Dr. Hilary Koprowski is the pioneer of live polio vaccine, the first researcher to advance the diagnostic and therapeutic use of monoclonal antibodies, and the developer of the "gold standard" rabies vaccine. A world-reknowned maverick in biomedical research, Koprowski's research methods were often considered controversial and even radical. Nonetheless, he acquired key positions in many research organizations, such as the Rockefeller Foundation, Lederle Labs, and Wistar Institute, initiating landmark studies from cancer research to multiple sclerosis. One of his crowning achievements, the successful crusade for monoclonal antibodies, resulted in his founding of Centocor, a forerunner in the corporate world of biomedicine. This account of Koprowski's life history is a mixture of personal interviews, anecdotes, and legends of the art and science behind the man.

For years, toxoplasmosis has been known as disease mostly affecting newborns. Since immunocompromised patients (AIDS) present a high risk of reactivation of chronic toxoplasmosis this parasitic disease has gained increasing interest. Besides presenting clinical and therapeutical concepts, this volume provides current knowledge about genetics and immunology of T. gondii and the interaction with its 'host'. Since in vivo and in vitro models of toxoplasmosis exist, and genetic manipulation has become possible, this protozoan parasite has recently been accepted as a model for understanding the pathogenesis and persistance of other intracellular parasites. The articles of the book compromise both reviewing current concepts and reporting on yet unpublished results of leading scientists in this field.

The First International Symposium on the Interface between Analytical Chemistry and Microbiology: Applications of Chromatography and Mass Spectrometry was held June 1987 at the University of South Carolina, Columbia, SC, U.S.A. The purpose of the "Interface" meeting was to forge connections between analytical chemists and microbiologists that are using chromatography and mass spectrometry to solve common problems. The goals were admirably fulfilled. Nearly a hundred participants from seven European countries, Japan, and the United States participated in hearing twenty-three plenary talks and thirty-six submitted papers and posters. The papers and discussions displayed the breadth and depth of current research applications and revealed future directions. This book "Analytical Microbiology Methods: Chromatography and Mass Spectrometry" is loosely based on some of the presentations and discussions at the meeting. Each chapter describes specific methodology and applications in the context of the relevant scientific background. The present book continues the theme of an earlier book, "Gas Chromatography/Mass Spectrometry Applications in Microbiology", edited by G. Odham, L. Larsson, and P-A. Mardh, published by Plenum Press in 1984.

IS CROHN'S DISEASE A MYCOBACTERIAL DISEASE'! The fact that the differential diagnosis of inflammatory bowel disease includes intestinal infections has been a source of much interest and clinical concern for many years. Since the recognition of ulcerative colitis and Crohn's disease as clinical entities, numerous attempts have been made to identify a specific organism resulting in the clinical and pathologic picture of Inflammatory Bowel Disease. The first suggestion about a connection between Johne's disease, a chronic mycobacterial enteritis in cattle, and Crohn' s disease occurred in 1913, when Dalziel described enteritis in humans which, although resembling intestinal tuberculosis, he believed to be a new disorder. Since the work of Crohn in the thirties a few investigators attempted to look for mycobacteria in Crohn's disease. Until now the work of Van Patter, Burnham and others did not receive widespread recognition. In 1984 the isolation of M. paratuberculosis was reported by Chiodini et al. This report initiated the current interest and controversy about a mycobacterial etiology in Crohn's disease. The hypothesis "Crohn's disease is Johne's disease" did not receive widespread recognition, but has lead to the first muIticentered efforts to determine whether or not mycobacteria are associated with Crohn's disease.

Chronic viral hepatitis has emerged as one of the most common causes of disease and death worldwide. Because of their unique modes of replication and intimate association with the host immune system, hepatitis B virus (HBV) and hepatitis C virus (HCV) pose challenging problems to scientists in basic and applied research as well as to clinicians engaged in disease management. Although approved antiviral therapy is available for chronic HBV, the emergence of viral resistance provides a rationale for the development of novel chemotherapeutic agents. The lack of a robust cell culture system for HCV replication and a readily accessible small-animal model of HCV infection have hampered the development of antiviral agents for HCV. Neverthe-less, new antiviral agents targeting HCV are now in preclinical and clinical development.

This monograph, providing an up-to-date overview of the field of Hepatitis Prevention and Treatment, includes contributions from internationally recognized experts in the field of viral hepatitis, and covers the current state of knowledge and practice regarding the molecular biology, immunology, biochemistry, pharmacology and clinical aspects of chronic HBV and HCV infection. The volume includes salient topics such as: the history and epidemiology of HBV and HCV; recent insights into the molecular mechanisms of viral replication; the host immune response to infection and a discussion of the use (HBV) or potential development (HCV) of vaccines; the current standard of care for chronically-infected patients; and emerging therapies and issues associated with current antiviral treatments. The latest information to researchers and clinicians actively engaged in viral hepatitis research is provided, but also sufficient background and discussion of the literature to benefit the newcomer to the field.

The explosion of new information on Helicobacter pylori-related disease, both in the basic sciences and in clinical medicine, has continued to progress at an unprecedented pace. In many instances H. pylori infection, both in man and in the laboratory animal, has become a model to investigate fundamental biological issues such as micro-organism host interactions, intracellular signaling, development of mucosal atrophy, mechanism of microbial resistance, disease modifying factors etc. In view of this bewildering flood of new information, another meeting on H. pylori in the successful series Basic mechanisms to clinical cure' was organized in January 1998 in San Diego, California, to define the state-of-affairs' in H. pylori research at this time. The main objective was to integrate this new information in a series of top-quality presentations and discussions between investigators and clinicians addressing all aspects of H. pylori research and to review the current position and future research directions. The format included state-of-the-art presentations by world experts heavily involved in H. pylori research followed by in-depth discussion on intriguing or controversial issues. The presentations were grouped according to the leading theme: characteristics of the organism, mode of transmission, mechanisms of H. pylori-induced inflammation, causation of disturbances of gastric secretory and motor function, aspects of clinical presentation and management, problems related to H. pylori-associated gastric adenocarcinoma and MALT-lymphoma, novel aspects of antimicrobial therapy and vaccination. The meeting concluded with a synoptic agenda of suggested future studies for the microbiologist, the histopathologist and the clinician. The chapters published in these proceedings accurately reflect the content of the superb presentations. The reader will readily appreciate the excellent level of the cutting-edge' research which was described and discussed. These proceedings are another testimony to the enormous impact on basic science and clinical medicine of the H. pylori discovery. Although much was achieved, it is also readily apparent that many questions remain to be answered and many problems remain to be solved.

In the last few decades there has been an ever-increasing component in most BSc Zoology degree courses of cell biology, physiology and genetics, for spectacular developments have taken place in these fields. Some aspects of biotechnology are now also being included. In order to accommodate the new material, the old zoology courses were altered and the traditional two-year basis of systematics of the animal kingdom, comparative anatomy (and physiology) and evolution, was either severely trimmed or reduced and presented in an abridged form under another title. Soon after these course alterations came the swing to modular teaching in the form of a series of shorter, separate courses, some of which were optional. The entire BSc degree course took on a different appearance and several different basic themes became possible. One major result was that in the great majority of cases taxonomy and systematics were no longer taught and biology students graduated without this basic training. We field biologists did appreciate the rising interest in ecology and environ mental studies, but at the same time lamented the shortage of taxonomic skills, so that often field work was based on incorrect identifications. For years many of us with taxonomic inclinations have been bedevilled by the problem of teaching systematics to undergraduates. At a guess, maybe only 5% of students find systematics interesting. It is, however, the very basis of all studies in biology - the correct identification of the organism concerned and its relationships to others in the community."

In this book, outstanding researchers from the US and Japan review recent progress in Epstein-Barr virus research. Most people carry EBV in memory B-cells in a latent stage. Many malignancies such as T/NK cell lymphoma, AIDS-associated B-cell lymphoma, gastric carcinoma and Hodgkin's disease have been causally linked to EBV. The development of molecular biology technique has allowed us to study the roles of individual EBV genes that act in the maintenance and disruption of EBV latency.

The means by which non-enveloped viruses penetrate cellular membranes during cell entry remain poorly defined. Recent findings indicate several members of this group share a common mechanism of membrane penetration in which the virus particle undergoes programmed conformational changes, leading to capsid disassembly and release of small membrane-interacting peptides. A complete understanding of host cell entry by this minimal system will help elucidate the mechanisms of non-enveloped virus membrane penetration in general

-Integration of Systems Biology with Bioprocess Engineering: L-Threonine Production by Systems Metabolic Engineering of Escherichia Coli, By Sang Yup Lee and Jin Hwan Park; -Analysis and Engineering of Metabolic Pathway Fluxes in Corynebacterium glutamicum, By Christoph Wittmann; -Systems Biology of Industrial Microorganisms, Marta Papini, Margarita Salazar, and Jens Nielsen; -De Novo Metabolic Engineering and the Promise of Synthetic DNA, By Daniel Klein-Marcuschamer, Vikramaditya G. Yadav, Adel Ghaderi, and Gregory N. Stephanopoulos; -Systems Biology of Recombinant Protein Production in Bacillus megaterium, Rebekka Biedendieck, Boyke Bunk, Tobias Furich, Ezequiel Franco-Lara, Martina Jahn, and Dieter Jahn; -Extending Synthetic Routes for Oligosaccharides by Enzyme, Substrate and Reaction Engineering; By Jurgen Seibel, Hans-Joachim Joerdening, and Klaus Buchholz; -Regeneration of Nicotinamide Coenzymes: Principles and Applications for the Synthesis of Chiral Compounds; By Andrea Weckbecker, Harald Groeger, and Werner Hummel;

This compendium presents some of the major applications of neutron scattering techniques to problems in biology. It is a record of the papers presented at the Neutrons in Biology Conference, the third in an occasional series held to highlight progress in the field and to provide a focus for future direction. The strength ofthe neutron scattering technique remains principally in the manipula tion of scattering density through hydrogen and deuterium atoms. The development ofad vanced detectors, innovative instrument and beamline components, and sophisticated data acquisition systems through the 1970s and early 1980s provided a sound foundation for the technique. With continued development, some of the exotic and expensive equipment has become affordable by the medium-sized facilities, thereby broadening the user base considerably. Despite problems with the major neutron sources in the late 1980s and early 1990s, some spectacular results have been achieved. Whilst the high and medium flux beam reac tors will continue to make a major impact in the field, the results from the first experi ments, and the planned developments on spallation neutron sources, clearly indicate that the technique has enormous potential.

This volume is based on the Proceedings of the International Conference on "Microbial Infections: Role of Biological Response Modifiers" held in Tampa, FL, May 29-31, 1991. The major purpose of this conference was to bring together in one forum prominent investigators from around the world studying a variety of microbial pathogens, including bacteria, viruses, and fungi, and the effects of biological response modifiers (BRM) on the immune response to these microorganisms. BRM have been widely utilized in the area of antitumor resistance and include not only experimental tumor cell vaccines, but also biologically active substances such as cytokines, i. e., interferons, tumor necrosis factor, and interleukins, as well as products from bacteria which influence host resistance mechanisms. It is the belief of the organizers of this Conference that it was very timely to discuss in detail BRMs as they impact on microbial infections per se. It is now widely accepted that immunocompromised individuals, including those exposed to immunosuppressive substances such as antimetabolites used for chemothera py of malignancies, or infectious agents, such as the human immunodeficiency virus and other viruses which depress the immune response and, in turn, affect a host so as to become highly susceptible to opportunistic microorganisms, benefit from BRM stimulation of their immune system. A wide variety of immunomodulators are now being studied in terms of treating infectious diseases, as well as malignancy and autoimmune diseases."

Viruses, being obligatory parasites of their host cells, rely on a vast supply of cellular components for their replication, regardless of whether infection leads to cell death or to the state of persistence. Animal viruses are providing scientists with relatively simple models to study the molecular biology of genome replication and gene expression. Whereas viruses use, in general, pathways of macromolecular biosynthesis common to the host cell, they have a cunning ability to adopt unusual mechanisms of gene expression and gene replication, provided these special pathways offer an advantage in competition for cellular resources. Any study of viral gene expression and replication is likely to lead also to new insights in cellular metabolism. The discoveries of cis-acting regulatory elements in transcription, the phenomenon of splicing of pre mRNA, and cap-dependent and cap-independent initiation of translation may be cited as examples. In addition, animal virus genomes contain elements and encode proteins that are very useful for the design of vectors for gene cloning and expression in mammalian cells. Apart from the basic interest in their biology, viruses have gained notoriety, of course, because they are pathogens. Human animal viruses may cause diseases ranging from the deadly (AIDS) to the benign (common cold). All studies on animal viruses potentially lead to the development of tools for their control, be it through prevention by immunization or treatment with antiviral drugs. Finally, viruses have yielded invaluable reagents in molecular biology as, for example, the vaccinia virus vector for the expression of foreign genes.

Varicella-zostervirus(VZV)isamedicallyimportanthumanherpesvirus,belo- ingtothesubfamilyAlphaherpesviridae. Thecapacitytopersistinsensoryneurons isade?ningcharacteristicoftheAlphaherpesviridaesubgroupwhichalsoincludes herpessimplexvirus1and2;likeVZV,simianvaricellavirus(SVV),pseudorabies virus-1(PRV-1),andequineherpesvirus-1(EHV-1)belongtotheVaricellovirus genus. ThebasicelementsoftheinfectiouscycleofVZVinthehumanhostarethat infectionofthena?vehostresultsinvaricella,commonlyknownaschickenpox, latencyisestablishedinsensoryganglia,andreactivationcauseszosteror"sh- gles. "Therelationshipbetweenthecausative agentofvaricellaandzoster was demonstratedmorethan100yearsagowhenchildreninoculatedwithmaterialfrom zosterlesionswereshowntodevelopvaricella. Thelocalizeddistributionofthe zosterrashwasalsorecognizedasdemarcatingthedematomeinnervatedbyaxons fromneuronsineachofthesensoryganglia. Earlyelectronmicroscopystudies showedthatvirusparticleswerepresentinhighconcentrationsinthevesicular ?uidfrombothvaricellaandzosterlesions,andVZVwasamongthe?rstviruses propagatedinvitrobyJohnEndersandThomasWeller. Theintroductionofim- nosuppressivetherapiesformalignancyledtoobservationssuggestingtheneed forcell-mediatedimmunityinthehostresponsetovaricellaanditsroleinma- tainingVZVlatency. Fortunately,earlystudiesofthemolecularvirologyofVZV revealedthatitwasinhibitedbyinterferencewiththethymidinekinasegene,and thelife-threateningandoftenfatalVZVinfectionsexperiencedbythesepatients becametreatablewithantiviraldrugs. Subsequently,thecapacitytogrowVZVin tissueculturewasexploitedtocreatealiveattenuatedVZVvaccinebyMichiaki Tashihaki. Whilenowtakenforgranted,theseearlyinsightsaboutVZVandits characteristicsasahumanpathogenaswellasthedevelopmentofeffectivean- viral drugs and vaccines occurred over many decades. Importantly, these early observationssetthestagefortheremarkableprogressthathasbeenmadeinour understandingofthemolecularbiologyofVZV,thesubtletiesofitstropismfor differentiatedhumancells,includinglymphocytesaswellasskinandneurons,and themechanismsbywhichthevirusachievesanequilibriumwiththehostsothatit persistsnotjustintheindividualbutinthehumanpopulation. v vi Preface Thepurposeofthisvolumeistoreviewkeyareasofprogressinthe?eldofVZV research,aswellasworkontherelatedSVV,writtenbythosewhohavecontributed manyofthenew? ndingsthathaveenrichedourknowledgeoftheuniquech- acteristicsofthisubiquitoushumanpathogen. AlthoughtheVZVgenomeisthe smallestamongthehumanherpesviruses,therapidlyacceleratingpaceofdiscovery about VZV and VZV-host interactions re?ected in these reviews promises to continueasnewtoolsareavailableandnewhypothesesaregeneratedtoexplain howVZVhascreatedandmaintaineditsnicheinthehuman"virome"Therelationshipbetweenthecausative agentofvaricellaandzoster was demonstratedmorethan100yearsagowhenchildreninoculatedwithmaterialfrom zosterlesionswereshowntodevelopvaricella. Thelocalizeddistributionofthe zosterrashwasalsorecognizedasdemarcatingthedematomeinnervatedbyaxons fromneuronsineachofthesensoryganglia. Earlyelectronmicroscopystudies showedthatvirusparticleswerepresentinhighconcentrationsinthevesicular ?uidfrombothvaricellaandzosterlesions,andVZVwasamongthe?rstviruses propagatedinvitrobyJohnEndersandThomasWeller. Theintroductionofim- nosuppressivetherapiesformalignancyledtoobservationssuggestingtheneed forcell-mediatedimmunityinthehostresponsetovaricellaanditsroleinma- tainingVZVlatency. Fortunately,earlystudiesofthemolecularvirologyofVZV revealedthatitwasinhibitedbyinterferencewiththethymidinekinasegene,and thelife-threateningandoftenfatalVZVinfectionsexperiencedbythesepatients becametreatablewithantiviraldrugs. Subsequently,thecapacitytogrowVZVin tissueculturewasexploitedtocreatealiveattenuatedVZVvaccinebyMichiaki Tashihaki. Whilenowtakenforgranted,theseearlyinsightsaboutVZVandits characteristicsasahumanpathogenaswellasthedevelopmentofeffectivean- viral drugs and vaccines occurred over many decades. Importantly, these early observationssetthestagefortheremarkableprogressthathasbeenmadeinour understandingofthemolecularbiologyofVZV,thesubtletiesofitstropismfor differentiatedhumancells,includinglymphocytesaswellasskinandneurons,and themechanismsbywhichthevirusachievesanequilibriumwiththehostsothatit persistsnotjustintheindividualbutinthehumanpopulation. v vi Preface Thepurposeofthisvolumeistoreviewkeyareasofprogressinthe?eldofVZV research,aswellasworkontherelatedSVV,writtenbythosewhohavecontributed manyofthenew?ndingsthathaveenrichedourknowledgeoftheuniquech- acteristicsofthisubiquitoushumanpathogen. AlthoughtheVZVgenomeisthe smallestamongthehumanherpesviruses,therapidlyacceleratingpaceofdiscovery about VZV and VZV-host interactions re?ected in these reviews promises to continueasnewtoolsareavailableandnewhypothesesaregeneratedtoexplain howVZVhascreatedandmaintaineditsnicheinthehuman"virome"sos- cessfully. Further improvements in the clinical management of VZV infection shouldemergeinparallelwithbetterinsightsintoVZVmolecularvirologyand pathogenesis. Stanford,CA,June,2010 AllisonAbendroth AnnM. Arvin JenniferF. Moffat Contents TheVaricella-ZosterVirusGenome ...1 JeffreyI. Cohen VZVMolecularEpidemiology ...15 JudithBreuer RolesofCellularTranscriptionFactorsinVZVReplication ...43 WilliamT. Ruyechan EffectsofVaricella-ZosterVirusonCellCycleRegulatoryPathways ...67 JenniferF. MoffatandRebeccaJ. Greenblatt Varicella-ZosterVirusOpenReadingFrame66ProteinKinase andItsRelationshiptoAlphaherpesvirusUS3Kinases ...79 AngelaErazoandPaulR. Kinchington VZVORF47SerineProteinKinaseandItsViralSubstrates ...99 TeriK. KenyonandCharlesGrose OverviewofVaricella-ZosterVirusGlycoproteinsgC,gHandgL ...113 CharlesGrose,JohnE. Carpenter,WallenJackson,andKarenM. Duus AnalysisoftheFunctionsofGlycoproteinsEandIandTheirPromoters DuringVZVReplicationInVitroandinSkinandT-CellXenografts intheSCIDMouseModelofVZVPathogenesis ...129 AnnM. Arvin,StefanOliver,MikeReichelt,JenniferF. Moffat, MarvinSommer,LeighZerboni,andBarbaraBerarducci Varicella-ZosterVirusGlycoproteinM ...147 YasukoMoriandTomohikoSadaoka vii viii Contents VaricellaZosterVirusImmuneEvasionStrategies ...155 AllisonAbendroth,PaulR. Kinchington,andBarrySlobedman VZVInfectionofKeratinocytes:ProductionofCell-FreeInfectious VirionsInVivo ...173 MichaelD. GershonandAnneA. Gershon Varicella-ZosterVirusTCellTropismandthePathogenesis ofSkinInfection ...189 AnnM. Arvin,JenniferF. Moffat,MarvinSommer,StefanOliver, XibingChe,SusanVleck,LeighZerboni,andChia-ChiKu ExperimentalModelstoStudyVaricella-ZosterVirusInfection ofNeurons ...211 MeganSteain,BarrySlobedman,andAllisonAbendroth MolecularCharacterizationofVaricellaZosterVirusinLatently InfectedHumanGanglia:PhysicalStateandAbundanceofVZV DNA,QuantitationofViralTranscriptsandDetection ofVZV-Speci?cProteins ...229 YevgeniyAzarkh,DonGilden,andRandallJ. Cohrs NeurologicalDiseaseProducedbyVaricellaZosterVirusReactivation WithoutRash ...2 43 DonGilden,RandallJ. Cohrs,RaviMahalingam,andMariaA. Nagel Varicella-ZosterVirusNeurotropisminSCIDMouse-Human DorsalRootGangliaXenografts ...255 L. Zerboni,M. Reichelt,andA. Arvin RodentModelsofVaricella-ZosterVirusNeurotropism ...277 JeffreyI. Cohen SimianVaricellaVirus:MolecularVirology ...291 WayneL. Gray SimianVaricellaVirusPathogenesis ...309 RaviMahalingam,IlhemMessaoudi,andDonGilden Varicella-ZosterVirusVaccine:MolecularGenetics ...323 D. ScottSchmid VZVTCell-MediatedImmunity ...341 AdrianaWeinbergandMyronJ. Levin Contents ix PerspectivesonVaccinesAgainstVaricella-ZosterVirusInfections ...359 AnneA. GershonandMichaelD. Gershon Index ...373 . Contributors Allison Abendroth Department of Infectious Diseases and Immunology, UniversityofSydney,BlackburnBuilding,Room601,Camperdown,NSW 2006, Australia and Centre for Virus Research, Westmead Millennium Institute,Westmead,NSW2145,Australia,allison. abendroth@sydney. edu. au AnnM. Arvin StanfordUniversitySchoolofMedicine,G311,Stanford,CA 94305,USA,aarvin@stanford.

Pseudomonas comprises three volumes covering the biology of pseudomonads in a wide context, including the niches they inhabit, the taxonomic relations among members of this group, the molecular biology of gene expression in different niches and under different environmental conditions, the analysis of virulence traits in plants, animals and human pathogens as well as the determinants that make some strains useful for biotechnological applications and promotion of plant growth. There has been growing interest in pseudomonads and a particular urge to understand the biology underlying the complex metabolism of these ubiquitous microbes. These bacteria are capable of colonizing a wide range of niches, including the soil, the plant rhizosphere and phylosphere, and animal tissues; more recently they have attracted attention because of their capacity to form biofilms, a characteristic with potentially important medical and environmental implications. The three volumes cover the following topics: - Taxonomy, - Genomics, - Life styles, - Cell Architecture, - Virulence, - Regulation, - Macromolecules, - Alternative Respiratory Substrates, - Catabolism and Biotransformations. Pseudomonas will be of use to all researchers working on these bacteria, particularly those studying microbiology, plant crops, pathogenesis, and chemical engineering. Advanced students in biology, medicine and agronomy will also find these three volumes a valuable reference during their studies.

In eukaryotic cells, the nuclear genome and its transcriptional apparatus is separated from the site of protein synthesis by the nuclear envelope. Thus, a constant flow of proteins and nucleic acids has to cross the nuclear envelope in both directions. This transport in and out of the nucleus is mediated by nuclear pore complexes (NPCs) and occurs in an energy and signal-dependent manner. Thus, nucleocytoplasmic translocation of macro molecules across the nuclear envelope appears to be a highly specific and regulated process. Viruses that replicate their genome in the cell nucleus are therefore forced to develop efficient ways to deal with the intracellulZlr host cell transport machinery. Historically, investigation of Polyomavirus replication allowed identification ofsequences that mediate nuclear import, which led subsequently to our detailed understanding of the cellular factors that are involved in nuclear import. Transport ofmacromolecules in the opposite direction, however, is less well understood. The investigation of retroviral gene expression in recent years pro vided the first insights into the cellular mechanisms that regulate nuclear export. In particular, the detailed dissection of the function of the human immunodeficiency virus type I (HIV-I) Rev trans-activator protein identified CRMI, as a hona fide nuclear export receptor. CRM I appears to be involved in the nucleocytoplasmic translocation of the vast majority of viral and cellular proteins that have subsequently been found to contain a Rev-type leucine-rich nuclear export signal (NES)."

Assembling the latest research by an international group of contributors, this volume covers the epidemiology, pathogenesis, clinical features, and control measures of this elusive microorganism. It will provide a deeper understanding of the pathogen to physicians and surgeons caring for patients infected, or at risk of becoming infected, with Pseudomonas Aeruginosa.

Forty years after the discovery of the helix nature of DNA and more than twenty after the first applications of recombinant DNA technology to the pharmaceutical industry, the Pandora's vase of biotechnology seems far from being empty. New products for agriculture and the food industry are constantly being placed on the market, and powerful monitoring techniques have been developed to track non-modified and genetically modified vaccines, viruses, microbes and plants released into the environment. Molecular approaches for taxonomic purposes, which might also be useful for quality control and assurance, have been successfully developed and used for taxonomic purposes in the last decade for both prokaryotic and eukaryotic cells, including yeasts and filamentous fungi. Mycorrhizae are one example of a traditional biotechnology that can greatly benefit from the latest molecular approaches. These universal symbioses between soil fungi and plant roots playa central role in most of the natural and agricultural ecosystems in such key processes as nutrient cycling, soil structural conservation and plant health. For these reasons, mycorrhizae have been successfully used to improve the quality of forest and agricultural seedlings, to produce high-quality micropropagated plants and to increase the production of edible mushrooms of high economic value, such as truffles. However, although controlled inoculation of oak and hazel seedlings with ectomycorrhizal truffles has been carried out for decades in France and Italy, and is still expanding commercially, several technological gaps remain to be filled.

In this volume, a distinguished international group of contributors present the latest molecular, organismal, and epidemiological research on arenaviruses. Their work will broaden both the clinician's and the researcher's knowledge of basic mechanisms of immunological tolerance, viral immunosuppression, the nature of protective immune responses to vaccination, and viral effects on cell functions.

An extensive assessment of combination therapy of AIDS. Main focus is put on the Highly Active Antiretroviral Therapy (HAART) but other therapies like salvage therapy are also discussed. The chapters cover efficacy, treatment, causes of treatment failure, clinical care, guidelines, pharmacology. The volume closes with an outlook on future perspectives.

Infection Control in the ICU Environment provides the details of the most common infection control problems facing intensive care units. Authors include noted scientists, intensivists and epidemiologists from the United States and Europe as well as infection control experts from the Centers for Disease Control and Prevention. Acinetobacter, methicillin resistant staphylococcus aureus and vancomycin resistant enterococci are examined in detail. This volume also includes cutting edge information regarding the potential for prophylactic and pre-emptive therapy of fungal infections in intensive care units. Innovations in vascular catheter care and prevention of bloodstream infections are discussed in this volume as well as the newest information in mathematical modeling to understand the epidemiology and control of infections in intensive care units.

During the past decade, the rapid growth of molecular and cellular knowledge of macrophages, as a specialized host defense and homeostatic system, has begun to offer attractive targets for therapeutic intervention. Macrophages play a central role in a wide range of disease processes, from genetically determined lysosomal storage diseases, to acute sepsis, chronic inflammation and repair, tissue injury and cell death. Under- or overactivity of macrophage clearance, immune effector functions and responses to metabolic abnormalities contribute to common disorders such as autoimmunity, atherosclerosis, Alzheimer s disease and major infections including AIDS and Tuberculosis. Whilst the goals of therapeutic intervention based on improved understanding of macrophage functions and their contribution to pathogenesis may seem self evident, there are considerable difficulties in producing useful new agents.

The present volume covers a range of subjects and provides opportunities for a more focused macrophage-targeted approach. The individual chapters review selected topics briefly, to place cellular processes and molecular targets in perspective. Overall, the volume should provide a broad sample of the state of the art. Useful reviews and references in the literature are cited within individual chapters."

PAS proteins control numerous physiological and developmental events, and span phylogeny from bacteria to man. Bacterial and plant PAS proteins act as sensors of environmental stimuli, including light, oxygen, and energy status. Not surprising, given these roles, there is intense investigation of the roles of bHLH-PAS proteins in issues of human health including: (1) cancer induction, (2) cancer growth and vascularity, (3) birth defects, including Down syndrome, (4) appetite control and obesity, (5) sleep rhythm disorders, and (6) mental health disorders such as social interactions and learning. PAS proteins encompass many fields of biology, and scientists who work in these fields (circadian rhythms, oxygen regulation, toxin metabolism, bacterial sensors, and development) are an audience, particularly those who actively work on PAS proteins and researchers interested in transcriptional control, signal transduction, and evolution.

Viruses are studied either because they cause significant human, animal or plant disease or because they are useful materials for probing basic phenomena in biology, chemistry, genetics and/or molecular biology. Arenaviruses are unusually interesting in that they occupy both categories. Arenaviruses cause several human diseases known primarily as the hemorrhagic fevers occurring in South and Latin America (Bolivia: Machupo, Argentine, Junin virus, and Brazil: Sabia virus) and in Africa (Lassa fever virus). Because such viruses produce profound disabilities and often kill the persons they infect, they are a source of health concern and economic hardship in the countries where they are prevalent. Further, they provide new problems for healthcare persons owing to the narrowing of the world as visitors from many countries travel increasingly to and from endemic areas and may incubate the infectious agent taking it from an endemic area into an area where the virus is not expected. Such cases are now being re corded with increasing frequency. In addition to these hemor rhagic fever viruses, the arenavirus lymphocytic choriomeningitis virus (LCMV) can infect humans worldwide, although the illness is most often less disabling and severe than those elicited by the other arenaviruses. Yet, LCMV is of greater concern to non arenavirologists and experimentalists using tissue culture or ani mals, etc. , because normal-appearing cultured cells or tissues from animals used for research may be persistently infected with LCMV without manifesting clinical disease or cytopathology and may transmit that infection to laboratory workers.