BACKGROUND & AIMS: PURPOSE:Consistent condom use is critical to efforts to prevent sexually transmitted infections among adolescents, but condom use may decline as relationships and contraceptive needs change. The purpose of this research is to assess changes in condom non-use longitudinally in the context of changes in relationship quality, coital frequency and hormonal contraceptive choice. METHODS:Participants were women (aged 14-17 years at enrollment) recruited from three urban adolescent medicine clinics. Data were collected at three-month intervals using a face-to-face structured interview. Participants were able to contribute up to 10 interviews, but on average contributed 4.2 interviews over the 27-month period. Independent variables assessed partner-specific relationship quality (five items; scale range 5-25; alpha = .92, e.g., this partner is a very important person to me); and, number of coital events with a specific partner. Additional items assessed experience with oral contraceptive pills (OCP) use and injected depo medroxy-progesterone acetate (DMPA). The outcome variable was number of coital events without condom use during the past three months. Analyses were conducted as a three-level hierarchical linear growth curve model using HLM 6. The Level 1 predictor was time, to test the hypothesis that condom non-use increases over time. Level 2 predictors assessed relationship quality and coital frequency across all partners to assess hypotheses that participants' condom non-use increases over time as a function of relationship quality and coital frequency. Level 3 predictors assessed the participant-level influence of OCP or DMPA experience on time-related changes in condom non-use. RESULTS:A total of 176 women reported 279 sex partners and contributed 478 visits. Both average coital frequency and average condom non-use linearly increased during the 27-month follow-up. At any given follow-up, about 35% reported recent OCP use, and 65% reported DMPA use. HLM analyses showed that condom non-use increased as a function of time (beta = .12; p = .03, Level 1 analysis). Increased condom non-use over time was primarily a function of increased coital frequency (beta = .01; p = .00), although higher levels of relationship quality were associated with increased condom non-use at enrollment (beta = .44; p = .00, Level 2 analysis). The temporal rise in condom non-use significantly increased among DMPA users (beta = .06; p = .00) but not OCP users (Level 3 analysis) (beta = -.04; p = .06). CONCLUSIONS:Developmentally, relationship characteristics and coital frequency appear to have increasing weight in decisions about condom use. Hormonal contraceptive methods are not equivalently associated with the overall temporal decline in condom use. Future research associated with dual contraceptive/condom use should address differential factors associated condom use in combination with different hormonal methods.

背景与目标： 目的：持续使用避孕套对于预防青少年性传播感染至关重要，但是随着人际关系和避孕需求的变化，避孕套的使用可能会减少。这项研究的目的是在关系质量，性交频率和激素避孕选择的变化的背景下，纵向评估未使用安全套的变化。
方法：参与者是从三个城市青少年医学诊所招募的女性（入学年龄14-17岁）。使用面对面的结构化访谈，每三个月收集一次数据。参加者最多可以贡献10个访谈，但在27个月内平均贡献了4.2个访谈。自变量评估了特定于伴侣的关系质量（五个项目；等级范围5-25；α= 0.92，例如，这个伴侣对我来说是非常重要的人）；以及与特定伴侣发生性行为的次数。其他项目评估了口服避孕药（OCP）的使用经验和注射醋酸去甲羟孕酮（DMPA）的经验。结果变量是在过去三个月中未使用安全套的性交事件的数量。使用HLM 6作为三级分层线性增长曲线模型进行了分析。1级预测因子是时间，以检验安全套不使用随时间增加的假设。 2级预测变量评估了所有伴侣之间的关系质量和性交频率，以评估以下假设：参与者不使用安全套会随着时间的推移而增加，这是关系质量和性交频率的函数。 3级预测变量评估了OCP或DMPA经验对安全套不使用时间相关变化的参与者水平影响。
结果：总共176名妇女报告了279个性伴侣，并贡献了478次探视。在27个月的随访中，平均性交频率和平均不使用安全套均呈线性增加。在任何给定的随访中，约35％的患者报告了最近的OCP使用，而65％的患者报告了DMPA的使用。 HLM分析表明，不使用安全套随时间增加（β= .12； p = .03，1级分析）。随着时间的流逝，不使用安全套的增加主要是性交频率增加的函数（β= .01； p = .00），尽管较高的关系质量与入学时不使用安全套的增加相关（β= .44； p = .00，第2级分析）。在DMPA用户中，未使用安全套的时间增加显着增加（β= .06； p = .00），但在OCP用户中则没有（第三级分析）（β= -.04； p = .06）。
结论：在发展上，关系特征和性交频率似乎在有关使用安全套的决策中具有越来越大的重要性。激素避孕方法与使用避孕套的总体时间下降没有同等的联系。与双重避孕/避孕套使用相关的未来研究应解决与不同激素方法结合使用避孕套相关的差异因素。

BACKGROUND & AIMS: :Gliomas are highly lethal neoplasms that cannot be cured by currently available therapies. Temozolomide is a recently introduced alkylating agent that has yielded a significant benefit in the treatment of high-grade gliomas. However, either de novo or acquired chemoresistance occurs frequently and has been attributed to increased levels of O6-methylguanine-DNA methyltransferase or to the loss of mismatch repair capacity. However, very few gliomas overexpress O6-methylguanine-DNA methyltransferase or are mismatch repair-deficient, suggesting that other mechanisms may be involved in the resistance to temozolomide. The purpose of the present study was to generate temozolomide-resistant variants from a human glioma cell line (SNB-19) and to use large-scale genomic and transcriptional analyses to study the molecular basis of acquired temozolomide resistance. Two independently obtained temozolomide-resistant variants exhibited no cross-resistance to other alkylating agents [1,3-bis(2-chloroethyl)-1-nitrosourea and carboplatin] and shared genetic alterations, such as loss of a 2p region and loss of amplification of chromosome 4 and 16q regions. The karyotypic alterations were compatible with clonal selection of preexistent resistant cells in the parental SNB-19 cell line. Microarray analysis showed that 78 out of 17,000 genes were differentially expressed between parental cells and both temozolomide-resistant variants. None are implicated in known resistance mechanisms, such as DNA repair, whereas interestingly, several genes involved in differentiation were down-regulated. The data suggest that the acquisition of resistance to temozolomide in this model resulted from the selection of less differentiated preexistent resistant cells in the parental tumor.

背景与目标： ：胶质瘤是高度致死性的肿瘤，目前尚无法治愈。替莫唑胺是最近引入的烷基化剂，已在治疗高级神经胶质瘤中产生了显着的益处。然而，从头或获得性化学抗性经常发生，并且归因于O6-甲基鸟嘌呤-DNA甲基转移酶水平的增加或失配修复能力的丧失。但是，极少的神经胶质瘤过表达O6-甲基鸟嘌呤-DNA甲基转移酶或错配修复缺陷，提示其他机制可能与对替莫唑胺的抗性有关。本研究的目的是从人类神经胶质瘤细胞系（SNB-19）产生抗替莫唑胺的变体，并使用大规模的基因组和转录分析来研究获得的替莫唑胺抗性的分子基础。两个独立获得的替莫唑胺抗性变体对其他烷基化剂[1,3-双（2-氯乙基）-1-亚硝基脲和卡铂]无交叉抗性，并且共有遗传变异，例如2p区域丢失和扩增丢失染色体4和16q区域。核型改变与亲本SNB-19细胞系中先前存在的抗性细胞的克隆选择相容。基因芯片分析显示，在17,000个基因中，有78个在亲代细胞和两种替莫唑胺耐药变体之间差异表达。没有人参与已知的抗性机制，例如DNA修复，而有趣的是，参与分化的几个基因被下调。数据表明，在该模型中获得对替莫唑胺的抗药性是由于在亲本肿瘤中选择了分化程度较低的抗药性细胞而引起的。

BACKGROUND & AIMS: :In the last few years, our knowledge of genetically determined causes of short stature has greatly increased by reports of challenging patients, who offered the opportunity to study genes that play a role in growth. Since the first paper that showed the etiology of Laron syndrome [Godowski PJ, et al: Proc Natl Acad Sci USA 1989;86:8083-8087], many mutations in the growth hormone (GH) receptor have been identified. Recently, new mutations or deletions have been found in several components of the GH-insulin-like growth factor-I (IGF-I) axis: a homozygous mutation of the GH1 gene, resulting in a bio-inactive GH; mutations in the STAT5b gene, which plays a major role in the GH signal transduction; a homozygous missense mutation in the IGF-I gene; heterozygous mutations in the IGF-I receptor gene and a homozygous deletion of the acid-labile subunit gene. In this mini review, we describe the clinical and biochemical features of these genetic defects. Genetic analysis has become essential in the diagnostic workup of a patient with short stature. However, regarding the time consuming nature of molecular analysis, it is important to carefully select the patient for specific genetic evaluation. To help in this selection process, we developed flowcharts, based on the recently described patients, that can be used as guidelines in the diagnostic process of patients with severe short stature of unknown origin.

背景与目标： ：在过去的几年中，由于挑战性患者的报道，我们对遗传决定的矮小身高原因的了解大大增加了，这些患者为研究在生长中起作用的基因提供了机会。自从第一篇显示Laron综合征病因的论文以来[Godowski PJ等人：Proc Natl Acad Sci USA 1989; 86：8083-8087]，已经确定了生长激素（GH）受体的许多突变。最近，在GH-胰岛素样生长因子-I（IGF-I）轴的几个组成部分中发现了新的突变或缺失：GH1基因的纯合突变，导致了生物失活的GH； STAT5b基因的突变，在GH信号转导中起主要作用； IGF-I基因的纯合错义突变； IGF-1受体基因中的杂合突变和对酸不稳定的亚基基因的纯合缺失。在这个小型综述中，我们描述了这些遗传缺陷的临床和生化特征。遗传分析已成为身材矮小的患者的诊断检查中必不可少的。但是，考虑到分子分析的耗时性质，重要的是要仔细选择患者进行特定的基因评估。为了帮助选择过程，我们根据最近描述的患者制定了流程图，可以将其用作诊断患有严重身材矮小，来源不明的患者的诊断过程中的指导原则。

BACKGROUND & AIMS: :The genetic understanding of the muscular dystrophies has advanced considerably in the last two decades. Over 25 different individual genes are now known to produce muscular dystrophy, and many different "private" mutations have been described for each individual muscular dystrophy gene. For the more common forms of muscular dystrophy, phenotypic variability can be explained by precise mutations. However, for many genetic mutations, the presence of the identical mutation is associated with marked phenotypic range that affects muscle function as well as cardiac function. The explanation for phenotype variability in the muscular dystrophies is only now being explored. The availability of genetically engineered animal models has allowed the generation of single mutations on the background of highly inbred strain. Phenotypic variation that is altered by genetic background argues for the presence of genetic modifier loci that can ameliorate or enhance aspects of the dystrophic phenotype. A number of individual genes have been implicated as modifiers of muscular dystrophy by studies in genetically engineered mouse models of muscular dystrophy. The value of these genes and products is that the pathways identified through these experiments may be exploited for therapy.

背景与目标： 在过去的二十年中，人们对肌肉营养不良的遗传学认识有了很大的提高。现在已知产生肌营养不良症的超过25个不同的个体基因，并且对于每个个体肌营养不良症基因已经描述了许多不同的“私人”突变。对于更常见的肌肉营养不良形式，表型变异性可以通过精确的突变来解释。然而，对于许多遗传突变，相同突变的存在与影响肌肉功能以及心脏功能的显着表型范围有关。肌肉营养不良症的表型变异性的解释目前才被探索。基因工程动物模型的可用性允许在高度近交系的背景下产生单个突变。由遗传背景改变的表型变异主张存在可以改善或增强营养不良表型方面的遗传修饰基因座。通过对肌营养不良症的基因工程小鼠模型的研究，许多个体基因被认为是肌营养不良症的修饰因子。这些基因和产物的价值在于通过这些实验确定的途径可用于治疗。

BACKGROUND & AIMS: :Iron is an essential trace-element for most organisms. However, because high concentration of free intracellular iron is cytotoxic, cells have developed complex regulatory networks that keep free intracellular iron concentration at optimal range, allowing the incorporation of the metal into iron-using enzymes and minimizing damage to the cell. We built a mathematical model of the network that controls iron uptake and usage in the bacterium Escherichia coli to explore the dynamics of iron flow. We simulate the effect of sudden decrease or increase in the extracellular iron level on intracellular iron distribution. Based on the results of simulations we discuss the possible roles of the small RNA RyhB and the Fe-S cluster assembly systems in the optimal redistribution of iron flows. We suggest that Fe-S cluster assembly is crucial to prevent the accumulation of toxic levels of free intracellular iron when the environment suddenly becomes iron rich.

背景与目标： 铁是大多数生物必不可少的微量元素。但是，由于高浓度的游离细胞内铁具有细胞毒性，因此细胞已开发出复杂的调节网络，可将游离细胞内铁的浓度保持在最佳范围，从而将金属掺入使用铁的酶中，并将对细胞的损害降至最低。我们建立了控制该细菌大肠杆菌中铁的吸收和使用的网络数学模型，以探索铁流量的动态变化。我们模拟了细胞外铁水平突然降低或增加对细胞内铁分布的影响。基于模拟的结果，我们讨论了小RNA RyhB和Fe-S簇组装系统在铁流的最佳重新分配中的可能作用。我们建议，当环境突然变得富含铁时，Fe-S簇组装对于防止游离细胞内铁的毒性水平的积累至关重要。

BACKGROUND & AIMS: The exact mechanism for the decrease in intestinal calcium absorption with age is not yet understood. A decrease with age in serum 1,25-dihydroxyvitamin D (1,25(OH)2D) or a decrease in the intestinal vitamin D receptor (VDR) protein concentration are possible causes. The objective of this study was to examine the effect of age on these factors. Fifty-nine young women age 25-35 years were compared with 41 elderly women age 65-83 years who underwent measurements of VDR, calcium absorption using a 20 mg and 100 mg calcium carrier, and calciotropic hormones. Calcium absorption by both tests was lower in the elderly women compared with the young women (p < 0.05). Serum 1,25(OH)2D and duodenal VDR protein concentration were not significantly different between the two age groups. Serum 1,25(OH)2D correlated with the 20 mg calcium absorption test in both young (r = 0.35, p < 0.007) and elderly women (r = 0.58, p < 0.0001) and with the 100 mg calcium absorption in the elderly (r = 0.32; p < 0.05). VDR did not correlate with calcium absorption in young women or elderly women, nor did VDR correlate with serum 1,25(OH)2D and serum 25-hydroxyvitamin D. In summary, the decrease in calcium absorption cannot be explained by a decrease in intestinal VDR. The correlation between serum 1,25(OH)2D and both calcium absorption tests only accounts for 12-30% of the variance in the age-related change in the calcium absorption tests. Other factors, not yet understood, are responsible for the decline in calcium absorption with age.

背景与目标： 随着年龄的增长，肠道钙吸收减少的确切机制尚不清楚。血清1,25-二羟基维生素D（1,25（OH）2D）随年龄的减少或肠道维生素D受体（VDR）蛋白质浓度的减少是可能的原因。这项研究的目的是研究年龄对这些因素的影响。比较了59名年龄在25-35岁之间的年轻女性与41位年龄在65-83岁之间的女性，这些女性进行了VDR测量，使用20 mg和100 mg钙载体的钙吸收量以及亲钙性激素。与年轻女性相比，老年女性的两种测试中的钙吸收均较低（p <0.05）。在两个年龄组之间，血清1,25（OH）2D和十二指肠VDR蛋白浓度无显着差异。血清1,25（OH）2D与年轻（r = 0.35，p <0.007）和老年妇女（r = 0.58，p <0.0001）的20 mg钙吸收测试以及老年人的100 mg钙吸收相关（r ＝ 0.32； p ＜0.05）。 VDR与年轻妇女或老年妇女的钙吸收无关，也不与血清1,25（OH）2D和血清25-羟维生素D相关。 VDR。血清1,25（OH）2D与两种钙吸收试验之间的相关性仅占钙吸收试验中与年龄相关的变化方差的12％至30％。钙吸收随着年龄的增长而下降的其他原因尚不明确。

BACKGROUND & AIMS: Cytogenetic and molecular genetic studies were performed on a pleomorphic sarcoma removed from the left atrium of a 15-year-old girl. Histologic analysis was consistent with a storiform-pleomorphic malignant fibrous histiocytoma (MFH). Although MFH is the most common soft-tissue sarcoma of late adulthood. It is extremely rare in childhood and its existence in the pediatric population remains controversial. Cytogenetic analysis revealed several alterations previously associated with adult MFH, including abnormalities of chromosomal bands 11p11 and 19p13. Moreover, the tumor demonstrated homogeneously staining regions (HSR) and double minute chromosomes (dmin) suggestive of gene amplification. We therefore screened the case for amplification of genes localized to chromosomal bands 12q13-14, including the putative protooncogenes MDM2, CDK4, SAS, CHOP, and CLI, which are frequently amplified and overexpressed in adult MFH. Southern and Northern blot analysis confirmed the coamplification of MDM2, CDK4, SAS, and CHOP. To our knowledge, such coamplification studies of the 12q13-14 amplicon have not been previously detected in pediatric MFH. Our results provide cytogenetic and molecular genetic evidence that pediatric and adult MFH are histogenetically related entities.

背景与目标： 细胞遗传学和分子遗传学研究是从一个15岁女孩的左心房切除的多形性肉瘤。组织学分析与星形样多形性恶性纤维组织细胞瘤（MFH）一致。尽管MFH是成年后期最常见的软组织肉瘤。它在儿童时期极为罕见，其在儿科人群中的存在仍然引起争议。细胞遗传学分析揭示了以前与成人MFH相关的几种改变，包括染色体条带11p11和19p13的异常。此外，肿瘤表现出均一的染色区（HSR）和双分钟染色体（dmin），提示基因扩增。因此，我们筛选了扩增位于染色体12q13-14的基因的案例，包括推定的原癌基因MDM2，CDK4，SAS，CHOP和CLI，这些基因在成年MFH中经常被扩增和过表达。 Southern和Northern印迹分析证实了MDM2，CDK4，SAS和CHOP的共扩增。据我们所知，这种12q13-14扩增子的共扩增研究以前未在儿科MFH中检测到。我们的研究结果提供了细胞遗传学和分子遗传学证据，表明小儿和成人MFH是组织遗传学相关的实体。

BACKGROUND & AIMS: :The yeast S. cerevisiae is a central model organism in eukaryotic cell studies and a major component in many food and biotechnological industrial processes. However, the wide knowledge regarding genetics and molecular biology of S. cerevisiae is based on an extremely narrow range of strains. Studies of natural populations of S. cerevisiae, not associated with human activities or industrial fermentation environments, are very few. We isolated a panel of S. cerevisiae strains from a natural microsite, "Evolution Canyon" at Mount Carmel, Israel, and studied their genomic biodiversity. Analysis of 19 microsatellite loci revealed high allelic diversity and variation in ploidy level across the panel, from diploids to tetraploids, confirmed by flow cytometry. No significant differences were found in the level of microsatellite variation between strains derived from the major localities or microniches, whereas strains of different ploidy showed low similarity in allele content. Maximum genetic diversity was observed among diploids and minimum among triploids. Phylogenetic analysis revealed clonal, rather than sexual, structure of the triploid and tetraploid subpopulations. Viability tests in tetrad analysis also suggest that clonal reproduction may predominate in the polyploid subpopulations.

背景与目标： ：酿酒酵母是真核细胞研究中的中心模型生物，在许多食品和生物技术工业过程中都是主要成分。但是，关于酿酒酵母的遗传学和分子生物学的广泛知识是基于非常狭窄的菌株。与人类活动或工业发酵环境无关的酿酒酵母自然种群研究很少。我们从以色列卡梅尔山的天然微型站点“进化峡谷”中分离出一组酿酒酵母菌株，并研究了它们的基因组生物多样性。对19个微卫星基因座的分析显示，从二倍体到四倍体，整个等位基因组中的高等位基因多样性和倍性水平存在差异，这已通过流式细胞仪进行了确认。在来自主要地区或微生态位的菌株之间，微卫星变异水平没有发现显着差异，而具有不同倍性的菌株在等位基因含量上的相似性很低。在二倍体中观察到最大的遗传多样性，而在三倍体中观察到了最小的遗传多样性。系统发育分析显示三倍体和四倍体亚群的克隆结构，而不是有性结构。四元分析中的生存力测试还表明，在多倍体亚群中克隆繁殖可能占主导地位。

BACKGROUND & AIMS: Recent genome searches suggest a putative linkage of many loci to susceptibility to type I diabetes. The chromosome 2q31-35 region is reported to be linked to susceptibility to type I diabetes and is thought to contain several diabetes susceptibility loci. These candidate genes include the HOXD gene cluster, BETA2, CTLA4, CD28, IGFBP2, and IGFBP5. Association studies in populations and families are required to confirm and/or identify the actual susceptibility loci. We hereby report several previously unknown DNA polymorphisms for HOXD8, BETA2, and IGFBP5, which we have used along with previously known polymorphisms of HOXD8 and CTLA4 to test whether these candidate loci are the susceptibility genes on chromosome 2q31-35. Using a case-control design with a subsequent family-association approach to confirm associations, we find no evidence that these candidate genes are associated with susceptibility to type I diabetes.

背景与目标： 最近的基因组搜索表明，许多基因位点与I型糖尿病易感性的推测联系。据报道，染色体2q31-35与I型糖尿病易感性相关，并被认为含有几个糖尿病易感性基因座。这些候选基因包括HOXD基因簇，BETA2，CTLA4，CD28，IGFBP2和IGFBP5。需要在人群和家庭中进行协会研究，以确认和/或识别实际的易感基因座。我们在此报告了HOXD8，BETA2和IGFBP5的几种先前未知的DNA多态性，并将其与HOXD8和CTLA4的先前已知多态性一起用于测试这些候选基因座是否为2q31-35染色体上的易感性基因。使用病例对照设计和随后的家庭关联方法来确认关联，我们没有发现这些候选基因与I型糖尿病易感性相关的证据。

BACKGROUND & AIMS: :Despite the successful identification of several relevant genomic loci, the underlying molecular mechanisms of schizophrenia remain largely unclear. We developed a computational approach (NETBAG+) that allows an integrated analysis of diverse disease-related genetic data using a unified statistical framework. The application of this approach to schizophrenia-associated genetic variations, obtained using unbiased whole-genome methods, allowed us to identify several cohesive gene networks related to axon guidance, neuronal cell mobility, synaptic function and chromosomal remodeling. The genes forming the networks are highly expressed in the brain, with higher brain expression during prenatal development. The identified networks are functionally related to genes previously implicated in schizophrenia, autism and intellectual disability. A comparative analysis of copy number variants associated with autism and schizophrenia suggests that although the molecular networks implicated in these distinct disorders may be related, the mutations associated with each disease are likely to lead, at least on average, to different functional consequences.

背景与目标： ：尽管成功鉴定了几个相关的基因组位点，但精神分裂症的潜在分子机制仍不清楚。我们开发了一种计算方法（NETBAG），该方法可以使用统一的统计框架对与疾病相关的多种遗传数据进行综合分析。这种方法在使用无偏态全基因组方法获得的精神分裂症相关遗传变异中的应用，使我们能够鉴定出与轴突导向，神经元细胞移动性，突触功能和染色体重塑有关的几个内聚基因网络。形成网络的基因在大脑中高度表达，在产前发育过程中大脑表达更高。所确定的网络在功能上与先前与精神分裂症，自闭症和智力障碍有关的基因有关。对与自闭症和精神分裂症有关的拷贝数变异的比较分析表明，尽管与这些独特疾病有关的分子网络可能是相关的，但与每种疾病有关的突变可能至少平均而言导致不同的功能后果。

BACKGROUND & AIMS: :We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 × 10-7; OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation.

背景与目标： ：我们使用严格定义的表型进行了神经性厌食症（AN）的全基因组关联研究（GWAS）。对表型变异性的分析导致鉴定出一种接近全基因组重要性的特定遗传危险因素（EBF1中的rs929626（早期B细胞因子1）; P = 2.04×10-7; OR = 0.7; 95％置信区间（ CI）= 0.61-0.8）具有独立复制（P = 0.04），表明瘦素信号传导的变体介导的失调可能在AN中起作用。 LD中带有变体的多个SNP支持名义关联。这表明，尽管AN的临床和病因学异质性得到了普遍认可，但对病例进行进一步的仔细分型可能会提供更精确的基因组信号。在这项研究中，通过完善AN的表型谱，我们提出了名义上与AN相关的可复制GWAS信号，突出了潜在的重要候选基因座，需要进一步研究。

BACKGROUND & AIMS: :Individuals at 50% risk of Huntington's disease (HD) who prefer not to know their carrier status, might opt for exclusion prenatal diagnosis (ePND) or exclusion preimplantation genetic diagnosis (ePGD). This study aims to provide a better understanding of couples' motives for choosing ePND or ePND, and surveys couples' experiences in order to make recommendations for the improvement of counselling for exclusion testing. This qualitative retrospective interview study focussed on couples who underwent ePND or ePGD for HD in the period 1996-2010. Seventeen couples were included of which 13 had experienced ePND and 6 ePGD. Mean time-interval since exclusion-testing was 3.9 years. Couples' moral reservations regarding termination of pregnancy (TOP) or discarding healthy embryos were counterbalanced by the wish to protect their future child against HD. Seven couples had terminated a total of 11 pregnancies with a 50% HD risk, none showed regret. ePGD was used by couples who wanted to avoid (another) TOP. ePND and ePGD are acceptable reproductive options for a specific group of counsellees. To guarantee sound standards of care, it is imperative that candidate couples be given in-depth non-directive counselling about all possible scenarios, and adequate professional and psychological support prior to, during and after ePND/ePGD.

背景与目标： ：那些不知道自己的携带者状况，患亨廷顿氏病（HD）风险为50％的个体，可能会选择排除产前诊断（ePND）或排除植入前遗传学诊断（ePGD）。这项研究旨在更好地了解夫妻选择ePND或ePND的动机，并调查夫妻的经历，以便为改善排除测试的咨询意见提供建议。这项定性的回顾性访谈研究的重点是在1996-2010年期间接受HD的ePND或ePGD的夫妇。其中包括17对夫妇，其中13对有ePND经历和6对ePGD。自排除测试以来的平均时间间隔为3.9年。保护夫妻免于高清的愿望抵消了夫妻在终止妊娠（TOP）或丢弃健康胚胎方面的道德保留。 7对夫妇共终止了11例妊娠，HD风险为50％，没有人表示遗憾。希望避免使用（另一种）TOP的夫妇使用了ePGD。 ePND和ePGD是特定人群的可接受的生殖选择。为了保证合理的护理标准，在ePND / ePGD之前，之中和之后，必须为候选夫妇提供有关所有可能情况的深入非指导性咨询，并提供适当的专业和心理支持。

BACKGROUND & AIMS: :Results from pharmacogenetic investigations of methylphenidate (MPH) response in patients with ADHD are still inconsistent, especially among adults. This study investigates the role of genetic variants (SLC6A4, HTR1B, TPH2, DBH, DRD4, COMT, and SNAP25) in the response to MPH in a sample of 164 adults. Genes were chosen owing to previous evidence for an influence in ADHD susceptibility. No significant differences in allele or genotype frequencies between MPH responders and nonresponders were detected. In conclusion, our findings do not support an effect of these genes in the pharmacogenetics of MPH among adults with ADHD.

背景与目标： ：多动症患者的哌醋甲酯（MPH）反应的药物遗传学研究结果仍然不一致，尤其是在成年人中。这项研究调查了164个成年人样本中遗传变异（SLC6A4，HTR1B，TPH2，DBH，DRD4，COMT和SNAP25）的作用。由于先前证据对ADHD易感性有影响，因此选择了基因。在MPH应答者和非应答者之间，在等位基因或基因型频率上未检测到显着差异。总之，我们的发现不支持这些基因在多动症成年人中MPH的药物遗传学中起作用。

BACKGROUND & AIMS: OBJECTIVE:To investigate: (1) the course of coronary heart disease risk factors (lipid profiles and body mass index (BMI)) in the first five years after discharge from inpatient spinal cord injury (SCI) rehabilitation and (2) the association between lifestyle (physical activity, self-care related to fitness, smoking, alcohol, body mass and low-fat diet) and coronary heart disease risk factors during that period. DESIGN:Prospective cohort study. PARTICIPANTS/METHODS:Individuals with SCI (N=130). Total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG) and BMI were determined at discharge from inpatient rehabilitation and 1 and 5 years after discharge. Using multilevel regression models, the effects of lifestyle (drinking alcohol, smoking, active lifestyle and self-care) on the lipid profiles and BMI were determined. RESULTS:After correction for lesion and personal characteristics, no changes in lipid profiles in the five years after discharge were seen, whereas the BMI increased significantly with 1.8 kg m(-2). A high percentage was at risk of cardiovascular disease due to high BMI (63-75%) or HDL (66-95%). The individuals who indicated to maintain their fitness level as good as possible and the individuals with a low BMI showed better lipid profiles. Individuals with a more active lifestyle showed higher HDL levels. Individuals who avoid smoking showed a 1.5 kg m(-2) higher BMI. CONCLUSION:Lipid profiles seem to stabilize in the years after discharge from inpatient SCI rehabilitation, whereas the BMI increased. Lifestyle factors associated with a favorable lipid profile and BMI could be identified.

背景与目标： 目的：调查：（1）住院脊髓损伤（SCI）康复出院后的最初五年中，冠心病危险因素（血脂和体重指数（BMI））的病程，以及（2）在此期间的生活方式（体育锻炼，与健身，吸烟，饮酒，体重和低脂饮食有关的自我保健）和冠心病的危险因素。
设计：前瞻性队列研究。
参与者/方法：具有SCI的个人（N = 130）。在住院康复出院时以及出院后1和5年测定总胆固醇（TC），高密度脂蛋白（HDL），低密度脂蛋白（LDL），甘油三酸酯（TG）和BMI。使用多级回归模型，确定了生活方式（饮酒，吸烟，积极的生活方式和自我保健）对血脂和BMI的影响。
结果：校正病灶和个人特征后，出院后五年内血脂没有变化，而BMI显着增加，为1.8 kg m（-2）。高百分比的BMI（63-75％）或HDL（66-95％）导致罹患心血管疾病的风险较高。表示要尽可能保持健康水平的个体和BMI较低的个体表现出更好的血脂状况。生活方式更加活跃的人表现出较高的HDL水平。避免吸烟的人的BMI升高1.5 kg m（-2）。
结论：住院SCI康复出院后的几年中，脂质分布似乎稳定，而BMI升高。可以确定与良好的脂质状况和BMI相关的生活方式因素。

BACKGROUND & AIMS: :Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

背景与目标： ：认知能力下降是老龄化的一个令人恐惧的方面。它是导致生活质量下降和老年失去独立感的主要因素。我们调查了遗传因素对五组老年人非病理性认知衰老个体差异的影响。在英国和苏格兰的认知衰老遗传学（CAGES）项目中，我们对3511名无关亲戚的成年人使用549 692单核苷酸多态性（SNP）进行了全基因组关联分析。这些个体具有详细的纵向认知数据，根据这些数据构建了测量每个个体认知变化的表型。位于TOMM40（线粒体外膜40同源物的转位酶）中的一个SNP-rs2075650具有与认知衰老相关的全基因组显着关联（P = 2.5×10（-8））。该结果在三个独立的瑞典队列的荟萃分析中得到了重复（P = 2.41×10（-6））。先前与认知老化相关的载脂蛋白E（APOE）单倍型（与TOMM40相邻）对CAGES样本的认知老化具有显着影响（P = 2.18×10（-8）；女性，P = 1.66×10（- 11）；男性，P = 0.01）。对TOMM40 / APOE区域进行的精细SNP定位将APOE（rs429358; P = 3.66×10（-11））和TOMM40（rs11556505; P = 2.45×10（-8））都与认知老化相关。发现和复制队列中的归因和条件分析强烈表明，这种影响归因于APOE（rs429358）。功能基因组分析表明，TOMM40 / APOE区的SNP具有功能性，调节性非蛋白质编码作用。 APOE地区与非病理性认知老化显着相关。一种或多种因果变体的身份和机制尚不清楚。