and their encoded pro teins. The second chapter discusses the molecular mechanisms involved in the expression and replication of the viral genome. In addition to other subjects, this chapter deals with one of the most distinctive features of influenza virus, namely the unique mechanism whereby viral messenger RNA synthesis is initiated by primers deaved from newly synthesized host-cell RNAs in the nudeus. Among the most significant accomplish ments in influenza virus research has been the delineation of the three dimensional structure of the two surface glycoproteins of the virus, the hemagglutinin and neuraminidase. This has provided a structural basis for mapping both the antigenic sites and the regions involved in the major biological functions of these two molecules."

Recent reviews of respiratory-tract affections caused by M. pneumoniae under- score the benign and often subclinical course of the infection. Severe pneumonia with a reticular or acinar pattern is certainly unusual and a fatal outcome is rare, but the incidence of both is underestimated. Erythromycin and tetracyclines are the first-choice antibiotics. There is evidence indicating the importance of im- munopathogenic mechanism in provoking pneumonia and even respiratory failure. REFERENCES 1. Krech U, Price PC, Jung M: The laboratory diagnosis and epidemiology of mycoplasma pneumoniae in Switzerland. Infection 4:33, 1976. 2. Fischman RA, Marschall KE, Kislak JW: Adult respiratory distress syndrome caused by mycoplasma pneumoniae. Chest 74:471, 1978. 3. Reigner Ph, Domenighetti G, Feihl F, Bonjour JPh, Perret CI: Syndrome de detresse respiratoire aigu sur infection a mycoplasme. Sch Med W 110:220, 1980. 4. Kaufman JM, Cuvelier CA, Van der Straeten M: Mycoplasma pneumonia with fulminant evolution into diffuse interstitial fibrosis. Thorax 35:140, 1980. 5. Murray HW, Masur H, Senterfit L, Roberts R: The protean manifestations of mycoplasma pneumoniae infection in adults. Am J Med 58:229, 1975. 6. Levine DP, Lerner AM: The clinical spectrum of Mycoplasma pneumoniae infections. Med Clin N Am 62:961,1978. 7. Twomey JA, Espir ML: Neurological manifestations and Mycoplasma pneumoniae infection. BMJ 2:832, 1979. 8. Kingston JR, Chankock RM, Mufson MA, Hellman LP, James WD, Fox HH, Mankoma C, Boyers J: Eaton agent pneumonia. JAMA 176:118, 1961.

S. TRACY Late in the 1940s, a virus was isolated from a young patient with a flaccid par alysis in the sleepy Hudson River town of Coxsackie in the state of New York. Within the next few years, it was apparent that this and other similar viruses were not polioviruses but were indeed a new group of viruses, viruses that by the mid- 1950s had been found to be commonly associated with pediatric inflammatory heart disease. Two groups of coxsackieviruses (A and B) were differentiated on the basis of the type of paralysis induced in suckling mice by these viruses. Group B coxsackieviruses, because of their primacy as etiologic agents of human acute viral myocarditis and its relatively common sequela, dilated cardiomyopathy, are the focus of this volume. of the century approaches, the massive international effort to eradi As the end cate polioviruses through vaccination as causes of human disease has been success ful in the Western Hemisphere and in many parts of Europe, and it is expected that worldwide eradication may be achieved within the near future. While this is wonderful news, there are sadly no similar efforts being planned to combat the numerous other human enteroviruses that daily incur widespread morbidity and mortality throughout the world. While this is due in part to the lack of specific know ledge about the other human enteroviruses, it is also due to the perceptions of industry that there is insufficient profit to be made by developing these vaccines.

The pathology caused by baculoviruses in insect popula- tions was described centuries ago, notably in the larvae of insects such as the silkworm (Bombyx mori) which has been appreciated for the quality and beauty of its products. In the 1940s baculoviruses and their structure and physiolo- gy were intensively investigated, particularly by Bergold's group in Tiibingen. The following decades saw excellent progress, laying a solid virological base for later investiga- tions on the system. Further studies mushroomed in the 1970s with the advent of tissue culture systems for insect cells which eventually facilitated the molecular biological approach that came to the fore in the 1980 s. One of the reasons for pursuing research on the baculo- virus system was the prospect of eventually using these vi- ruses as insect pest control agents. While this practical as- pect may appeal to many, molecular biologists had addi- tional reasons to be interested in baculoviruses. Here was a large DNA viral genome, probably fraught with problems of replication and regulation that hopefully would open inroads into the molecular biology of interesting insect cell systems. In the days when genetechnology promises laurels, and after several virus systems had been skilfully exploited as highly efficient eukaryotic expression vectors, it came as no surprise that baculoviruses were also investigated in that respect. Indeed, the Autographa californica nuclear po- lyhedrosis virus became a good vector. Insect cells also seem to collaborate in modifying and processing the gene- technologically synthesized polypeptides.

Elucidating Mechanisms of Eukaryotic Genetic Expression by Studying Animal Viruses AARON 1. SHATIGN* Eukaryotic genetic expression is carefully regulated. Normal cell growth and division, tis sue differentiation, and organism development all depend on a strictly ordered progres sion of specific events. Perturbation of the control of these processes, for example by ex posure to harmful chemicals or infection with viruses leads to aberrant forms of meta bolism, often resulting in malignancies and cell death. One of the most challenging problems in biology is to derme at the molecular level the mechanisms that govern gene function in higher organisms, including ultimately man. This goal serves to unify the diverse efforts of many investigators, whether studying the precise patterns of embryo genesis, the loss of control that occurs during neoplastic growth or the redirection of biosynthetic pathways in virus-infected cells. Recently there has been remarkable and exciting progress toward understanding the molecular biology of eukaryotic expression. Much of this rapidly increasing new infor mation has come from studies of animal virus systems. Just as investigations of the relatively simple, rapidly assayed, and easily manipulated bacteriophages lead to basic discoveries about prokaryotic cells, analyses of animal viruses and their interactions with host cells have provided fundamental information about how eukaryotic nucleic acids are organized for regulated replication, transcription, and translation. For example, the small genome of SV, like cellular DNA in chromatin, is associated with histones to 40 form nucleosomal arrays (Griffin 1975)."

par Prof. Dr. E. VAN OYE, Bruxelles Les Salmonella constituent un groupe de germes parmi les plus repandus, les plus cosmo- polites et les plus ubiquitaires des microorganismes potientiellement pathogi'mes. On les rencontre chez tous les animaux a sang froid ou a sang chaud, du plus humble puceron aux plus impressionnants des mammiferes tels les baleines ou les e16phants. On les retrouve aussi partout dans Ie milieu ambiant, en particulier dans les eaux superficielles, qu'elles aoient douces ou salees. nest aiae de comprendre que les aliments les plus divera et les produits les plus inattendus en sont parfois contamimls. Non seulement les Salmonella jouent un role de premier plan dans la pathologie humaine et dans la pathologie animale mais egalement, vu leur ubiquiM, dans de nombreux sec- teurs de l'economie et non seulement celui de l'alimentation. La lutte contre les affections que ces germes provoquent - les salmonelloses - est avant tout baaee sur la prevention. Celle-ci, pour etre efficace, demande d'iltre informe aussi exactement que possible, sur l'identite des germes en cause. Or il existe de par Ie monde plus de 2000 especes differentes de Salmonella pouvant presenter d'innombrables varian- tes sur les plans de la serologie, de la biochimie ou de la lysotypie.

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."

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.

Neurovirology is an interdisciplinary field representing a melding of virology, clinical neuroscience, molecular pathogenesis, diagnostic virology, molecular biology, and immunology. Neuroviral Infections: General Principles and DNA Viruses covers recent developments in the area of neuroviral infections and discusses their role in related fields such as immunology, cell biology, and molecular biology. It offers a complete discussion of the major neuroviral infections caused by DNA viruses, including information on emerging basic principles, neuroviral infections, and future challenges in virology.

those who deal with infectious diseases on a daily This two volume work stems from the belief of the Editors that infectious diseases are not only very basis. much with us today but, more importantly, that they There are several excellent textbooks dealing will continue to playa significant global role in mor with medical microbiology, and there are equally well-recognized books devoted to infectious dis bidity and mortality in all people. A continuing need for an informed and knowledgeable community of eases. The Editors of this work, on the other hand, laboratory scientists is fundamental. Data describing were persuaded that there was a need for a publica the global impact of infectious diseases are difficult tion that would bring together the most pertinent and to come by. Fortunately, a recent thoughtful and relevant information on the principles and practice of provocative publication by Bennett et al. (1987) pro the laboratory diagnosis of infectious diseases and vides us with data derived from several consultants include clinical relationships. While this two volume that clearly delineate the impact of infectious dis text is directed toward the role of the laboratory in eases on the United States today."

It has been slightly more than two decades since the Epstein-Barr virus (EBV) was discovered by Prof. M.A. Epstein and his colleagues at the University of Bristol in their search for the causative agent of Burkitt's lymphoma. For several years EBV was a "virus in search of a disease." The first documentation that EBV was pathogenic for humans was in 1969 when Drs. Gertrude and Werner Henle identified it as the causative agent for infectious mononucleosis. Seroepidemiologic and biochemical studies subsequently linked EBV to Burkitt's lymphoma (BL), nasopharyngeal carcinoma (NPC), and more recently to the X-linked lymphoproliferative syndrome. With its widespread pattern of infection and a predilection for producing clinical signs and symptoms in only certain individuals, EBV has provided a model for many other candidate oncogenic viruses, including papilloma viruses, herpes simplex, and HTLV/LAV. In 1975, an international workshop was sponsored by the National Cancer Institute to address the problem of EBV production, thus facilitating basic research on the virus. This proved to be the last international meeting on EBV for almost a decade. In the past, progress in both clinical and basic research on EBV has been presented in two types of international meetings, the international herpesvirus workshops devoted primarily to basic research on both human and animal herpesviruses, and the international symposia on NPC, in which EBV-related studies were interspersed with clinical, epidemiologic and other etiologic aspects of this important human neoplasm.

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.

A symposium seems an appropriate vehicle to review recent, as well as new, data on important topics. It is therefore our goal to present a symposium on selected topics of importance every three years. Some topics will be updated and new topics will be presented. A vast amount of information has been accumulated over the past ten years on the significance of anaerobic bacteria in infectious diseases. This symposium was organized to discuss laboratory aspects, normal flora, pathogenicity, serology, and the patients' immune re sponse to anaerobic infection. Important imformation on the patients' immune response and serology of anaerobes which has accumulated over the last few years made these topics an important part of the sympo sium. Development of serological diagnostic tests undoubtedly will provide quicker and less expensive identification of certain anaerobic species in the future. Utilization of the patients' immune response to anaerobic septicemia has the potential of providing a diagnosis of the causative agent within 24 hours after onset of symptoms. The development of such diagnostic methods and the use of these methods in the clinical laboratory in the future would provide rapid diag nostic information to the clinician on these life-threatening infec tions. Campylobacter was included in the symposium to emphasize the important role of this organism in human acute gastroenteritis. The pathogenesis of Campylobacter in gastroenteritis has been recognized in certain European countries since 1972, although we have recognized the importance of Campylobacter gastroenteritis in the United States only within the past two years."

Rabies is an ancient disease and a fearsome one. Although it may not have the economic or public health importance of some other infectious diseases, few are so well known or carry the same emotional impact. Mainly transmitted by the bite of an enraged animal, and with practically no hope for recovery among those afflicted, it has provided the substance of stories and legends throughout the ages. The pioneering work of many 19th century workers, culminating in the development of the first rabies vaccines by Louis Pasteur, provided the ground work for the modern era in the study of rabies. Since then, and particularly in the last quarter century, considerable advances have been made in our knowledge of the nature of the infectious agent, its mode of transmission and pathogenetic mechanisms. Yet even today, much remains to be learned about the disease. For example, although effective vaccines exist for humans and other animals, there is still no known practical cure once the neurological disease symptoms develop. Markers of virulence have been mapped at the molecular level, but it is yet unclear as to how rabies virus actually exerts its pathological effects.

Regulation of gene expression at the level of transcription is one of the major determinants of proper cellular proliferation and differentiation. The key players in these processes are sequence-specific DNA binding transcription factor proteins which coordinate programs of gene expression in the nucleus. The articles in this volume document the myriad of genetic and biochemical alterations sustained by human proto-oncogenic transcription factors which result in diverse neoplastic processes. This volume gives insights into how normal programs of gene expression can be subverted by the action of single transcription factors resulting in a specific tumor type. The book provides inspiration for exploiting these tumor-specific alterations as diagnostic, prognostic tools, or as selective therapeutic targets.