Identification of a founder mutation in TPM3 in nemaline myopathy patients of Turkish origin

To date, six genes are known to cause nemaline (rod) myopathy (NM), a rare congenital neuromuscular disorder. In an attempt to find a seventh gene, we performed linkage and subsequent sequence analyses in 12 Turkish families with recessive NM. We found homozygosity in two of the families at 1q12-21.2, a region encompassing the gamma-tropomyosin gene (TPM3) encoding slow skeletal muscle alpha-tropomyosin, a known NM gene. Sequencing revealed homozygous deletion of the first nucleotide of the last exon, c.913delA of TPM3 in both families. The mutation removes the last nucleotide before the stop codon, causing a frameshift and readthrough across the termination signal. The encoded alphaTm(slow) protein is predicted to be 73 amino acids longer than normal, and the extension to the protein is hypothesised to be unable to form a coiled coil. The resulting tropomyosin protein may therefore be non-functional. The affected children in both families were homozygous for the mutation, while the healthy parents were mutation carriers. Both of the patients in Family 1 had the severe form of NM, and also an unusual chest deformity. The affected children in Family 2 had the intermediate form of NM. Muscle biopsies showed type 1 (slow) fibres to be markedly smaller than type 2 (fast) fibres. Previously, there had been five reports, only, of NM caused by mutations in TPM3. The mutation reported here is the first deletion to be identified in TPM3, and it is likely to be a founder mutation in the Turkish population.European Journal of Human Genetics (2008) 16, 1055-1061; doi:10.1038/ejhg.2008.60; published online 2 April 2008.     

红霉素对支气管上皮细胞转录因子c-Jun和核因子-κB表达的影响

探讨红霉素对4-羟基壬烯醛(4-HNE)引起的支气管上皮细胞(16-HBE)核转录因子c-Jun及NF-κB的影响。将人支气管上皮细胞分为4-HNE组(10μmol/L 4-HNE)红霉素+4-HNE组、对照组,在4-HNE刺激细胞2、4、8及12h后,检测c-Jun及NF-κB的变化。结果表明,4-HNE和对照组比较,c-Jun、NF-κB自2h后各时间段两组差异有统计学意义,P均<0.05。红霉素+4-HNE组在4-HNE刺激2h后,c-Jun及NF-κB的表达较4-HNE组,差异有统计学意义,P均<0.01。4-HNE促进支气管上皮细胞c-Jun及NF-κB的表达。红霉素可抑制4-HNE诱导的c-Jun及NF-κB的表达。     

Mitral Valve Repair Using ePTFE Sutures for Ruptured Mitral Chordae Tendineae: A Computational Simulation Study

Mitral valve (MV) repair using expanded polytetrafluoroethylene sutures is an established and preferred interventional method to resolve the complex pathophysiologic problems associated with chordal rupture. We developed a novel computational evaluation protocol to determine the effect of the artificial sutures on restoring MV function following valve repair. A virtual MV was created using three-dimensional echocardiographic data in a patient with ruptured mitral chordae tendineae (RMCT). Virtual repairs were designed by adding artificial sutures between the papillary muscles and the posterior leaflet where the native chordae were ruptured. Dynamic finite element simulations were performed to evaluate pre- and post-repair MV function. Abnormal posterior leaflet prolapse and mitral regurgitation was clearly demonstrated in the MV with ruptured chordae. Following virtual repair to reconstruct ruptured chordae, the severity of the posterior leaflet prolapse decreased and stress concentration was markedly reduced both in the leaflet tissue and the intact native chordae. Complete leaflet coaptation was restored when four or six sutures were utilized. Computational simulations provided quantitative information of functional improvement following MV repair. This novel simulation strategy may provide a powerful tool for evaluation and prediction of interventional treatment for RMCT.     

希—内学习能力测验在中国聋儿中使用的信度和效度

采用经部分修改的希－内学习能力测验（Ｈ－ＮＴＬＡ）量表对全国２１个省、市、自治区１７５８名３－１７岁聋儿逐人测试。样本人群地区分布、家长职业构成与１９９０年全国人口普查资料一致。１７５８名聋儿智商呈现正态分布（ｇ１＝０．０１１Ｐ＞０．０５，ｇ２＝０．０５８Ｐ＞０．０５）。测试员间信度系数０．９８１（Ｎ＝２４），复测信度０．８４１（Ｎ＝１３６），分半信度０．９２７（３－８岁）及０．８５４（９－１７岁）。各分测验得分随年龄增加而增加，小年龄组增加明显，大年龄组增加缓慢。各分测验之间、各分测验和总离差智商之间大多数相关系数有显著统计学意义。智商与学习成绩（语文及数学）相关系数０．２０８（Ｐ＜０．０１Ｎ＝２２４），与教师评语等级相关系数０．４４（Ｐ＜０．０５ｄｆ＝１６），表明经修订的Ｈ－ＮＴＬＡ量表适用于中国听力语言障碍人群进行智力评定。     

Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer's disease

The allelic frequency of the gene for the K variant of butyrylcholinesterase (BCHE-K) was 0.17 in 74 subjects with late-onset (age > 65 years) histopathologically diagnosed Alzheimer's disease (AD), which was higher than the frequencies in 104 elderly control subjects (0.09), in 14 early-onset cases of confirmed AD (0.07) and in 29 confirmed cases of other dementia (0.10). The association of BCHE-K with late-onset AD was limited to carriers of the epsilon 4 allele of the apolipoprotein E gene (APOE), among whom the presence of BCHE-K gave an odds ratio of confirmed late-onset AD of 6.9 (95% C.I. 1.65-29) in subjects > 65 years and of 12.8 (1.9-86) in subjects > 75 years. In APOE epsilon 4 carriers over 75 years, only 1/22 controls, compared with 10/24 confirmed late-onset AD cases, had BCHE-K. We suggest that BCHE-K, or a nearby gene on chromosome 3, acts in synergy with APOE epsilon 4 as a susceptibility gene for late-onset AD.      

创伤病人的手术与焦虑状态调查

采用状态——特质焦虑问卷及１０项躯体性焦虑测试题，对４０例外科创伤病人手术前后的焦虑状态调查显示：术前状态焦虑量表评分显著高于术后；术前躯体性焦虑评分显著高于术后；高特质焦虑评分亚组与低特质焦虑评分亚组术前状态焦虑评分无显著差异，但术后则前者显著高于后者；急诊手术者手术前后状态焦虑评分显著高于择期手术者。     

Automated postural responses are modified in a functional manner by instruction

The restoration of upright balance after a perturbation relies on highly automated and, to a large extent, stereotyped postural responses. Although these responses occur before voluntary control comes into play, previous research has shown that they can be functionally modulated on the basis of cognitive set (experience, advanced warning, instruction, etc.). It is still unknown, however, how the central nervous system deals with situations in which the postural response is not necessarily helpful in the execution of a task. In the present study, the effects of instruction on automated postural responses in neck, trunk, shoulder, and leg muscles were investigated when people were either instructed to recover balance after being released from an inclined standing posture [balance recovery (BR) trials], or not to recover at all and fall onto a safety mattress in the most comfortable way [fall (F) trials], in both backward and leftward directions. Participants were highly successful in following the instructions, consistently exhibiting stepping responses for balance recovery in BR trials, and suppressing stepping in the F trials. Yet EMG recordings revealed similar postural responses with onset latencies between 70 and 130 ms in both BR and F trials, with slightly delayed responses in F trials. In contrast, very pronounced and early differences were observed between BR and F trials in response amplitudes, which were generally much higher in BR than in F trials, but with clear differentiation between muscles and perturbation directions. These results indicate that a balance perturbation always elicits a postural response, irrespective of the task demands. However, when a specific balance recovery response is not desired after a perturbation, postural responses can be selectively downregulated and integrated into the motor output in a functional and goal-oriented way.     

Clara cell protein 16 (CC16) gene polymorphism influences the degree of airway responsiveness in asthmatic children

BACKGROUND: Several studies have indicated linkage of chromosome 11q12-13 to asthma and associated traits. Among other candidate genes, the Clara cell protein 16 (CC16) gene maps to this region. CC16 is expressed in the bronchial epithelium and exhibits potent anti-inflammatory properties. A single-nucleotide polymorphism (SNP) in the CC16 gene (A38G) was previously associated with asthma. OBJECTIVE: We evaluated the role of the CC16 SNP in pediatric asthma and asthma severity in 2 German study populations. METHODS: The German Multicenter Allergy Study (MAS) cohort (n = 872, 94 asthmatic patients) and 112 allergic asthmatic children recruited in Freiburg, Germany, were included in the present study. Histamine provocations were performed at the age of 7 years in the MAS cohort to determine bronchial hyperreactivity; in the Freiburg study population a standardized exercise-induced decrease in FEV1 was evaluated. For genotyping, melting-curve analysis and restriction enzyme digestion were applied. RESULTS: No association of the CC16*38A allele with asthma could be observed in either study population. However, in asthmatic subjects (MAS cohort) PC(20)FEV(1) values were significantly lower in individuals homozygous or heterozygous for the CC16*38A allele compared with those in subjects with the CC16*38GG genotype (P <.05 and P <.03, respectively). Similarly, allergic asthmatic patients in the Freiburg cohort showed a significantly greater decrease in FEV1 after exercise when homozygous for the CC16*38A allele compared with that seen in asthmatic patients with the *38AG or *38GG genotype (P <.04 and P =.006, respectively). CONCLUSION: We conclude that the CC16*A38G SNP influences bronchial hyperreactivity and might be a genetic determinant of asthma severity in German children.     

Cytokine mRNA expression in Mycobacterium ulcerans-infected human skin and correlation with local inflammatory response

Cytokine mRNA expression in biopsies of Mycobacterium ulcerans-infected human tissue was investigated using real-time PCR, and the findings were correlated with the clinical stages of disease and histopathologies. A broad range of cytokine mRNAs were detected in 16 early nodules and 28 late-stage ulcers, including those for the Th1 cytokines tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) and the Th2 cytokine interleukin 10 (IL-10). IFN-gamma was strongly expressed in both nodules and ulcers, suggesting that a Th1 response begins early in the disease. There was a significantly higher expression of IL-8 and other proinflammatory cytokines in results from 32 biopsies with neutrophilia than in those from 12 biopsies without acute inflammation. Ten tissue samples containing granulomas showed high mRNA expression for IFN-gamma, IL-1beta, IL-12p35, IL-12p40, IL-15, and TNF-alpha relative to 34 tissue samples without granulomas. These results suggest that the human immune response to M. ulcerans is similar to that seen with some other mycobacteria despite the presence of the toxin mycolactone in the tissues.