Current trends and new approaches in the management of diabetes mellitus

Current trends in the management of type 2 diabetes mellitus, based on the 20-year United Kingdom Prospective Diabetic Study, include intensive treatment to control the blood glucose level and blood pressure in order to prevent or delay microvascular and cardiovascular complications. In the new millennium, type 2 diabetes will become epidemic in developing countries. If diabetes were to develop in 10% of the 1.2 billion population of China, the expense of intensive treatment would be immense. Laboratory tests are useful for detecting risk factors before the onset of the disease and convincing the general public to take preventive measures. Glucose tolerance testing is one of these tests. When glucose tolerance is impaired, 25% of beta-cell function is lost. Determining the plasma proinsulin level is another useful evaluation; impaired glucose tolerance accompanied by increased plasma proinsulin level is indicative of an enhanced risk that type 2 diabetes will develop within 5 years. Educating the public about eating a healthy diet and exercising may prevent the development of diabetes and thereby reduce the global prevalence of type 2 diabetes.     

The Secreted Larval Acidic Proteins (SLAPs) of Onchocerca spp. are encoded by orthologues of the alt gene family of Brugia malayi and have host protective potential

Onchocerca volvulus is a tissue-dwelling, vector-borne nematode parasite of humans and the causative agent of onchocerciasis, or 'River Blindness'. Resistance to infection is associated with immune responses to the infective, third-stage (L3) larvae. The antigens of greatest interest for their vaccine potential are surface and secreted molecules. We have previously identified a family of Secreted Larval Acidic Proteins (SLAPs) from the L3 larvae of O. volvulus by biosynthetic labelling. Here, we provide further characterisation of these molecules following cloning and expression of the corresponding cDNAs. Using protein sequencing, we show that SLAPs are members of the alt gene family, first described in the lymphatic filarial parasite, Brugia malayi. Ov-ALT-1 and Ov-ALT-2 correspond with 20 and 18kDa SLAPs. Both proteins are highly acidic and related by sequence, differing chiefly in an 8-amino acid deletion from Ov-ALT-2. By immunochemistry, we confirm that Ov-ALTs are highly stage-specific, being expressed exclusively in late L2 and L3 larvae during growth in the vector. They are synthesised and stored in the glandular oesophagus. Secretion is triggered by the resumption of development in the definitive host and occurs via the pseudocoelom and cuticle. Serological responses in humans to recombinant Ov-ALT-1 indicate that the level of IgG production may be governed by the force of transmission but does not overtly reflect infection status. Immunisation of mice with recombinant Ov-ALT-1 resulted in a modest level of protection against challenge with O. volvulus L3 larvae (P = 0.036). We conclude that Ov-ALT genes, like those of other filariae, are of interest from the standpoint of parasite transmission and infectivity. They may also offer promise as components of a future sub-unit vaccine should the means to enhance protection be achieved.     

芦荟大黄素对豚鼠皮肤黑色素细胞NOS的影响--免疫组织化学研究

目的探讨豚鼠皮肤黑色素细胞在大黄有效成分的作用下,一氧化氮合酶(Nitric OxideSynthse;NOS)表达的变化,阐明大黄在活体皮肤中对黑素细胞的有效作用浓度和作用机制.方法将21只雄性豚鼠随机分成对照组及5个实验组,用芦荟大黄素5种浓度对局部皮肤皮下注射处理,48小时后取材,免疫组织化学方法(SABC)法显示NOS的表达,用光学显微镜和图象分析仪对结果进行统计分析.结果芦荟大黄素作用下,表皮黑素细胞NOS表达明显减少,光密度明显下降(P<0.05);不同浓度药物作用之间无显着差异(P＞0.05),加注侧与未加注侧之间无显著差异.结论芦荟大黄素对黑色素细胞NOS的表达具有调节作用,提示大黄对黑素细胞的调节是经NO信号介导途径,为大黄的临床应用提供实验依据.     

Episomal and stable expression of the luciferase reporter gene for quantifying Leishmania spp. infections in macrophages and in animal models

We have expressed the reporter firefly luciferase gene (LUC) in Leishmania donovani and Leishmania major either as part of episomal vectors or integrated into the parasite genome under the control of their respective ribosomal promoter regions. An excellent linear correlation between parasite number and luciferase activity was observed with all the transfectants. LUC-expressing recombinant parasites were useful to monitor Leishmania spp. infections in macrophages or in animal models. For prolonged growth in absence of drug selection, such as within animal models, quantitation of parasites is more reliable when the reporter gene LUC is stably integrated in the parasite genome. These recombinant strains should be useful tools to monitor Leishmania growth under a number of conditions.     

How self-initiated memorized movements become automatic: a functional MRI study

We used functional magnetic resonance imaging (fMRI) and dual tasks to investigate the physiology of how movements become automatic. Normal subjects were asked to practice some self-initiated, self-paced, memorized sequential finger movements with different complexity until they could perform the tasks automatically. Automaticity was evaluated by having subjects perform a secondary task simultaneously with the sequential movements. Our secondary task was a letter-counting task where subjects were asked to identify the number of times a target letter from the letter sequences was seen. Only the performances that achieved high accuracy in both single and dual tasks were considered automatic. The fMRI results before and after automaticity was achieved were compared. Our data showed that for both conditions, sequential movements activated similar brain regions. No additional activity was observed in the automatic condition. There was less activity in bilateral cerebellum, presupplementary motor area, cingulate cortex, left caudate nucleus, premotor cortex, parietal cortex, and prefrontal cortex during the automatic stage. These findings suggest that most of the motor network participates in executing automatic movements and that it becomes more efficient as movements become more automatic. Our results do not provide evidence for any area to become more activated for automatic movements.     

Linkage Disequilibrium and Haplotype Architecture for two ABC Transporter Genes (ABCC1 and ABCG2) in Chinese Population: Implications for Pharmacogenomic Association Studies

Information about linkage disequilibrium (LD) patterns and haplotype structures for candidate genes is instructive for the design and analysis of genetic association studies for complex diseases and drug response. ABCC1 and ABCG2 are genes coding for two multidrug resistance (MDR) associated transporters; they are also related to some pathophysiological traits. To pinpoint the LD profiles of these MDR genes in Chinese, we systemically screened 27 unrelated individuals for single nucleotide polymorphisms (SNPs) in the coding and regulatory regions of these genes, and thereby characterized their haplotype structures. Despite marked variations in haplotype diversity, LD pattern and intragenic recombination intensity between the two genes, both loci could be partitioned into several LD blocks, in which a modest number of haplotypes accounted for a high fraction of the sampled chromosomes. We concluded that each locus has its own genomic LD profile, but that they still share a common segmental LD architecture with low haplotype diversity. Our data will benefit genetic association studies of complex traits and drug response possibly related to these genes.     

Altered sensitivity to sodium channel-specific neurotoxins in cultured neurons from temperature-sensitive paralytic mutants of Drosophila

In vitro culture of central nervous system neurons from Drosophila larvae enables direct examination of effects of neurological mutations at a single-cell level not readily amenable to in vivo experimentation. Using this system, we examined the cytotoxic effect of veratridine, which selectively causes persistent activation of sodium channels, on the mutants parats1 and napts known to have a temperature-dependent block in propagation of nerve action potentials. Even at a permissive temperature (22 degrees C) for the mutant flies, the veratridine-induced neuronal lethality was significantly lower in both parats1 and napts cultures than in normal cultures. At a temperature (35 degrees C) causing paralysis of mutant flies, napts neurons showed the same high degree of resistance to veratridine; while parats1 neurons showed an increased resistance to a level similar to that of napts neurons. A similar reduction in the veratridine-induced neuronal death was also observed in normal cultures that were pretreated with the sodium channel blocker tetrodotoxin. These results support the idea that both parats and napts affect sodium channel functions at the level of isolated single neurons. It was also found that parats1 and napts mutations, like the sodium channel blocker tetrodotoxin, do not affect the morphological differentiation and survival of central nervous system neurons in culture. These findings indicate that functional sodium channels are not required for neurite outgrowth and survival of neurons at this developmental stage.     

Breakpoint clusters of the PML gene in acute promyelocytic leukemia: Primary structure of the reciprocal products of the PML-RARA gene in a patient with t(15;17)

DNA studies of the translocation t(15;17) in acute promyelocytic leukemia (APL) have shown that the retinoic acid receptor alpha (RARA) gene on chromosome 17 is juxtaposed to the promyelocytic leukemia (PML) gene on chromosome 15. The PML breakpoints have been mapped to 3 clusters: bcr1, bcr2, and bcr3. We have examined the PML breakpoint distribution in a series of 33 Chinese patients with APL Twenty-two patients fell within bcr1, 2 within bcr2, and 9 within bcr3. The primary structure of the reciprocal chromosome translocation joints of one patient and that of their normal counterparts have been determined and compared to those of 2 previously reported cases. These studies revealed possible topoisomerase II cleavage sites close to the breakpoints and suggested implications of DNA attachment sites to nuclear matrix. We propose that these features are relevant to the process of illegitimate recombination generating the translocation. © 1993 Wiley-Liss, Inc.     

Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios.

The glutamate pathways are involved in diverse processes such as learning and memory, epilepsy, and they play important roles in neural plasticity, neural development, and neurodegeneration. It has been proposed that autism could be a hypoglutamatergic disorder. Recently, Jamain et al. reported that the glutamate receptor 6 (GluR6 or GRIK2) is in linkage disequilibrium with autism. In the present study, the transmission disequilibrium test (TDT) and the haplotype transmission were performed to analyze the four SNPs (SNP1: rs995640; SNP2: rs2227281; SNP3: rs2227283; SNP4: rs2235076) of GluR6 in 174 Chinese Han parent-offspring trios. The TDT demonstrated that the two SNPs (SNP2 and SNP3) showed preferential transmission (TDT P = 0.032). The global chi(2) test for haplotype transmission also revealed an association between GluR6 and autism (chi(2) = 10.78, df = 3, P = 0.013). Our results suggested that GluR6 is in linkage disequilibrium with autism.