Ciba Foundation symposium最新文献

Enamel fluorosis occurs when fluoride concentrations in or in the vicinity of the forming enamel are excessive during its pre-eruptive development. Fluoride concentrations in plasma, enamel and other tissues reflect the difference between intake and excretion, i.e. fluoride balance. In addition to the diet, modern sources of ingested fluoride include a variety of dental products, some of which have been identified as risk factors for fluorosis. Fluoride absorption is inversely related to dietary calcium which, at high concentrations, may cause net fluoride secretion into the gastrointestinal tract. The excretion of absorbed fluoride occurs almost exclusively via the kidneys, a process which is directly related to urinary pH. Thus, fluoride balance and tissue concentrations and the risk of fluorosis are increased by factors such as high protein diets, residence at high altitude, and certain metabolic and respiratory disorders that decrease pH. Factors that increase urinary pH and decrease the balance of fluoride include vegetarian diets, certain drugs and some other medical conditions. Although several other fluoride-induced effects might be involved in the aetiology of fluorosis, it now appears that inhibition of enzymatic degradation of amelogenins, which may delay their removal from the developing enamel and impair crystal growth, may be of critical importance. In addition to the effects of fluoride, disturbances in enamel formation that can be confused with fluorosis are caused by chronic acidosis and hypoxia independently of the level of fluoride exposure.

The apatitic calcium phosphate crystals in dental enamel are too small for single crystal diffraction studies so the only possible direct structure determination must use whole-pattern-fitting Rietveld analysis of X-ray and neutron powder diffraction patterns. As a result, aspects of the structure are not known in detail. Further structural information can be obtained by consideration of published chemical analyses and infrared studies, taking into account studies of the crystal chemistry of synthetic apatitic analogues of enamel apatite. The apatitic constitutional water and total water content of enamel are particularly important, but there are difficulties in their determination. Making reasonable assumptions, a number of models of the unit cell can be derived. The weight per cent (including constitutional water) and density of the enamel apatite crystals for the most probable model are about 98 wt.% and 3.0 g cm-3, respectively. The apatite volume per cent calculated from these values is about 96%. The weight per cent and volume per cent of enamel apatite are higher than normally accepted values because of inclusion of constitutional water and use of a density for enamel apatite that takes into account its known lattice expansion over hydroxyapatite and probable lattice vacancies.

Tuftelin is a novel acidic enamel protein thought to play a major role in enamel mineralization. Its identity and localization has been confirmed by amino acid composition, enzyme-linked immunosorbant assay, Western blots, indirect immunohistochemistry and high resolution protein-A gold immunocytochemistry. The deduced tuftelin protein (pI 5.2) contains 389 amino acids and has a calculated peptide molecular mass of 43,814 Da. Immunological studies suggest conservation of tuftelin structure between species throughout vertebrate evolution. The cDNA sequence encodes for several putative post-translation sites including one N-glycosylation consensus site, seven O-glycosylation sites and seven phosphorylation sites, as well as an EF-hand calcium-binding domain (with mismatch), localized towards the N-terminal region. At the C-terminal region (residues 252-345) tuftelin contains structurally relevant determinants for self assembly. We recently cloned and partially sequenced the human tuftelin gene (four exons have now been sequenced). These sequences include exon 1 and over 1000 bases of the putative promoter region. Employing fluorescent in situ hybridization, we mapped the human tuftelin gene to chromosome 1q 21-31. Localization of the human tuftelin gene to a well-defined cytogenetic region may be important in understanding the aetiology of autosomally inherited amelogenesis imperfecta, the most common enamel hereditary disease.

The biochemistry and genetics of antibiotic resistance are far better known than the equally important events underlying the selection of resistant populations. The hidden selection of low-level resistant variants may be a key process in the emergence of high-level antibiotic resistance. Different low-level resistant bacterial subpopulations may be specifically selected by different low antibiotic concentrations. The space in the environment (human body) where a given selective concentration exists represents the selective compartment. For pharmacokinetic reasons, low antibiotic concentrations occur in a larger selective compartment and persist longer than high antibiotic concentrations. The specific selection of low-level variants by low concentrations of antibiotic can be reproduced in experimental in vitro models using mixtures of susceptible and low-level resistant populations. We demonstrated this in Escherichia coli strains harbouring TEM-1, TEM-12 and TEM-10 beta-lactamases challenged by cefotaxime, and also Streptococcus pneumoniae strains with various levels of penicillin resistance challenged by amoxicillin or cefotaxime. In both cases, four hours of antibiotic challenge produced selective peaks of low-level resistant variant populations at low-level antibiotic concentrations. We conclude that variants with small decreases in antibiotic susceptibility may be fully selectable under in vivo circumstances; on the other hand, low-level antibiotic concentrations may have a considerable selective effect on the emergence of antibiotic resistance.

The T cell hypothesis of asthma, particularly chronic asthma, is based around the concept that the disease is driven and maintained by the persistence of a specialized subset of chronically activated T memory cells sensitized against an array of allergenic, occupational or viral antigens which home to the lung after appropriate antigen exposure or viral infection. Allergens induce a CD4+ T helper (Th) cell response, whereas viruses recognize CD8+ T cytotoxic (Tc) cells. In the asthmatic airway there appears to be both CD4+ and CD8+ cells with a type 2 cytokine phenotype (i.e. Th2 and Tc2 type). These cells produce: interleukin (IL)-5, IL-3 and granulocyte macrophage colony-stimulating factor, which recruit, mobilize and activate eosinophils for subsequent mucosal tissue damage; and IL-4, an essential co-factor for local or generalized IgE production. This in turn leads to eosinophilic desquamative bronchitis, with epithelial shedding, mucus hypersecretion and bronchial smooth muscle contraction. Thus, although the eosinophil is largely responsible for airway symptoms, its function appears to be under T cell control. Support for this hypothesis includes: the observations that activated T cells and their products can be identified in biopsies from the major variants of the disease (atopic, nonatopic [intrinsic] and occupational asthma); the co-localization of mRNA for type 2 cytokines to CD4+ and CD8+ cells in atopic and non-atopic asthma; the presence of chronically activated cytokine-producing T cells in corticosteroid-resistant asthma; the association of disease severity with type 2 cytokines, especially IL-5; and the efficacy of cyclosporin A in chronic steroid-dependent disease. Inhibitors and/or antagonists directed against more precise T cell-associated molecular targets hold promise for the future treatment of chronic asthma.

The Chernobyl accident made it clear that the contaminants released after a severe nuclear accident may spread over large areas, and thereby form a significant external radiation hazard in areas of high population density. Since then, the weathering effects on the deposited radiocontaminants (essentially radiocaesium) have been followed on different types of surface in urban, suburban and industrial areas in order to enable an estimation of the long-term impact of such events. Analytical expressions have been derived for the typical behaviour of radiocaesium on the different surfaces, and dose measurements and calculations for different urban environments have pinpointed which surfaces generally contribute most to the dose and consequently are most important to clean. At this point, after nearly a decade, the dose rate from horizontal pavements has decreased by at least a factor of 10, whereas the dose rate from an area of soil or a roof has generally only been halved. The contamination on walls is the most persistent: it has only decreased by 10-20%.

Scoring of dicentrics in metaphase preparations of human T lymphocytes is the method of choice for estimating individual whole-body doses of radiation exposure. A quantification of partial-body exposures or non-uniform distribution of the dose is more complicated but it can be achieved by using specific mathematical approaches. For retrospective biodosimetry, conventional scoring of dicentrics is less precise because these unstable aberrations are eliminated with time post-exposure. Symmetrical translocations are not selected against during mitotic division in the haematopoietic cell reproductive centres, so the frequencies of these stable aberrations are generally assumed to remain constant even for decades. They can now be analysed precisely by fluorescence in situ hybridization using whole chromosome-specific DNA probes (chromosome painting) with an alpha-satellite DNA probe for centromere detection. Based on in vitro calibration curves established with single or multicolour paints covering 4-22% of the total human genomic DNA content, scoring of translocations has been applied for dose reconstruction in smaller groups of atomic bomb survivors and victims of the Chernobyl and Goiania radiation accidents. However, prior to routine use, the method requires further validation. Such work includes the precise evaluation of the unexpectedly high frequency of complex exchanges (> or = 3 breaks in > or = 2 chromosomes) found both at > 2 Gy doses of low linear energy transfer (LET) radiation and generally for high LET alpha-particles. Data on the long-term stability of translocations and the appearance of clonal abberrations, as well as improved measurements of the linear coefficient of standard calibration curves, are also required.

Animal information processing and decision making are often considered to be adaptations that allow individuals to behave optimally under particular ecological conditions. Numerous examples demonstrate how cues from the biotic and abiotic environments affect the ways in which animals process information and make decisions. Information gained from interactions with living organisms is the most complex because individuals have to respond to heterospecifics or conspecifics which may decide on what to do depending on the behaviour of a focal individual. Evolutionary conflicts of interest include: (i) interactions between hosts and parasites, predators and prey, and between competitors; (ii) sperm competition interactions between females, male mates and male non-mates, and (iii) interactions between mate-searching females and their potential mates. Brains may evolve particularly rapidly under the influence of evolutionary conflicts and they may enhance the importance of adapted psychologies in these contexts.

Cognitive and neural adaptations in animals have been analysed using the comparative method. Comparisons between closely related species that differ in a cognitive or neural character, and comparison between distantly related species that share a cognitive or neural character, can be used to identify adaptations. Recent research has identified adaptive modifications of memory and the hippocampus that have evolved convergently in two clades of food-storing birds, the chickadees and tits (Paridae), and the jays and nutcrackers (Corvidae). Similar modifications of the hippocampus occur in other groups of animals, such as the cowbird brood parasites, in which there has been selection for spatial memory. Three general patterns that emerge from the comparative study of animal cognition provide a framework for research on human psychological adaptations: the existence of both specialized and general cognitive capacities; a clear relation between specialized capacities and specific selective pressures; and evolutionary change in the relative size of brain areas with cognitive functions.