Ciba Foundation symposium最新文献

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.

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.

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.

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%.

Cell nuclei contain several abundant enzymes that bind rapidly and avidly to exposed termini of DNA. The properties and physiological roles of such factors are described; they include poly (ADP-ribose) polymerase, DNA-dependent protein kinase, several DNA ligases and excision-repair enzymes. Telomeres normally seem shielded from these activities by telomere-binding proteins. If incomplete protection of telomeres occurred, the functions of the DNA end-specific enzymes would be relevant for processing of telomeres. This could include alternative pathways for telomere propagation in telomerase-negative cells.

Drosophila melanogaster has an unusual telomere elongation mechanism. Instead of short repeats that are synthesized by telomerase, long retrotransposons, HeT-A and TART, transpose to the ends of chromosomes. This mechanism generates tandem arrays of these elements at the chromosome ends, in which all elements are oriented with their oligo(A) tails towards the centromere. Structural features of HeT-A and TART elements may provide clues as to their transposition mechanism. Drosophila telomere length polymorphism is mainly due to terminal retrotransposon arrays that differ between chromosome tips and that change with time. In addition, stable terminal chromosome deletions can be generated that do not contain terminal HeT-A and TART arrays, suggesting that, unlike the equivalent terminal repeats in yeast and humans, the presence and length of terminal arrays in Drosophila may not be critical for cell cycle progression.

The Tc1 and Tc2 subsets of CD8+ T effector cells secrete different patterns of cytokines, but have similar functions, including perforin- and Fas-dependent cytotoxicity, and induction of delayed type hypersensitivity (DTH) reactions involving oedema and granulocytic infiltration. The characteristic cytokines of Tc1 (gamma-interferon) and Tc2 (interleukins 4 and 5) are expressed in vivo during the DTH reaction. Tc1 cells that are deficient in cytokine synthesis also induce similar levels of DTH, supporting the lack of correlation between CD8+ T cell cytokine patterns and DTH. CD8+ T cells often produce lower cytokine levels than CD4 cells because the CD8 cells kill their antigen-presenting cells before full stimulation can occur. This effect can be counteracted by increasing the frequency of stimulation, or using perforin-deficient T cells. A multiparameter analysis of cytokine effects on CD8+ T cell differentiation has been initiated, on the basis of the principle that normal immune responses involve complex cytokine mixtures. All combinations of seven cytokines were tested. In some combinations, the combined effect could not have been predicted from individual cytokine functions. Conditions were identified in which each of interleukins 4, 10 and 12 could have opposite effects on CD8+ T cell differentiation.