All the patients hospitalised at Besan?on Hospital between October 2000 and December 2000 were included in a prospective study in order to determine the incidence of bloodstream infections caused by coagulase-negative staphylococci (CNS), the prevalence of decreased susceptibility to glycopeptides and the molecular epidemiology of these pathogens. CNS isolates from bloodstream infections were collected and characterised by analysis of antibiotic susceptibility and restriction fragment length polymorphism using pulsed field gel electrophoresis. Forty-five episodes of CNS bacteremia occurred in 43 patients. The crude incidence of infected patients was 0,51 per 1,000 days of hospitalisation. These 45 bacteremia represented 23.3% of the total number of bacteraemia. Forty three of 45 bacteremia were studied, 36 were positive with a single PFGE pattern, 5 bacteraemias with 2 PFGE patterns, and 2 bacteraemias with 3 PFGE patterns. We identified 52 distinct PFGE patterns and 42 major PFGE patterns (35 were isolated in a single patient, 5 in 2 patients and 2 in 3 patients). The dendrogram generated showed deep but limited branching, each large branch corresponding to a species. Of these CNS isolates, 28.8% and 25.0% showed decreased susceptibility to teicoplanin, with the reference method and E-test respectively. The 16 strains belonging to multiple PFGE patterns were not more resistant to teicoplanin. Clonal dissemination did not seem to play a major role in the spread of glycopeptides resistance among CNS. 相似文献
Summary The timing of mentally executed movements was measured in ten patients with hemiplegia, tetraplegia and paraplegia. In hemiplegic patients a significant difference in mental duration times was found between the paralysed and the normal represented limb. The paralysed limb was mentally much slower than the healthy one. In contrast, movement times in tetraplegic and paraplegic patients did not differ from those in normal subjects. All patients reported a sensation of subjective effort accompanying the execution of the mental tasks. These observations are compatible with an outflow processing underlying motor imagery. 相似文献
The 677cytosine mutation identified in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been frequently associated with an elevated plasma homocysteine concentration. The aim of the present study was to determine the impact of this MTHFR common mutation on plasma and erythrocyte folate (RCF) and plasma total homocysteine (tHcy) concentrations in healthy French adults. A cohort of 291 subjects living in the Paris area and participating in the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study were analysed to assess the impact of MTHFR polymorphism 677C-->T on folate status and plasma tHcy concentration. The frequency of the mutant homozygote for 677C-->T polymorphism (677TT genotype) in the present cohort was 16.8%. There were significant differences in plasma tHcy between 677CC, 677CT and 677TT genotype groups. The RCF concentrations were significantly different between each genotype, the lowest levels being associated with the 677TT genotype. When segregated by gender, no differences in tHcy between homozygous 677TT, heterozygous 677CT and wild-type 677CC genotype groups in women were observed. The fasting tHcy in women was unrelated to the 677C-->T mutation. However, tHcy was significantly increased in men with the homozygous 677TT genotype. We also analysed the possible implication of a second new MTHFR polymorphism (1298A-->C) in subjects with mild hyperhomocysteinaemia (4th quartile of homocysteinaemia; tHcy >11.1 micromol/l). The polymorphism 1298A-->C did not have a notable effect on tHcy or on the RCF levels. Our observations confirm a relatively high frequency of the 677TT genotype in the French population. Women with this genotype did not show the same increase in tHcy observed in men. In the present study dietary folate intake was not measured. Thus, the interaction of dietary folate with the MTHFR genotype in the French population needs further study. 相似文献
Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.Negative (or purifying) selection is the natural process by which deleterious alleles are selectively purged from the population (1). In diploid species, the strength of negative selection at a given locus is predicted to increase with decreasing fitness and increasing dominance of the genetic variants controlling traits: Variation causing early death in the heterozygous state are the least likely to be transmitted to the next generation, as their carriers have fewer offspring than noncarriers (2). Human genetic variants that cause severe diseases are, thus, expected to be the primary targets of negative selection, particularly for diseases affecting heterozygous individuals. In humans, several studies have ranked protein-coding genes according to their levels of negative selection (3–5). Nevertheless, the extent to which negative selection affects human disease-causing genes, and the factors determining its strength, remain largely unknown, particularly because our knowledge of the severity, mode, and mechanism of inheritance of the corresponding human diseases remains incomplete (3, 6–8).The strength of negative selection at a given gene has been traditionally approximated by comparing the coding sequence of the gene in a given species with that of one or several closely related species; it depends on the proportion of amino acid changes that have accumulated during evolution (9–11). With the advent of high-throughput sequencing, intraspecies metrics have been developed, based on the comparison of the probability of predicted loss-of-function (pLOF) mutations for a gene under a random model with the frequency of pLOF mutations observed in population databases (5, 12, 13), which capture the species-specific evolution of genes. Using an interspecies-based method and a hand-curated version of the Online Mendelian Inheritance in Man (hOMIM) database, a previous study elegantly showed that most human genes for which mutations cause highly penetrant diseases, including autosomal dominant (AD) diseases in particular, evolve under stronger negative selection than genes associated with complex disorders (6). However, other studies based on OMIM genes have reported conflicting results (3, 14–17), probably due to the incompleteness and heterogeneity of the datasets used. Moreover, no study has yet addressed this problem with intraspecies metrics, even though it has been suggested that the choice of the reference species for interspecies metrics contributes to discrepancies across studies (6).We aimed to improve the identification of the drivers of negative selection acting on human disease-causing genes, by developing a negative selection score combining several informative intraspecies and interspecies statistics, focusing on inborn errors of immunity (IEI). IEI, previously known as primary immunodeficiencies (18), are genetic diseases that disrupt the development or function of human immunity. They form a large and expanding group of genetic diseases that has been widely studied, and they are well characterized physiologically (immunologically) and phenotypically (clinically) (19–21). IEI are often symptomatic in early childhood, and at least until the turn of the 20th century and the introduction of antibiotics, most individuals with IEI probably died before reaching reproductive maturity. Accordingly, IEI genes have probably been under strong negative selection from the dawn of humankind until very recently. In this study, we investigated whether the severity of IEI and their mode and mechanism of inheritance have left signatures of negative selection of various intensities in the corresponding human genes. Furthermore, we validated our model on genes underlying inborn errors of neurodevelopment (IEND), another group of well-characterized severe genetic diseases. 相似文献
A study is carried out in order to better understand the kinetic behavior of two different metallocene precursors supported on an activating silica support, and, in particular, to attempt to reduce the significance of catalyst deactivation through the use of different alkylating agents. It is observed that it is difficult to prevent the deactivation of the rac‐EtInd2ZrCl2 sites on the activating support, and, furthermore, the deactivation is accompanied by the disappearance of sites producing the highest‐molecular‐weight polymer. On the contrary, with the (nBuCp)2ZrCl2 precursor, it is possible to manipulate the addition of either tri‐isobutylaluminum (TIBA) or triethylaluminum (TEA) to significantly reduce the deactivation of the catalyst on the activating supports. Finally, the molecular‐weight distribution seems to depend much more on the intrinsic properties of the active sites than on how the active sites are treated.