晚发型糖原贮积病Ⅱ型1例患者的临床和病理及其家系GAA基因分析

目的研究1例晚发型糖原贮积病Ⅱ型(GSDⅡ)患者的临床、病理和遗传特征。方法回顾性分析1例晚发型GSDⅡ患者的临床资料和骨骼肌病理特征,同时取得患者和家属知情同意后对其家系进行遗传咨询,提取外周血白细胞基因组DNA,应用聚合酶链反应(PCR)扩增酸性-α-葡萄糖苷酶(GAA)的基因编码区,直接测序分析GAA基因突变情况。结果 1患者男性21岁,临床表现为呼吸肌、四肢近端肌无力。肌电图提示肌源性损害。三角肌病理和免疫组化染色提示肌源性损害,酸性磷酸酶染色(+)。血GAA活性明显低于正常,符合晚发型GSDⅡ诊断。2家系GAA基因分析提示,患者及其父亲和2位姑姑(父亲的妹妹)均携带一个未见报道的GAA基因新突变:位于第8号外显子的缺失突变(p.Met439del);患者及其母亲、外祖母均携带一个已报道的GAA基因16号外显子错义突变(p.Trp746Cys);该家系中发现一些非致病性杂合突变。结论在晚发型GSDⅡ家系中发现一个新的GAA基因第8号外显子缺失突变p.Met439del。先证者因存在双杂合突变导致GAA活性下降并出现晚发型GSDⅡ的临床和病理改变。     

多巴反应性肌张力障碍三磷酸鸟苷环化水解酶Ⅰ基因突变检测

目的　检测多巴反应性肌张力障碍 (dopa responsivedystonia,DRD)三磷酸鸟苷环化水解酶Ⅰ(guanosinetriphosphatecyclohydrolaseⅠ, GCH1)基因编码区的突变。方法　对 2个DRD家系的 5例患者和 6例散发患者及其 18名亲属和 20名健康对照者的GCH1基因编码区进行聚合酶链反应 单链构象多态性(PCR SSCP)分析;对PCR SSCP异常的外显子进行PCR产物直接测序,若患者 6个外显子PCR SSCP均无异常,则对所有外显子测序;为了确证突变,引入SphⅠ限制性内切酶位点进行聚合酶链反应 限制性片段长度多态性 (PCR RFLP)分析。结果　在 1个呈常染色体显性遗传DRD家系中发现 1个新的杂合型点突变(A224G)。此突变位于 1号外显子,由酪氨酸错义突变为半胱氨酸(Tyr75Cys), 20名健康对照者等位基因无此突变。另 1家系和其他散发患者在GCH1基因编码区未发现基因突变。序列分析提示与 2号外显子邻近的 1号内含子部分和与 3号外显子邻近的 3号内含子部分存在基因多态性。结论　我们描述了一个新的错义突变Tyr75Cys,GCH1基因编码区突变能解释部分DRD患者的发病原因。     

Ⅰ型神经纤维瘤病基因28及31号外显子突变的检测

目的　探讨国人Ⅰ型神经纤维瘤病 (NF1)基因突变的热点。方法　用PCR SSCP方法检查NF1基因 2 8和 3 1号外显子共约 10 60bp ,约占NF1基因全部编码区的 6 95 %。结果　在 2 7个家系中 ,发现 4个家系 (14 82 % )、13例病人(2 3 64 % )存在NF1基因突变。结论　提示本组病例 2 8和 3 1号外显子可能为突变热点。对突变性质的定论有赖于DNA序列分析。     

5,10-亚甲基四氢叶酸还原酶基因多态性及补充叶酸与非综合征性唇腭裂的相关性

背景：对于5, 10-亚甲基四氢叶酸还原酶(5, 10-methylene tetrahydrofolate reductase, MTHFR)基因C677T位点多态性与唇腭裂相关性的研究国内外结果不一,未见结合干预因素叶酸影响的相关报道。 目的：探讨河南地区汉族人群MTHFR基因C677T位点多态性及补充叶酸与非综合征性唇腭裂的发病关系。 方法：选取2008-09/2010-03在郑州大学第一附属医院及郑州市第一人民医院整形外科就诊的非综合征性唇腭裂患者110例,采用PCR-RFLP法检测外周血中MTHFR基因C677T位点基因型并与40例健康对照比较频数差异。同时结合母孕期是否补充叶酸进行统计学分析。 结果与结论：病例组和对照组C677T基因型及等位基因频率比较差异均具有显著性意义(P < 0.01),且有家族史的患者TT基因型及T等位基因频率高于无家族史患者(P < 0.05)。对母孕期是否补充叶酸进行比较,发现非综合征性唇腭裂与叶酸摄入呈负相关(χ2=4.304,r=-0.169,P < 0.05)。结果提示MTHFR基因C677T位点突变与河南汉族人群非综合征性唇腭裂的发生相关,母孕期补充叶酸能降低非综合征性唇腭裂的发病风险。     

Dravet综合征患者电压依赖性钠通道α1亚基基因5'-非翻译区外显子的遗传变异

目的 筛查Dravet综合征患者的电压依赖性钠通道α1亚基(voltage-gated sodium channel α1-subunit,SCN1A)基因5'-非翻译区外显子突变位点,分析并预测其致病易患性.方法 收集24例Dravet综合征患者的外周血,抽提基因组DNA,采用直接测序法进行SCN1A基因5'-非翻译区外显子突变位点的筛查;用生物信息学方法分析SCN1A基因5'-非翻译区外显子变异位点邻近序列的保守性及潜在的转录因子结合元件,推测其致病易患性.结果 发现位于外显子h2u上的突变位点166.642.520G>A,先证者1为新生突变,而先证者2的突变来自临床表型正常的母亲,该突变位点在100名健康对照者中均未发现.突变位点在哺乳动物中呈中度保守(62.5%),人与其他哺乳动物之间在突变位点邻近序列的平均同源率高达88.5%;166.642.520野生型位点的序列上预测得到一种转录因子结合元件,而突变型位点的序列上预测得到两种转录因子结合元件.结论 突变位点166.642.520G>A与Dravet综合征存在一定程度的相关性,其致病机制有待于进一步实验证实.     

晚发型Pompe病患者的临床、病理及GAA基因突变特点

目的探讨1例晚发型Pompe病(LOPD)患者的临床、病理特点及酸性α-葡萄糖苷酶(GAA)基因突变特点。方法分析1例LOPD患者的临床资料,对患者进行右股四头肌活检,并应用PCR产物直接测序法进行GAA基因所有外显子及其侧翼序列的突变检测,采用逆转录PCR法观察突变位点对mRNA剪切的影响。结果患者23岁女性,主要表现为II型呼吸衰竭及体重指数显著降低,伴肺动脉高压、右心功能不全及四肢近端无力。骨骼肌病理检查发现肌纤维内出现大量嗜碱性空泡,部分空泡内可见糖原物质沉积。GAA基因分析显示患者存在错义突变c.2238G>C及剪切突变c.1551+3_c.1551+6del AAGT,后者导致mRNA上第10号外显子缺失。结论发现1例LOPD患者中存在新突变c.1551+3_c.1551+6del AAGT,该患者主要表现为严重的呼吸功能障碍伴低体重。     

嵌合蛋白1基因启动子两多态位点与阿尔茨海默病的相关性研究

目的探讨嵌合蛋白1(chimerin1,CHN1)基因启动子区多态性、载脂蛋白E(apolipoprotein,APOE)基因多态性和阿尔茨海默病(Alzheimer's disease,AD)的相关性。方法通过使用TaqMan-PCR法检测单核苷酸多态性方法,观察380例日本AD患者(包括327例迟发型AD与53例早发型AD)和380例非痴呆对照组CHN1基因启动子(rs3732315与rs1320875)及APOE基因的多态性分布,并分析与AD的相关性。结果CHN1基因启动子rs3732315上A/T多态位点与rs1320875上A/G多态位点分别与AD无明显相关性(P值分别为0.094,0.17)。进一步在LOAD,EOAD与对照组的比较中发现rs3732315AA基因型与rs1320875GG基因型与EOAD无明显相关(P值分别为0·055,0·065)。结论CHN1基因启动子区rs3732315与rs1320875多态位点与AD无明显相关性,但不能排除rs3732315AA基因型与rs1320875GG基因型微弱增加了EOAD的发病风险,其真正意义有待在大样本、多中心人群中进一步阐明。     

结节性硬化症TSC1基因编码外显子全长的突变检测与分析

目的研究结节性硬化症(TSC)TSC1基因所有编码外显子的基因突变特征和多态现象。方法采用聚合酶链反应单链构象多态(PCR SSCP)技术结合DNA测序对来源于21个家系的23例TSC患者、22名父母及60名健康对照进行TSC1基因编码外显子全长的基因突变和多态的检测。结果共检测出10种异常的SSCP带型,经DNA测序后证实为4种突变和6种多态,突变包括2种移码突变(352insA和2332insT)、1种剪接突变(729 1G→T)、1种无义突变Tyr761Ter(2504C→A),其中2332insT, 729 1G→T及Tyr761Ter为新型突变。以上突变均见于散发型患者,突变频率为4 /15。6种多态包括4种单核苷酸多态(347A→C, 1186T→C, 1556A→G, 1947T→C), 1种内含子区多态(2218 71delAG)及1种3′UTR区多态(3716 36T→C),其中3种为新多态。结论本组结果对研究我国TSC1基因突变特征提供了重要资料,未发现TSC1基因突变热区,且TSC1基因突变多见于散发型患者,提示中西方TSC1基因突变可能存在差异。     

三磷酸腺苷结合盒转运子A1基因多态性与散发性阿尔茨海默病的关系

目的 探讨三磷酸腺苷结合盒转运子A1（ATP—binding cassette transporter 1，ABCA1）基因第6外显子D→A（R219K）多态性位点与散发性阿尔茨海默病（sporadic Alzheimer disease，SAD）易患性的关系。方法 采用病例．对照研究方法，利用聚合酶链反应．限制性片段长度多态性（PCR—RFLP）技术对168例SAD患者和215名健康对照的ABCA1基因多态性进行检测，比较不同基因型与阿尔茨海默病（AD）发病风险之间的关系。结果 SAD组ABCA1基因第6外显子G—A多态位点A等位基因频率明显低于对照组（37．8％ vs 48．1％，）（X^2=8．204，P=0．004）；SAD组AA基因型频率也明显低于对照组（14．3％ vs 22．8％，）（X^2=8．230，P=0．016）。Logistic回归分析表明，校正年龄、性别和ApoEe4等位基因的影响后，携带A等位基因者（G／A＋A／A基因型）比携带GG基因型者AD发病风险降低43．0％（OR 0．57，95％CI 0．36—0．91，P=0．019），而AA纯合子比携带GG基因型者AD发病风险降低60．0％（OR 0．40，95％ CI 0．21—0．77，P：0．006）。结论 ABCA1基因第6外显子D—A多态性与SAD相关，携带A等位基因或者AA基因型对SAD发病可能有一定的保护作用。     

原发性低钾型周期性麻痹相关离子通道基因突变研究进展

目前已知原发性低钾型周期性麻痹(hypokalaemic periodic paralysis,HypoPP)与遗传有关,约69.0%与电压门控钙通道α1亚单位基因CACNA1S(1q31-32)突变相关(Ⅰ型),约8.6%与电压门控钠通道α亚单位基因SCN4A(17q23.1-25.3)突变相关(Ⅱ型),22.4%未知。所有的错义突变均位于离子通道电压感受器上带正电荷的精氨酸(Arg),大部分被组氨酸(His)替代,有时被甘氨酸(Gly)、丝氨酸(Ser)替代。从CACNA1S基因编码的钙通道α1亚单位的第Ⅱ和第Ⅳ结构域S4跨膜区发现了Arg528His/Gly、Arg1239His/Gly突变,从SCN4A基因编码的钠通道α亚单位第Ⅱ结构域S4跨膜区发现Arg669His,Arg672His/Gly/Ser突变。突变通道的功能研究发现,突变钙通道出现钙电流密度下降,钙通道激活减慢;突变钠通道失活明显增强,动作电位达到峰值的速率和传导速率减低。该文对HypoPP相关离子通道基因突变及其突变基因的功能进行综述,以利对HypoPP的深入理解。     

Efficacy and Effectiveness of Child and Adolescent Psychotherapy and Pharmacotherapy

Decades of intervention research have produced a rich body of evidence on the effects of psychotherapies and pharmacotherapies with children and adolescents. Here we summarize and critique that evidence. We review findings bearing on the efficacy of psychosocial treatments and medications under controlled experimental conditions. We also report evidence, where available, on the effectiveness of both classes of treatment with clinically referred youth treated in real-world clinical contexts. In general, the large body of evidence on efficacy contrasts sharply with the small base of evidence on effectiveness. Addressing this gap through an enriched research agenda could contribute importantly to linking scientific inquiry and clinical practice—to the benefit of both ventures. This is one element of a multifaceted agenda for future research and for synthesis of research, which will require the interplay of multiple disciplines related to child and adolescent mental health.     

Opiate and digitalis receptor assays distinguish between neuroexcitant and inactive organochlorines and between anesthetics and convulsants

Specific binding of [3H]naloxone to rat brain tissue in vitro was inhibited by the excitant organochlorinated insecticides (OCI), by ether (E) and octanol (OCT), and by the convulsant indoklon (IND) and its anesthetic isomer, isoindoklon (ISO). In the presence of 100 mM NaCl the inhibition of naloxone binding by E, OCT and ISO was greatly potentiated, whereas that by OCI and IND was attenuated. KCl (100 mM) was equally effective as NaCl on the action of anesthetics, but the effect of the excitant drugs was, in contrast to NaCl, unaffected by KCl. Specific binding of [3H]ouabain in the absence of Na, was depressed by anesthetics and enhanced by neuroexcitants. In the presence of NaCl, which by itself inhibits ouabain binding to brain, both anesthetics and excitants enhanced ouabain binding. DDE, a non-insecticidal analog of DDT, and the dimethyl derivative of the OCI, lindane, were inactive in the receptor assays. These observations point to a unique isolated system which responds consistently to anesthetic agents as a class and, in a different way, to neuroexcitant compounds.     

Learning and forgetting new names and objects in MCI and AD

We studied how subjects with mild cognitive impairment (MCI), early Alzheimer's disease (AD) and age-matched controls learned and maintained the names of unfamiliar objects that were trained with or without semantic support (object definitions). Naming performance, phonological cueing, incidental learning of the definitions and recognition of the objects were tested during follow-up. We found that word learning was significantly impaired in MCI and AD patients, whereas forgetting patterns were similar across groups. Semantic support showed a beneficial effect on object name retrieval in the MCI group 8 weeks after training, suggesting that the MCI patients’ preserved semantic memory can compensate for impaired episodic memory. The MCI group performed equally well as the controls in the tasks measuring incidental learning and recognition memory, whereas the AD group showed impairment in this respect. Both the MCI and the AD group benefited less from phonological cueing than the controls. Our findings indicate that word learning is compromised in both MCI and AD, whereas long-term retention of newly learned words is not affected to the same extent. Incidental learning and recognition memory seem to be well preserved in MCI.     

Necdin蛋白与神经元的生长分化

在神经系统 ,Necdin只在成熟神经元的细胞核中表达 ,可能与成熟神经元分裂静止状态的保持有关。近年的研究表明 ,Necdin是一种生长抑制蛋白 ,能与多种因子如SV4 0大T抗原 ,腺病毒E1A ,转录因子E2F1以及肿瘤抑制蛋白p5 3等结合 ,在功能上类似于成视网膜瘤蛋白Rb。necdin基因缺陷时 ,会引起脑内 ,特别是下丘脑神经元分化障碍。人类necdin基因位于PWS综合征的基因缺失区 ,可能与PWS的一些症状有关。本文从Necdin蛋白的基本概况 ,生物功能以及Necdin与疾病三个方面进行了综述     

Satellite cells and myonuclei in young and elderly women and men

The overall aim of this study was to assess the effects of aging on the satellite cell population. Muscle biopsies were taken from the tibialis anterior muscle of healthy, moderately active young (age range, 20-32 years; n = 31) and elderly (age range, 70-83 years; n = 27) women and men with comparable physical activity pattern. Satellite cells and myonuclei were visualized using a monoclonal antibody against neural cell adhesion molecule and counterstained with Mayer's hematoxylin. An average of 211 (range, 192-241) muscle fibers were examined for each individual. Compared with the young women and men, the elderly subjects had a significantly lower (P < 0.011) number of satellite cells per muscle fiber but a significantly higher (P < 0.004) number of myonuclei per muscle fiber. The number of satellite cells relative to the total number of nuclei [satellite cells/(myonuclei + satellite cells)] was significantly lower in the elderly than in the young women and men. These results imply that a reduction in the satellite cell population occurs as a result of increasing age in healthy men and women.     

Retrospective and prospective design and data

The study of the presentation, symptomatology and family characteristics of an exclusively adolescent sample of patients with borderline personality disorder (BPD) was undertaken. Twenty-four cases of borderline personality disorder, 20 females, 4 males, identified using chart review and meeting the criteria of the Diagnostic Interview for Borderlines (DIB) and DSM III-R, were matched with psychiatric controls. Adolescents with borderline personality disorder were found to have high rates of affective symptomatology with Axis I diagnosis of major depressive disorder - MDD (DSM-III-R), and high rates of interpersonal psychopathology, i.e., manipulation, devaluation, and a pervasive sense of boredom. The latter seem to be characteristic as for adults with borderline personality disorder. The families were particularly angry and volatile.     

Necdin蛋白与神经元的生长分化

在神经系统,Necdin只在成熟神经元的细胞核中表达,可能与成熟神经元分裂静止状态的保持有关.近年的研究表明,Necdin是一种生长抑制蛋白,能与多种因子如SV40大T抗原,腺病毒E1A,转录因子E2F1以及肿瘤抑制蛋白p53等结合,在功能上类似于成视网膜瘤蛋白Rb.necdin基因缺陷时,会引起脑内,特别是下丘脑神经元分化障碍.人类necdin基因位于PWS综合征的基因缺失区,可能与PWS的一些症状有关.本文从Necdin蛋白的基本概况,生物功能以及Necdin与疾病三个方面进行了综述.     

Cortisol levels and depression in men and women using heroin and cocaine

Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are well documented in men using illicit drugs and/or infected with HIV; however, less is known about HPA function, or the health consequence of HPA dysfunction, in their female counterparts. People with depression exhibit hypercortisolemia, and depression is common in people with HIV or substance use problems. The current study investigated cortisol secretion in 209 demographically matched men and women, stratified by their HIV and drug use status. Self-reported depressive symptoms were evaluated using a standardized, validated questionnaire (CES-D). Women reported more depressive symptoms than men (p=.01). Male and female drug users exhibited higher cortisol concentrations (p=.03), and were more likely to report depressive symptoms (p=.04), than non-users. Depression was related to elevated cortisol concentrations for the study population (p=.03), and women with elevated cortisol concentrations were significantly more depressed than all other participants (p=.05). While it is unknown whether high cortisol concentrations precede depressive symptoms or vice versa, these data indicate that higher cortisol concentrations are associated with depressive symptoms in heroin and cocaine users, and that this association is more pronounced in women than men. HIV status did not act in an additive or synergistic way with drug use for either cortisol or CES-D measures in the current study. Unique therapies to treat the endocrine and mental health consequences of illicit drug use in men and women deserve consideration as depressive symptoms, and high cortisol concentrations associated with depressive symptoms, differ by gender.     

相关性和一致性：这对相仿概念和测量方法的回顾与阐明

概述：一致性(agreement)和相关性(correlation)是两个广泛使用的概念,用来评估变量之间的关联。虽然二者相似且相关,但是它们代表关联完全不同的概念。评估变量之间的一致性假设变量测量的是相同的结构,而在变量测量完全不同的结构时也可以评估它们之间的相关性。这种概念上的差异就要求使用不同的统计方法,并且当评估一致性或相关性时,统计方法根据数据的分布和研究者的兴趣可能会有所不同。例如, Pearson相关性,作为评估连续变量之间相关性的一种普遍测量方法,只有用于符合线性关系的变量时才能提供有用的信息;当用于不符合线性关系的变量时就无法提供准确信息甚至会产生误导。同样地,内部相关性,作为一种评估连续变量之间一致性的常用方法,如果一致性不好的实质正好是研究兴趣所在,那么该测量就不能为研究者提供充分的信息。本报告回顾了一致性和相关性的概念,并讨论了几种常用方法在应用中的差异。