加巴喷丁对绝经后 MPS 的临床疗效观察

目的：探讨加巴喷丁片对绝经后妇女更年期综合征（MPS）的临床效果。方法根据随机数字表法将122例患有绝经后 MPS 的患者分为观察组和实验组,每组各61例,观察组给予口服利维爱片,实验组给予口服加巴喷丁片,分别于给药前和给药后30、60、90 d 时,比较两组的 Kupperman 得分、焦虑、抑郁、睡眠情况和不良反应。结果实验组的 Kupperman 评分在各时间点均低于观察组,治疗90 d 后,实验组的评分降至（9.3±1.5）分,观察组评分降至（16.1±3.3）分,组间比较差异均有统计学意义（P ﹤0.05）;实验组的焦虑、抑郁及睡眠质量评分均较对照组降低明显（P ﹤0.05）;两组的不良反应发生率分别是24.2％、9.1％,对照组明显高于实验组（P ﹤0.05）。结论口服加巴喷丁片对绝经期妇女 MPS 有明显的改善作用,不良反应发生率较低,且不会提高药物治疗费用,值得在临床推广应用。     

小探头超声内镜诊断贲门失驰缓症12例临床分析

目的探讨小探头超声内镜在诊断贲门失驰缓症中的临床价值。方法对我院2008年9月至2011年9月间收治的12例经常规食管吞钡或者上消化道钡餐造影检查提示为贲门失驰缓症的患者(A组),及30例无吞咽困难等贲门疾患的患者(B组)均行小探头超声内镜检查,了解其胃镜图像、贲门处管壁厚度、固有肌层厚度及有无异常回声。结果 A组胃镜图像显示食管不同程度扩张,内容物滞留,贲门口强力收缩狭窄呈玫瑰花样,小探头超声内镜示贲门处层次结构清楚,无异常回声,管壁厚度平均4.9cm,固有肌层厚度3.4mm。A组管壁厚度与固有肌层厚度分别为(4.9±0.5)mm和(3.4±0.2)mm,B组分别为(3.3±0.3)mm和(2.1±0.2)mm,两组比较差异具有统计学意义(P<0.05,P<0.01)。结论小探头超声内镜能清楚显示消化道壁的层次及结构,与胃镜图像结合可作为贲门失驰缓症确诊的最佳检查方法。     

Massively parallel sequencing of autosomal STRs and identity-informative SNPs highlights consanguinity in Saudi Arabia

While many studies have been undertaken of Middle Eastern populations using autosomal STR profiling by capillary electrophoresis, little has so far been published from this region on the forensic use of massively parallel sequencing (MPS). Here, we carried out MPS of 27 autosomal STRs and 91 identity-informative SNPs (iiSNPs) with the Verogen ForenSeq™ DNA Signature Prep Kit on a representative sample of 89 Saudi Arabian males, and analysed the resulting sequence data using Verogen’s ForenSeq Universal Analysis Software (UAS) v1.3 and STRait Razor v3.0. This revealed sequence variation in the composition of complex STR arrays, and SNPs in their flanking regions, which raised the number of STR alleles from 238 distinct length variants to 357 sequence sub-variants. Similarly, between one and three additional polymorphic sites were observed within the amplicons of 37 of the 91 iiSNPs, forming up to six microhaplotypes per locus. These further enhance discrimination compared to the biallelic target SNP data presented by the primary UAS interface. In total, we observed twenty-two STR alleles previously unrecognised in the STRait Razor v3.0 default allele list, along with nine SNPs flanking target iiSNPs that were not highlighted by the UAS. Sequencing reduced the STR-based random match probability (RMP) from 2.62E-30 to 3.49E-34, and analysis of the iiSNP microhaplotypes reduced RMP from 9.97E-37 to 6.83E-40. The lack of significant linkage disequilibrium between STRs and target iiSNPs allowed the two marker types to be combined using the product rule, yielding a RMP of 2.39E-73. Evidence of consanguinity was apparent from both marker types. While TPOX was the only locus displaying a significant deviation from Hardy-Weinberg equilibrium, 23 out of 27 STRs and 63 out of 91 iiSNPs showed fewer than expected heterozygotes, demonstrating an overall homozygote excess probably reflecting the high frequency of first-cousin marriages in Saudi Arabia. We placed our data in a global context by considering the same markers in the Human Genome Diversity Panel (HGDP), revealing that the Saudi sample was typical of Middle Eastern populations, with a higher level of inbreeding than is seen in most European, African and Central/South Asian populations, correlating with known patterns of endogamy. Given reduced levels of diversity within endogamous groups, the ability to combine the discrimination power of both STRs and SNPs offers significant benefits in the analysis of forensic evidence in Saudi Arabia and the Middle East region more generally.     

Developmental validation of STRmix™ NGS,a probabilistic genotyping tool for the interpretation of autosomal STRs from forensic profiles generated using NGS

We describe the developmental validation of the probabilistic genotyping software – STRmix™ NGS – developed for the interpretation of forensic DNA profiles containing autosomal STRs generated using next generation sequencing (NGS) also known as massively parallel sequencing (MPS) technologies. Developmental validation was carried out in accordance with the Scientific Working Group on DNA Analysis Methods (SWGDAM) Guidelines for the Validation of Probabilistic Genotyping Systems and the International Society for Forensic Genetics (ISFG) recommendations and included sensitivity and specificity testing, accuracy, precision, and the interpretation of case-types samples. The results of developmental validation demonstrate the appropriateness of the software for the interpretation of profiles developed using NGS technology.     

婴幼儿对乙肝疫苗低应答和无应答对策的研究

本文对１０１名低、无应答儿童采用不同方案加强免疫，进行随机对照前瞻性研究观察，表明，对母亲ＨＢｓＡｇ阳性的低、无应答婴幼儿采用注射分枝杆菌多糖与乙肝疫苗（３０μｇ×３）联合应用，免后１年抗体阳转率可达９０％左右；对母亲ＨＢｓＡｇ阴性的低、无应答婴幼儿采用加强１支１０μｇ乙肝疫苗，可使近一半婴幼儿产生抗－ＨＢｓ。利用ＰＣＲ检测低、无应答者的ＨＢＶ－ＤＮＡ，仅有３.８５％为ＨＢＶ感染者，母亲为ＨＢｓＡｇ阳性者的无应答婴幼儿若不进行加强免疫，仍存在着ＨＢＶ感染的危险性。     

Residual activity and proteasomal degradation of p.Ser298Pro sulfamidase identified in patients with a mild clinical phenotype of Sanfilippo A syndrome

Mucopolysaccharidosis type IIIA (MPS IIIA, Sanfilippo syndrome) is a fatal inherited lysosomal storage disease accompanied by progressive neurologic degeneration. The gene underlying MPS IIIA, SGSH, encodes a lysosomal enzyme, N-sulfoglucosamine sulfohydrolase (sulfamidase). Mutational analysis of a large cohort of MPS IIIA patients showed a correlation of the missense mutation p.Ser298Pro and a slowly progressive course of the disease. We report here on the expression of the mutant p.Ser298Pro sulfamidase in BHK cells retaining low residual activity. Pulse-chase experiments showed that rapid degradation is responsible for the low steady state level of the mutant protein. Processing and secretion of p.Ser298Pro sulfamidase suggests that small amounts of the newly synthesized enzyme are transported to lysosomes. Most of the mutant sulfamidase exits the endoplasmic reticulum for proteasomal degradation. The ability to predict the clinical course of MPS IIIA in patients with the p.Ser298Pro mutation, as well as the residual enzymatic activity, and the reduced stability of the mutant sulfamidase suggest that this subgroup of patients is especially well suited to early sulfamidase replacement therapy or treatment with selective pharmacological chaperones.     

Mucopolysaccharidosis IVA (Morquio A): identification of novel common mutations in the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene in Italian patients

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Mutation screening of the GALNS gene was performed by RT-PCR with one amplicon and direct sequence analyses using cDNA samples from 15 Italian MPS IVA patients. Each mutation was confirmed at the genomic level. In this study, 13 different gene mutations with four common mutations (over 10% of mutant alleles) were identified in 12 severe and three milder (attenuated) MPS IVA patients. The gene alterations in 12 out of 13 were found to be point mutations and only one mutation was deletion. Ten of 13 mutations were novel. The c.1070C>T (p.Pro357Leu) mutation coexisted with c.1156C>T (p.Arg386Cys) mutation on the same allele. Together they accounted for 100% of the 30 disease alleles of the patients investigated. Four common mutations accounted for 70% of mutant alleles investigated. Urine keratan sulfate (KS) concentrations were elevated in all patients investigated. These data provide further evidence for extensive allelic heterogeneity and importance of relation among genotype, phenotype, and urine KS excretion as a biomarker in MPS IVA.     

Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic,clinical, and biological implications

Mucopolysaccharidosis (MPS) types IIIA, B, C, and D are a group of autosomal recessive lysosomal storage diseases caused by mutations in one of four genes which encode enzyme activities required for the lysosomal degradation of heparan sulfate. The progressive lysosomal storage of heparan sulfate eventually results in the clinical onset of disease, which is predominantly characterized by severe central nervous system degeneration. MPS‐IIIA and MPS‐IIIB involve deficiencies of heparan sulfate sulfamidase (SGSH) and α‐N‐acetylglucosaminidase (NAGLU), respectively. Both the SGSH and NAGLU genes have been cloned and characterized, thereby permitting mutation analysis of MPS‐IIIA and MPS‐IIIB patients. A total of 62 mutations have now been defined for MPS‐IIIA consisting of 46 missense/nonsense mutations, 15 small insertions/deletions, and one splice site mutation. A total of 86 mutations have been identified in the NAGLU gene of MPS‐IIIB patients; 58 missense/nonsense mutations, 27 insertions/deletions, and one splice site mutation. Most of the identified mutations in the SGSH and NAGLU genes are associated with severe clinical phenotypes. Many of the missense, nonsense, and insertion/deletion mutations have been expressed in mammalian cell lines to permit the characterization of their effects on SGSH and NAGLU activity and intracellular processing and trafficking. For MPS‐IIIA and MPS‐IIIB many of the reported mutations are unique making screening the general population difficult. However, molecular characterization of MPS‐IIIA patients has revealed a high incidence of particular mutations of different geographical origins, which will be beneficial for the molecular diagnosis of MPS‐IIIA. Hum Mutat 18:264–281, 2001. © 2001 Wiley‐Liss, Inc.