De novo mutations (GAG deletion) in the DYT1 gene in two non-Jewish patients with early-onset dystonia

The DYT1 gene recently has been cloned and shown to contain a three nucleotide (GAG) deletion responsible for most cases of autosomal dominant early-onset torsion dystonia. This deletion results in the loss of one of a pair of glutamic acids in a conserved region of a novel ATP-binding protein (torsinA). Previous haplotype analysis revealed that this same deletion had arisen at least two different times in history, suggesting independent mutational events. This deletion is the only sequence change found thus far to be associated uniquely with the disease status, regardless of ethnic origin. Here we describe two patients with typical early-onset torsion dystonia of Swiss-Mennonite and non-Jewish Russian origin, respectively, that both carry this same mutation as a de novo GAG deletion. This finding proves that this 3 bp deletion in the DYT1 gene is indeed a mutation that causes early-onset torsion dystonia. The DYT1 mutation is one of the rare examples of the same recurrent mutation causing a dominantly inherited condition. The sequence surrounding the GAG deletion contains an imperfect 24 bp tandem repeat, suggesting a possible mechanism for the high frequency of this mutation.      

牙周病与糖尿病关联性的Meta分析

目的用Meta分析方法评价牙周病与糖尿病之间的关联性。方法检索中国知网、维普及万方数据库,以“糖尿病”和“牙周病”为检索词,对国内1999—2012年公开发表的牙周病与糖尿病相关性的文献进行筛选,根据RevMan5．0进行Meta分析,计算纳入文献数据的合并效应比值比（oddsratio,OR）。结果共检索到591篇文献,经严格筛查,符合纳入标准的文献8篇,异质性检验P〈0．00001,采用随机效应模型,Meta分析显示,牙周病合并糖尿病的OR值为2．36,95％可信区问为1．51～3．69,差异有统计学意义（P=0．0002）。结论牙周病患者并发糖尿病的患病率高于非牙周病患者,是非牙周病患者的2．36倍。     

锁阳与寄主白刺的ITS2条形码特征及遗传关系

目的:采用ITS2条形码对寄生植物锁阳-白刺进行分子标记鉴定,并分析它们之间及它们近缘种的亲缘关系。方法:通过改良的CTAB法提取基因组DNA,通用引物扩增r DNA-ITS2的内转录间隔区,经DNAstar软件校对拼接,预测植物的ITS2二级结构图;利用MEGA 6.06软件计算种内、属间Kimura-2-parameter遗传距离;通过中药材DNA条形码鉴定系统比对和邻接法构建系统聚类树,分析属间、种间和种内遗传关系。结果:锁阳和白刺的ITS2序列长度分别为229 bp和232 bp,GC含量分别为48%和63%。锁阳和白刺的种内遗传距离分别为0~0.004 4和0~0.022;锁阳和白刺的属间遗传距离为2.234 0~2.443 3。结论:ITS2条形码可以很好地鉴定、区分锁阳、白刺及它们的近缘种之间的系统发生关系。     

A re-appraisal of Warfarin control in the treatment of Deep Vein Thrombosis and / or Pulmonary Embolism

Background

Warfarin is commonly used for management of deep vein thrombosis (DVT) and pulmonary embolism (PE), controlling therapy by means of the International Normalized Ratio (INR).

Objectives

To identify differences in INR results between patients with thromboembolic and haemorrhagic complications and controls.

Methods

Two nested case-control studies from within a controlled trial of the duration of warfarin therapy (47 thrombotic and 16 haemorrhagic complications).

Results

Patients whose thromboembolism failed to resolve during treatment or recurred during or after treatment had non-significantly lower INR levels than matched controls (geometric mean 2.2 versus 2.3, p = 0.12). Patients with haemorrhage also had not statistically significant lower INR levels than their matched controls (2.1 versus 2.3, p = 0.22). The variability of INR levels was similar in both case groups and controls. The mean percentage of INR levels in the therapeutic range 2 – 3 was almost identical in thrombotic cases and controls (56.5% versus 56.1%). Compared to the haemorrhagic group, better control was achieved in controls (61.5% versus 43.0%, p=0.01), but controls had slightly more INR values above the therapeutic range (12.1% versus 10.5%, p = 0.74) whilst haemorrhagic cases had more INR values below the therapeutic range (46.6% versus 26.4%, p = 0.03).

Conclusion

In this study, higher INR levels were not associated with haemorrhage suggesting that, for patients being treated for DVT/PE, a modest increase in the target therapeutic range could be considered.Running head: Warfarin Control in treatment of DVT/PE     

Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states

Familial multiple endocrine neoplasia type 1 (FMEN1) is an autosomal dominant trait characterized by tumors of the parathyroids, gastro- intestinal endocrine tissue, anterior pituitary and other tissues. We recently cloned the MEN1 gene and confirmed its identity by finding mutations in FMEN1. We have now extended our mutation analysis to 34 more unrelated FMEN1 probands and to two related states, sporadic MEN1 and familial hyperparathyroidism. There was a high prevalence of heterozygous germline MEN1 mutations in sporadic MEN1 (8/11 cases) and in FMEN1 (47/50 probands). One case of sporadic MEN1 was proven to be a new MEN1 mutation. Eight different mutations were observed more than once in FMEN1. Forty different mutations (32 FMEN1 and eight sporadic MEN1) were distributed across the MEN1 gene. Most predicted loss of function of the encoded menin protein, supporting the prediction that MEN1 is a tumor suppressor gene. No MEN1 germline mutation was found in five probands with familial hyperparathyroidism, suggesting that familial hyperparathyroidism often is caused by mutation in another gene or gene(s).      

Nitric oxide synthase activity and localization do not change in uterus and placenta during human parturition

Animal studies have suggested that nitric oxide, a smooth muscle relaxant, is a fundamental mediator in the initiation of parturition. The purpose of this study was to test the hypothesis that the onset of human labour is associated with a reduction in the activity of the enzyme nitric oxide synthase (NOS), within the uterus. Samples of myometrium, placenta, decidua and fetal membranes were collected during Caesarean section from 11 women before and 11 women after the onset of labour at term. Immunocytochemistry was used to localize each of the three isoforms of NOS (endothelial NOS, brain NOS, and inducible NOS) in each of these tissues and the intensity of staining was qualitatively assessed. NOS enzyme activity was determined in homogenates of frozen myometrium, placenta and fetal membranes (with attached decidua), by measuring conversion of radio-labelled L-arginine to L-citrulline. Each of the three isoforms of NOS was localized in each of the tissues. We found no difference in either the expression or enzyme activity of NOS in myometrium, placenta or fetal membranes before and during labour at term. These results suggest that, in contrast to animal studies, a decrease in NOS enzyme activity may not be involved in the onset of parturition at term in the human.      

Mutation Spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and Genotype–Phenotype Correlations in Warburg Micro Syndrome and Martsolf Syndrome

Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal‐recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families. One‐hundred and forty‐four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases. These are listed in Leiden Open source Variation Databases, which was created by us for all three genes. Genotype–phenotype correlations for these genes have now established that the clinical phenotypes in Micro syndrome and MS represent a phenotypic continuum related to the nature and severity of the mutations present in the disease genes, with more deleterious mutations causing Micro syndrome and milder mutations causing MS. RAB18 has not yet been linked to the RAB3 pathways, but mutations in all three genes cause an indistinguishable phenotype, making it likely that there is some overlap. There is considerable genetic heterogeneity for these disorders and further gene identification will help delineate these pathways.