Graves病甲亢白细胞减少与HLA-DQA1基因多态性的关联性

目的：研究天津地区汉族Graves病甲状腺功能亢进症（GD甲亢）白细胞减少与HLA-DQA1基因多态性的关联。方法：采用限制性片段长度多态性聚合酶链反应（PCR-RFLP）法检测60例GD甲亢白细胞减少患者、60例GD甲亢白细胞正常患者、100例正常对照者的HLA-DQA1基因型，计算和比较3组的HLA-DQA1等位基因频率。结果：（1）GD甲亢患者DQA1^＊0301频率高于对照组（P〈0．05，OR=1．528），而DQAI^＊0201频率和DQAI^＊0401频率低于对照组（P〈0．05，0R=0．474；P〈0．05，OR=0．333）。（2）GD甲亢白细胞减少组DAQI^＊0301高于对照组（P〈0．05，0R=1．737）。而DQAI^＊0201和DQAI^＊0401低于对照组（P〈0．05，OR=0．310；P〈0．05，OR=0．132）。GD甲亢白细胞正常组与对照组差别无统计学意义。结论：HLA-DQAI^＊0301等位基因可能是天津地区汉族人GD甲亢的易感基因，但并非GD甲亢白细胞减少的易感基因；HLA-DQAI^＊0201和HLA-DQAI^＊0401可能是天津地区汉族人GD甲亢的保护基因，但并非GD甲亢白细胞减少的保护基因。     

小儿热性惊厥对HLA-Ⅱ类基因的遗传易感性

目的探索小儿热性惊厥（FC）的HLA-DOA1和HLA-DRB1等位基因的遗传易感性，揭示其遗传背景。方法采用病例对照研究策略．引入PCR-SSP技术．在祖籍三代居住包头地区，无血缘关系，无与异族通婚史及其他神经和免疫系统疾病史和家族史的汉族人群中，选择53例FC为病例组，53名健康儿童为对照组，作以HLA-DOA1和HLA-DRB1等位基因的型别分析。基因频率比较在单因素分析的基础上又作以多因素Lo-Nsac回归。结果病例组HLA-DQA1＊0101基因频率为8．5％，比对照组的1．9％高，P=0．047〈0．05。B=1．566〉0．OR=4．789〉1，其95％可信区间为1．021～22．547，其内不包含1。EF=0．647〉0。促进发病；而HLA-DQA1＊0401基因频率在病例组为0．9％，比对照组的8．5％低，P=0．035〈0．05。B=-2．240〈0，OR=0．106〈1，其95％可信区间为0．013～0．857，其内不包含1。PF=0．458〉0。阻止发病。HLA-DRB1基因频率比较均P〉0．05，OR的95％可信区间内亦包含1。结论HLA-DQA1＊0101等位基因可能是包头地区小儿FC发病单体型中一个遗传易感基因；而HLA-DOA1＊0401等位基因可能为其保护基因。HLA-DRB1等位基因与FC发病无关联性。     

HLA—DQB1等位基因与广东汉族人群系统性红斑狼疮相关性研究

应用微量序列特异性引物聚合酶链反应技术（Micro—PCR—SSP）,探讨我国广东籍汉族人群系统性红斑狼疮（SEE）与HLA-DQB1基因的相关性。对38例SEE患者和110例正常对照者的血样进行分析,实验表明,SEE患者DQB1＊0601等位基因频率显著升高（RR=2．19,P=0．0055）,可能是易感基因,而DQB1＊0301与DQB1＊0401基因频率则显著降低（DQB1＊0301,RR=0．1253,P=0．0001;DQB1＊0401,RR=0,P=0．0409）,可能为保护基因。     

HLA—DR／DQ，HLA—A／B与肺结核相关性研究

目的研究组织相容性白细胞抗原-DR／DQ、A／B（histocompatibility leukocyte antigen,HLA—DR／DQ,A／B）与肺结核之间的联系,探讨遵义市部分汉族人肺结核发病与HLA—DR／DQ,HLA—A／B基因相关性。方法选取36名已确诊肺结核的患者作为研究组,选取与研究组患者年龄、性别无统计学差异的100名健康人作为对照组,抽取外周血提取DNA。使用新型PCR—SSP方法对DNA进行HLA—DQ／DR,HLA—A／B等位基因位点的检测,结果进行SPSS10．0软件统计学处理,比较正常对照组和肺结核患者组间各等位基因频率分布,计算两组优势比（oddsratio,OR）。结果（1）共检测到HLA—DR位点上的13种等位基因,HLA—DQ位点上的7种等位基因,HLA—A位点上的10种等位基因,HLA—B位点上的20种等位基因。（2）HLA—DRB1＊16在患者组和正常对照组中的基因频率分别为6．9％和1．5％（OR=5．215,P=0．049）;HLA—A＊2在患者组和正常对照组中的基因频率分别为40．2％和9％（OR=18．87,P=0．000）;HLA—A＊24在患者组和正常对照组中的基因频率分别为8．3％和19．5％（OR=5．690,P=0．015）。结论HLA—DR＊16、HLA—A＊2基因表达与肺结核呈正相关,提示HLA-DR＊16、HLA-A＊2可能是肺结核的易感基因,HLA-A＊24基因在正常对照组中的表达明显高于结核患者组,其可能是肺结核患者发病的拮抗基因。     

Graves病低钾血症与HLA—DQA1等位基因的关联

目的:探讨天津地区汉族人Graves病(GD)低钾血症与HLA-DQA1等位基因多态性的关系.方法:采用PCR-限制性酶切片段长度多态性分析法(RFLP)测定GD患者及正常对照者的HLA-DQA1等位基因型,计算并比较GD和正常对照组的基因型频率;GD中周期性麻痹患者、非周期性麻痹低血钾患者和正常血钾患者的基因型频率.结果:GD患者HLA-DQA1*0301基因频率明显高于正常对照组(RR=1.577,P<0.05);而HLA-DQA1*0201和HLA-DQA1*0401基因频率明显低于正常对照组(RR=0.395,P<0.05;RR=0.113,P<0.01).GD中周期性麻痹患者、非周期性麻痹低血钾患者与正常血钾患者相比,HLA-DQA1等位基因的基因频率差异无统计学意义(P>0.05).结论:HLA-DQA1*0301可能是天津地区汉族人群GD甲亢的易感基因,而HLA-DQA1*0201和HLA-DQA1*0401可能是天津地区汉族人GD甲亢的保护基因;但未发现GD低钾血症与HLA-DQA1基因有关.     

蒙古族儿童过敏性紫癜及其器官损害与HLA-DRB1等位基因的关联性

目的探索内蒙地区蒙古族儿童过敏性紫癜（AP）及其累及肾脏、胃肠道和关节与HLA-DRB1等位基因的关联性。方法引入PCR-SSP技术，在内荥地区同是蒙古族但无血缘关系或蒙古族与其他民旅间无通婚史及其他风湿性疾病史和家族史的蒙古族人群中，收集AP病例57例，其中累及肾脏20例、胃肠道29例和关节26例，分别与102名健康儿童的HLA-DRB1等位基因进行型别分析。组间比较在单因素X^2检验的基础上，作以多因素Logistic回归分析。结果HLA-DRB1＊110x等位基因在AP及其累及关节、＊070x等位基因在累及胃肠道分别与对照组经Logistic回归分析，均P〈0．05，差异有显著意义。B均为正值，OR分别是2．251、2．215和2．552，均〉1，与B值相符，95％可信区间内均不包含1。表明排除其他进入模型的等位基因作用外，DRB1＊110等位基因在AP及其累及关节、＊070x等位基因累及胃肠道的致病优势分别是对照组的2．251、2．215和2．552倍，促进发病。EF均〉0；而DRB1＊040x和＊120x等位基因在AP病例组分别与对照组经Logistic回归分析，均P〈0．05，差异有显著意义。B均为负值，OR分别是0．422和0．424，均〈1，与B值相符，95％可信区间内均不包含1。表明排除其他进入模型等位基因作用外，DRB1＊040x和＊120x等位基因在AP病例组致病优势分别是对照组的0．422和0．424倍，阻止发病。PF均〉0。结论HLA-DRB1＊110x等位基因可能为内蒙地区蒙古族儿童AP及其累及关节、＊070x等位基因为累及胃肠道发病单体型申的遗传易感基因，而DRB1＊040x和＊120x等位基因为AP的遗传保护基因。     

HLA-DRB1基因与内蒙古地区汉族小儿支气管哮喘的关联性

目的探讨HLA-DRB1等位基因频率在内蒙古地区汉族小儿支气管哮喘患者中的分布,找出与支气管哮喘关联的易感和/或保护基因,探讨哮喘可能的部分发病机制及防治前景。方法采用病例对照研究,引入PCR-SSO技术,经Logistic回归分析,对66例内蒙古地区汉族小儿支气管哮喘患者和96名正常汉族小儿进行HLA-DRB1等位基因型别分析。结果病例组HLA-DRB1*1001的基因频率为7.6%,比对照组的0.5%增高,差异有显著性(Wald=5.553,P<0.05)。B为2.591,正值,OR=13.342>1,促进发病,表明排除进入模型的其他基因混杂作用外,病例组暴露在HLA-DRB1*1001等位基因的优势是对照组的13.342倍,其95%可信区间为1.547~115.099,其内不包含1,与P值意义相符,均有统计学意义。EF=0.82>0;病例组HLA-DRB1*040x基因频率为3%,比对照组11.9%降低。Wald=7.549,P<0.01,差异有非常显著性。B为-2.133,负值,OR=0.118<1,阻止发病,表明排除进入模型的其他基因混杂作用外,病例组暴露在HLA-DRB1*040x等位基因的优势是对照组的0.118倍,其95%可信区间为0.026~0.542,其内不包含1,与P值意义相符,均有统计学意义。PF=0.39<1。其余HLA-DRB1等位基因频率在2组间的分布差异无显著性(P>0.05)。结论HLA-DRB1*1001等位基因可能是内蒙古地区汉族小儿支气管哮喘发病单倍体型中的一个遗传易感基因。而HLA-DRB1*040x等位基因可能为其保护基因。     

突变阻断扩增法检测中国人CYP2D6＊10、＊14等位基因

目的根据突变阻断扩增原理,建立用于检测中国人CYP2D6＊10及＊14等位基因的方法。方法采用单管四引物法检测CYP2D6＊10等位基因,建立等位基因特异扩增法检测CYP2D6＊14等位基因,检测295名健康中国汉族人CYP2D6＊10等位基因。结果CYP2D6＊10及＊14等位基因基因频率分别为55．8％和1．8％,295位受试者中包括1位＊14／＊14、6位＊1／＊14、3位＊10／＊14,基因型分布符合Hardy—Weinberg平衡（Χ^2=2．15,df=5,P〉0．82）。结论本室建立的CYP2D6＊10、＊14等位基因分析法具有方便快捷、结果准确可靠的特点。     

山西汉族人群HLA-DQ基因多态性分析

目的 分析山西汉族人群HLA-DQA1、HLA-DQB1基因多态性.方法 应用聚合酶链反应-序列特异性引物(PCR-SSP)法对100例山西汉族健康人进行HLA-DQA1、HIA-DQB1基因分型,并与国内部分地区汉族人群进行比较.结果 ①共检出9种HLA-DQA1等位基因型别,分别是:HLA-DQA1*0301/2(24.5%)、*0102(14.0%)、*0103(12.5%)、*0201(12.O%)、*0501(12.O%)、*0104(8.5%)、*0401(8.O%)、*0601(4.5%)、*0101(4.0%).②在100个健康人中共检出13种HIA-DQB1等位基因型别,分别是:HLA-DQB1*0301/4(21.0%)、*0201(18.5%)、*0303(14.5%)、*0302(12%)、*0603/8(9.0%)、*0501(5.5%)、*0401(4.5%)、*0602(4.5%)、*0604(3.5%)、*0503(2.5%)、*0601(2.0%)、*0502(1.5%)、*0402(1.0%).③山西汉族HLA-DQ等位基因分布与北方汉族接近,又有其自身特征.结论 山西汉族人群HLA-DQ基因具有丰富的多态性.其分布特征与北方汉族人群接近,但又有其独特性.     

三磷酸腺苷结合盒转运子A1启动子区及7外显子基因突变与合并糖尿病的冠心病关联研究

目的首次研究汉族人群冠心病合并糖尿病与三磷酸腺苷结合盒转运子A1（ABCA1）基因启动子区-565C／T及7外显子R219K基因多态性关联分析。方法应用连接酶检测反应法对172例合并糖尿病冠心病患者及393例对照组测试-565C／T及R219K基因型。结果合并糖尿病冠心病患者-565C／T位点CC、CT及TT基因型频率分别为0．360（n=63）,0．482（n=83）,0．157（n=27）,与对照相比,TT基因型及T等位基因频率分别为0．157vs0．163,0．398vs0．409（均P〉0．05）。R219K位点AA＋AG基因型合并糖尿病的冠心病组与对照组分别为0．65vs0．73,P=0．079。关联分析显示,AA基因型系冠心病保护性因素,[OR=0．428（95％C10．227—0．603）,P=0．009]。结论ABCA1基因-565C／T位点T等位基因与合并糖尿病的冠心病无关联,R219K的A等位基因在合并糖尿病的冠心病组频率较低,提示A等位基因系冠心病保护性因子。     

Affective and Anxiety Disorders and Alcohol and Drug Dependence:

Depression and anxiety frequently coexist in patients with substance use disorders. This clinically-oriented article examiens the relationship between these conditions and emphasizes data showing that substances of abuse can cause signs and symptoms of both depression and anxiety. These substance-related syndromes appear to have a different course and prognosis than uncomplicated, independent anxiety and major depressive disorders, and clinicians should consider the role of alcohol and other drugs in all patients presenting with these complaints. The authors will also outline an approach for diagnosing and managing patients with the combination of a substance use and depressive or anxiety disorder.     

Synthesis and anti-nociceptive and anti-inflammatory effects of gaultherin and its analogs

The synthesis of gaultherin (1) and its analogs was carried out to provide 11 glycosides under phase-transfer catalytic conditions. The activities of all synthesized compounds were evaluated by nitric oxide production inhibitory assay in vitro. Methyl 2-O-(4-O-β-d-galactopyranosyl)-β-d-glucopyranosylbenzoate (5f) showed significantly anti-nociceptive and anti-inflammatory effects by the evaluation in vivo. Structure–activity relationships within these compounds were discussed.     

Modelling and simulation of variability and uncertainty in toxicokinetics and pharmacokinetics

Two important methodological issues within the framework of the variability and uncertainty analysis of toxicokinetic and pharmacokinetic systems are discussed: (i) modelling and simulation of the existing physiologic variability in a population; and (ii) modelling and simulation of variability and uncertainty when there is insufficient or not well defined (e.g. small sample, semiquantitative, qualitative and vague) information available. Physiologically based pharmacokinetic models are especially suited for separating and characterising the physiologic variability from the overall variability and uncertainty in the system. Monte Carlo sampling should draw from multivariate distributions, which reflect all levels of existing dependencies in the intact organism. The population characteristics should be taken into account. A fuzzy simulation approach is proposed to model variability and uncertainty when there is semiquantitative, qualitative and vague information about the model parameters and their statistical distributions cannot be defined reliably.     

成骨细胞的功能与损伤和骨质疏松的防治

骨质疏松是一种全身性骨骼疾病,导致骨折风险增加。成人的骨量通过破骨细胞的骨吸收和成骨细胞的骨形成作用来维持动态平衡,治疗骨质疏松症的理想策略是抑制破骨细胞的骨吸收和/或增强成骨细胞的骨形成功能。目前针对保护成骨细胞及增强其功能的骨质疏松疗法相对较少。因此,本文针对成骨细胞相关功能蛋白、各种细胞损伤机制（内质网应激、氧化应激、机械过载、微小RNA和长链非编码RNA的影响等）及骨质疏松的治疗与预防作一综述,以期为针对增强成骨细胞功能的骨质疏松治疗策略提供新思路。     

益生菌与肿瘤防治

益生菌广泛存在于自然界中,通过维持宿主体内菌群平衡、影响肠屏障功能和调节免疫应答等作用,提高宿主健康水平,被公认为"肠道健康卫士".一些益生菌可以增强机体的免疫功能,抑制致癌物质,影响肿瘤细胞的基因表达,对肿瘤具有拮抗作用.大量研究表明,益生菌在未来的肿瘤防治中有很好的应用和发展前景.     

Self-stimulation and amphetamine: Tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.     

Acamprosate and naltrexone treatment effects on ethanol and sucrose seeking and intake in ethanol-dependent and nondependent rats

Rationale  Two pharmacotherapies are approved for treating alcohol craving (acamprosate and naltrexone), but both have shown mixed findings in animals and humans. Objectives  The present experiments utilized a “reinforcer blocking” approach (i.e., rats were able to consume ethanol during treatment) to better understand the efficacy of these treatments for ethanol seeking and drinking using ethanol-dependent and nondependent rats. Materials and methods  In “nondependent” experiments, drugs (acamprosate 50, 100, and 200 mg/kg; naltrexone 0.1, 0.3, and 1.0 mg/kg) were administered over 3-week periods prior to operant sessions with a low response requirement to gain access to reinforcers for 20 min. For “dependent” experiments, rats were made dependent in vapor/inhalation chambers. Results  Acamprosate and naltrexone had similar effects on intake in nondependent and dependent rats; neither drug was selective for ethanol over sucrose drinking. In nondependent animals, naltrexone was more efficacious at more doses than acamprosate, and acamprosate’s effects were limited to a dose that also had adverse effects on body weight. Both pharmacotherapies showed more selectivity when examining reinforcer seeking. In nondependent rats, acamprosate and naltrexone had response-attenuating effects in ethanol, but not sucrose, groups. In dependent animals, acamprosate had selective effects limited to a decrease in sucrose seeking. Naltrexone, however, selectively decreased ethanol-seeking in nondependent rats. Conclusions  The naltrexone-induced decreases in seeking suggested a change in incentive motivation which was selective for ethanol in nondependent rats. The “nondependent” paradigm may model early stages of “problem drinking” in humans, and the findings suggest that naltrexone could be a good intervention for this level of alcohol abuse and relapse prevention.     

Antiinfective and encrustation-inhibiting materials--myth and facts

Catheters, urethral and ureteral stents and other urological implants are frequently affected by encrustration and infection due to their permanent contact with urine. Indwelling urinary catheters provide a haven for microorganisms and thus require extensive monitoring. Several surface modification techniques have been proposed to improve the performance of devices including the immobilization of biomolecules, the incorporation of hydrophilic grafts to reduce protein adsorption, the creation of hydrophobic surfaces, the creation of microdomains to regulate cellular and protein adhesion, new polymers and antimicrobial coatings. Physico-chemical explanation to elucidate the mechanism of such encrustation or infection inhibiting materials is still not available. Our series of experiments showed a marked decrease of silver-activity in biological fluids which corresponds with the controversial clinical results obtained with silver coated urinary catheters. Rifampicin/minocycline coated catheters had very low activity against Gram-negative rods, enterococci and Candida spp., the main causing organisms of urinary catheter infection. Surface engineered materials and antimicrobial drug delivery systems will be the next generation of sophisticated urinary catheters and stents, if both efficacy as well as efficiency has been proved clinically.     

Alprazolam and lorazepam single and multiple-dose effects on psychomotor skills and sleep

Summary The effects of alprazolam 0.5 mg and lorazepam 2 mg on cognitive and psychomotor skills were assessed in twelve normal volunteer subjects in a randomised, double-blind, crossover design. Single and multiple dose effects were monitored using a battery of tests comprising critical flicker fusion threshold (CFFT), choice reaction time (CRT), simulated car tracking, and subjective ratings of perceived sedation (LARS) and of sleep behaviour (LSEQ). Compared with placebo baseline scores, treatment with lorazepam 2 mg (both single and multiple doses) resulted in a widespread impairment of CRT, tracking accuracy, and CFFT. Single doses of alprazolam 0.5 mg reduced CFFT with respect to the placebo baseline. Single and multiple dose treatment with both drugs resulted in subjective reports of sedation, a reduction of sleep onset latency, and improved sleep quality. Only lorazepam 2 mg significantly disrupted the integrity of behaviour on waking from sleep. These results suggest important pharmacodynamic differences between the two drugs in the doses used.