Acinetobacter meningitis: acquired infection in a neonatal intensive care unit

A cluster of 4 cases of meningitis due to Acinetobacter calcoaceticus var anitratus occurred during a 5-day period in a neonatal intensive care unit. Three of the infants were preterm and all had a history of other medical problems. Initiation of intravenous therapy with carbenicillin was accompanied by clinical recovery and a bacteriological cure. Intensive bacteriological investigation failed to show a common source for the infections.     

Mutagenic evaluation of nitroparaffins in the Salmonella typhimurium/mammalian-microsome test and the micronucleus test.

Three nitroparaffins (nitroethane, 1-nitropropane, and 2-nitropropane) were studied in the Salmonella typhimurium/mammalian microsome (Ames) test, with and without microsomal activation systems. Nitroethane and 2-nitropropane also were studied in an in vivo mutagenic (micronucleus) test. These studies were undertaken because these solvents are widely used in the chemical and pharmaceutical industries and 2-nitropropane was reported to cause liver cancer in rats exposed by the inhalation route. Neither nitroethane nor 1-nitropropane was active in the Ames test with Salmonella tester-strains TA1537, TA92, TA98, or TA100. However, 2-nitropropane produced a significant increase in revertants in all of these tester strains, particularly strain TA100, where 3 microliter/plate doubled the number of revertants in the presence of microsomal enzymes. Negative results were obtained with both nitroethane and 2-nitropropane in micronucleus tests. These studies have shown that 2-nitropropane has the potential for causing point mutations in a microbial test system. However, this compound probably will not cause a chromosome mutation of the clastogenic type.     

Genetic heterogeneity in familial hyperinsulinism [published erratum appears in Hum Mol Genet 1998 Sep;7(9):1527]

Familial hyperinsulinism (HI) is a disorder characterized by dysregulation of insulin secretion and profound hypoglycemia. Mutations in both the Kir6.2 and sulfonylurea receptor (SUR1) genes have been associated with the autosomal recessive form of this disorder. In this study, the spectrum and frequency of SUR1 mutations in HI and their significance to clinical manifestations of the disease were investigated by screening 45 HI probands of various ethnic origins for mutations in the SUR1 gene. Single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses of genomic DNA revealed a total of 17 novel and three previously described mutations in SUR1 . The novel mutations comprised one nonsense and 10 missense mutations, two deletions, three mutations in consensus splice-site sequences and an in- frame insertion of six nucleotides. One mutation occurred in the first nucleotide binding domain (NBF-1) of the SUR1 molecule and another eight mutations were located in the second nucleotide binding domain (NBF-2), including two at highly conserved amino acid residues within the Walker A sequence motif. The majority of the remaining mutations was distributed throughout the three putative transmembrane domains of the SUR1 protein. With the exception of the 3993-9G-->A mutation, which was detected on 4.5% (4/88) disease chromosomes, allelic frequencies for the identified mutations varied between 1.1 and 2.3% for HI chromosomes, indicating that each mutation was rare within the patient cohort. The clinical manifestations of HI in those patients homozygous for mutations in the SUR1 gene are described. In contrast with the allelic homogeneity of HI previously described in Ashkenazi Jewish patients, these findings suggest that a large degree of allelic heterogeneity at the SUR1 locus exists in non-Ashkenazi HI patients. These data have important implications for genetic counseling and prenatal diagnosis of HI, and also provide a basis to further elucidate the molecular mechanisms underlying the pathophysiology of this disease.      

Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expanding CAG repeat coding for polyglutamine in the huntingtin protein. Recent data have suggested the possibility that an N-terminal fragment of huntingtin may aggregate in neurons of patients with HD, both in the cytoplasm, forming dystrophic neurites, and in the nucleus, forming intranuclear neuronal inclusion bodies. An animal model of HD using the short N-terminal fragment of huntingtin has also been found to have intranuclear inclusions and this same fragment can aggregate in vitro . We have now developed a cell culture model demonstrating that N-terminal fragments of huntingtin with expanded glutamine repeats aggregate both in the cytoplasm and in the nucleus. Neuroblastoma cells transiently transfected with full-length huntingtin constructs with either a normal or expanded repeat had diffuse cytoplasmic localization of the protein. In contrast, cells transfected with truncated N-terminal fragments showed aggregation only if the glutamine repeat was expanded. The aggregates were often ubiquitinated. The shorter truncated product appeared to form more aggregates in the nucleus. Cells transfected with the expanded repeat construct but not the normal repeat construct showed enhanced toxicity to the apoptosis- inducing agent staurosporine. These data indicate that N-terminal truncated fragments of huntingtin with expanded glutamine repeats can aggregate in cells in culture and that this aggregation can be toxic to cells. This model will be useful for future experiments to test mechanisms of aggregation and toxicity and potentially for testing experimental therapeutic interventions.      

应用丙戊酸钠调节组蛋白乙酰化对肿瘤细胞周期相关蛋白的调控作用

目的 探讨应用组蛋白脱乙酰酶抑制剂丙戊酸钠(VPA)调节染色体组蛋白低乙酰化修饰水平对肿瘤细胞增殖周期相关蛋白Cyclin A、Cyclin DI、Cyclin E和P21waf/cipl的调控作用. 方法 应用0.75～4.00 mmol/ VPA干预肝癌细胞HepG2、胃癌细胞BGC-823、乳腺癌细胞MCF-7 48 h后,PI标记流式细胞术检测细胞周期;间接免疫荧光法分析Cyclin A、Cyclin D1、Cyclin E、P21waf/cip1蛋白表达;RT-PCR检测分析Cyclin A、Cyclin D1、Cyclin E、P21waf/cip1 mRNA表达. 结果 HepG2、BGC-823、MCF-7这3种细胞系培养48 h后,流式细胞术分析可见0.75～4.00 mmol/L、VPA实验组随药物浓度的增加而出现逐渐递增的细胞增殖周期G1期阻滞趋势.HepG2、BGC-823细胞Cyclin A蛋白及mRNA表达被明显下调;MCF-7细胞Cyclin A蛋白及mRNA表达在两个浓度组均未见明显变化;Cyclin D1蛋白及mRNA表达在3个细胞系均被明显下调;P21waf/cip1蛋白及mRNA表达在3个细胞均被明显上调;Cyclin E蛋白及mRNA表达则未见明显变化. 结论 应用VPA干预组蛋白乙酰化修饰可对HepG2、BGC-823、MCF-7细胞Cyc-lin D1、P21waf/cip1表达起明显的调控作用;对Cychn A的调控作用则随肿瘤细胞来源及表型的不同而有所差异,而对Cyclin E则无明显的调控作用.在VPA诱导肿瘤细胞增殖周期G1期阻滞过程中,下调CyclinD1和上调P21waf/cip1蛋白及mRNA表达可能是其共同作用途径.     

Measured haplotype analysis of the angiotensin-I converting enzyme gene

Linkage and segregation analysis have shown that circulating angiotensin-I converting enzyme (ACE) levels are influenced by a major quantitative trait locus that maps within or close to the ACE gene. The D variant of a 287 bp insertion/deletion (I/D) polymorphism in intron 16 of the gene is associated with high ACE levels and may also be related to increased risk of cardiovascular disease. Multiple variants that are in linkage disequilibrium with the I/D polymorphism have been described, but it is unknown if any of these are directly implicated, alone or in combination with as yet undiscovered variants, in the determination of ACE levels. An analysis of 10 polymorphisms spanning 26 kb of the ACE gene revealed a limited number of haplotypes in Caucasian British families due to strong linkage disequilibrium operating over this small chromosomal region. A haplotype tree (cladogram) was constructed with three main branches (clades A-C) which account for 90% of the observed haplotypes. Clade C is most likely derived from clades A and B following an ancestral recombination event. This evolutionary information was then used to direct a series of nested, measured haplotype analyses that excluded upstream sequences, including the ACE promoter, from harbouring the major ACE-linked variant that explains 36% of the total trait variability. Residual familial correlations were highly significant, suggesting the influence of additional unlinked genes. Our results demonstrate that a combined cladistic/measured haplotype analysis of polymorphisms within a gene provides a powerful means to localize variants that directly influence a quantitative trait.      

世界卫生组织与热带病防治

简述世界卫生组织之缘起、架构、工作、人事及各区域分署等,及其热带病,例如疟疾、血吸虫、丝虫病、登革热、黑热病、麻风及锥虫病的防治状况。