Ciba Foundation symposium最新文献

beta-lactamases, the enzymes often associated with resistance to beta-lactam antibiotics, are found in most bacterial species. Although these enzymes protected bacteria from naturally occurring beta-lactams long before the introduction of synthetic antimicrobial agents, the numbers and varieties of beta-lactamases have increased dramatically with the introduction of modern penicillins and cephalosporins. Over the past twenty years it has become apparent that families of beta-lactamases have been selected as the result of antimicrobial usage. Outbreaks of beta-lactam-resistant bacteria can be traced to the introduction of specific classes of beta-lactams or to the introduction of a specific agent. Many of the most serious epidemics can be related to transferable beta-lactamase genes that are harboured on multidrug-resistant plasmids. The separation of beta-lactamases into three major functional groups or four structural classes has been proposed. Stepwise selection of variants within several of these classes has been documented both in the clinical setting and in the laboratory, e.g. the extended-spectrum (TEM and SHV) beta-lactamases and the inhibitor-resistant (TEM) beta-lactamases. Close relationships among the recently described plasmid-mediated 'cephamycinases' and the common chromosomal cephalosporinases have been identified. Carbapenem-hydrolysing metallo-beta-lactamases with broad spectrum hydrolysing activity have become serious concerns as they begin to be described on plasmids. Factors contributing to selection of beta-lactam-resistant strains include decreased outer membrane permeability and increased beta-lactamase production.

Since 1953, tetracycline-resistant bacteria have been found increasingly in humans, animals, food and the environment. Tetracycline resistance is normally due to the acquisition of new genes and is primarily due to either energy-dependent efflux of tetracycline or protection of the ribosomes from its action. Gram-negative efflux genes are frequently associated with conjugative plasmids, whereas Gram-positive efflux genes are often found on small mobilizable plasmids or in the chromosome. The ribosomal protection genes are generally associated with conjugative transposons which have a preference for the chromosome. Recently, tetracycline resistance genes have been found in the genera Mycobacterium, Nocardia, Streptomyces and Treponema. The Tet M determinant codes for a ribosomal protection protein which can be found in Gram-positive, Gram-negative, cell-wall-free, aerobic, anaerobic, pathogenic, opportunistic and normal flora species. This promiscuous nature may be correlated with its location on a conjugative transposon and its ability to cross most biochemical and physical barriers found in bacteria. The Tet B efflux determinant is unlike other efflux gene products because it confers resistance to tetracycline, doxycycline and minocycline and has the widest host range of all Gram-negative efflux determinants. We have hypothesized that mobility and the environment of the bacteria may help influence the ultimate host range of specific tet genes. If we are to reverse the trend towards increasingly antibiotic-resistant pathogenic bacteria, we will need to change how antibiotics are used in both human and animal health as well as food production.

Two particular issues make the interpretation of epidemiological studies in asthma problematic. The first is the lack of any clear definition of asthma. This is a perennial area of controversy. Thirty-eight years ago a Ciba Foundation guest symposium addressed this issue and suggested a solution. However, as J. G. Scadding, one of the participants of that symposium, pointed out after further consideration of the problem, what they had proposed was a description, not a definition. Since then, further attempts have been made but with little progress. They remain descriptive rather than definitive and have become, if anything, vaguer. The second problem has been the widespread failure to be precise about hypotheses or to define more precisely the hypothetical influences on asthma. Examples of this are the notions of 'inflammation' and 'atopy'. Standardization of methods for epidemiological studies of asthma is likely to provide a more rigorous framework for the comparison of results and the testing of hypotheses. Nevertheless, the development of such protocols should itself be seen as a hermeneutic device rather than an assertion of established knowledge.

Asthma prevalence and morbidity have increased in the past 10 years in the face of improved knowledge about pathophysiology and treatment. Changing patterns and interactions among asthma risk factors may contribute to these disease trends. Diet is a newly recognized potential risk factor for asthma occurrence. This chapter focuses on the methodological issues in the assessment of diet as a risk factor for asthma and the available data linking diet to asthma, airway inflammation and airway responsiveness, and it concludes with a consideration of research needs and future directions. Four types of dietary constituents are considered: breast feeding and food avoidance in infancy; antioxidant vitamins, specifically vitamin C; dietary cations, specifically sodium and magnesium; and N3-N6 fatty acids. At present, available data are insufficient to implicate any dietary constituent as a causal risk factor for asthma. Data are strongest for vitamin C, which is associated with protective effects of airway responsiveness, lung function and asthma symptoms. Prospective cohort studies of the effects of early childhood diet on the development of asthma in children (birth to age six years) are needed to assess diet as a risk factor for early childhood asthma and its interrelationship with other risk factors.

Immunity to viruses is used to define important biological parameters of immunology. Specificity, tolerance and T and B cell memory were analysed with murine model infections. The key parameters of antigen kinetics, localization and patterns of T and B cell response induction in maintaining memory and in causing deletion of reactive lymphocytes were compared for self and for viral foreign antigens. Evidence is reviewed that suggests that B cells essentially recognize antigen patterns, whereas T cells react against antigens newly brought into lymphoid tissues; antigens outside lymphoid tissues are ignored, and antigens always present in, or spreading too fast throughout, lymphoid tissues exhaust and delete T cell responses. Finally, effector mechanisms of antiviral immunity are summarized, as they vary with different viruses. On this basis immunological T and B cell memory against viruses is reviewed. Memory studies suggest that increased precursor frequencies of B and T cells appear to remain in the host independent of antigen persistence. However, in order to protect against cytopathic viruses, memory B cells have to produce antibody to maintain protective elevated levels of antibody: B cell differentiation into plasma cells is driven by persisting antigen. Similarly, to protect against infection with a non-cytopathic virus, cytotoxic T cells have to recirculate through peripheral organs. Activation and capacity to emigrate into solid tissues as well as cytolytic effector function are also dependent upon, and driven by, persisting antigen. Because no convincing evidence is yet available of the existence of identifiable B or T cells with specialized memory characteristics, the phenotype of protective immunological memory correlates best with antigen-driven activation of low frequency effector T cells and plasma cells.

Ordered rearrangements of immunoglobulin (Ig) gene loci, first as DH to JH, then as VH to DHJH, and finally as VL to JL segment-specific recombinations occur 'in-frame' and 'out-of-frame'. 'In-frame' rearrangements lead to the expression of truncated DHJH-microC proteins and to microH chains. These H chain proteins have two major effects on precursor B cells. They suppress (as DJC mu proteins) or enhance (as full microH chain) the proliferation of precursor cells at the point where these precursors express these proteins. At the same time, they signal allelic exclusion of the microH chain alleles, so that VH to DHJH rearrangement at the second allele is suppressed. Regulation of precursor B cell proliferation and H chain allelic exclusion is mediated by a pre-B cell receptor that is composed of the microH chains and a surrogate L chain. This surrogate L chain is made up of two proteins encoded by the Vpre-B and lambda 5 genes that are expressed only at the early precursor cell stages just before and when H chain genes are first expressed. They are not found in later B cell development, when L chains are expressed, nor in any other cell of the body tested so far. The physiological roles of surrogate L chain and of the pre-B receptor have been clarified by generating mutant mice in which the lambda 5 gene has been inactivated by targeted disruption. Molecular mechanisms and cellular developments, by which the pre-B receptor controls proliferation and allelic exclusion, are discussed.

This chapter discusses the events that led to the contamination of environments with the long-lived radionuclides of caesium, strontium and other elements, and to the internal exposure of populations living in contaminated areas. Among these events are radioactive releases into the river Techa from the Soviet nuclear weapons facility Mayak in 1949-1956, thermonuclear weapons tests in the 1950s and 1960s, the Kyshtim and Windscale accidents in 1957, and the Chernobyl and Tomsk-7 accidents in 1986 and 1993, respectively. Methods of environmental monitoring and individual internal dose monitoring of inhabitants are described. These are based on measuring the content of radionuclides not only in the air, drinking water and local food products, but also in humans using whole-body counters and analysing excreta and autopsy samples. The dynamics of internal exposure of people of different ages to radionuclides of caesium, strontium and plutonium from the environment are considered. Examples of radionuclide distributions in the environment, and of individual/collective internal doses and related medical effects are presented.

Historical experiments and observations in radioactively contaminated environments have documented radiation impacts on natural plant communities and animal populations. General findings from these studies are reviewed. Despite much information on the response of individual organisms to radiation in the laboratory, the database is more limited and the interpretations more complex for natural populations and communities exposed to radionuclides. These complications are discussed as they pertain to plants and animals in natural environments. Paradigms concerning the recovery of radiation-damaged communities and ecosystems, and areas of needed research are discussed.

Control of gene expression at the transcriptional level can be achieved with triplex-forming oligonucleotides provided that the target sequence is accessible within the chromatin structure of cell nuclei. Using oligonucleotide-psoralen conjugates as probes we have shown that the promoter region of the gene encoding the alpha subunit of the interleukin 2 receptor and the polypurine tract of integrated HIV provirus can form sequence-specific, triple-helical complexes in cell cultures. Oligonucleotide-intercalator conjugates can inhibit transcription initiation by competing with transcription factor binding. Oligonucleotide analogues containing N3'-->P5' phosporamidate linkages form stable triple helices that are able to arrest transcription at the elongation step. A triple helix can also be formed on a single-stranded target by clamp oligonucleotides. A clamp targeted to the polypurine tract of HIV RNA is able to block reverse transcription of the viral RNA.