纤维蛋白原-455G／A基因多态性与子痫前期相关性研究

目的通过检测子痫前期患者β-纤维蛋白原-455基因,分析其基因多态性及子痫前期发生的关系。方法利用聚合酶链反应,限制型长度多态性对2007年1至12月在广东省妇幼保健院分娩的96例子痫前期患者和98例正常孕妇进行不同β-纤维蛋白原-455G／A基因型分析,并观察两组血浆纤维蛋白原情况。结果子痫前期患者血浆纤维蛋白原水平显著高于正常妊娠者（P〈0．05）。β—FIB-455G／A基因多态性GA＋AA等位基因携带者血浆纤维蛋白原水平明显高于GG等位基因者（P〈0．05）,可见A等位基因与高纤维蛋白原水平相关。A等位基因频率及GA、AA基因型在子痫前期组和对照组间无明显区别（P〉0．05）。结论β—FIB-455G／A基因多态性A等位基因可能不是子痫前期的遗传易感基因,但与子痫前期患者血浆高纤维蛋白原水平相关。     

广东汉族人群细胞毒性T淋巴细胞相关抗原-4基因多态性与甲状腺相关性眼病的关系

目的探讨细胞毒性T淋巴细胞相关抗原（CTLA）-4基因外显子1的49位点A／G多态性与甲状腺相关性眼病（TAO）之间的关系。方法研究对象包括TAO患者45例、自身免疫性甲状腺疾病（AITD）无眼病患者100例和本院健康体检中心筛选的无亲缘关系的健康体检者100例。应用聚合酶链反应技术（PCR）对所有血液标本进行CTLA-4基因外显予1的49位点A／G酶切住点限制性片段长度多态性（RFLP）研究，分析比较此多态位点的基因型和等位基因频率在不同人群中分布的差异。结果①TAO组GG基因型频率、G等位基因频率均显著高于无眼病组及对照组（P〈0．05或P〈0．01）；无眼病组GG基因型频率、G等位基因频率亦均显著高于对照组（P〈0．01）。TAO组、无眼病组AA基因型频率均显著低于对照组（P〈0．01），但TAO组与无眼病组相比差异无统计学意义（P=0．118）。②按性别分层后，TAO组、无眼病组男性CG基因型频率及G等位基因频率均显著高于对照组（P〈0．05），而TAO组与无眼病组相比差异无统计学意义（P=0．053）。TAO组、无眼病组女性GG基因型频率及G等位基因频率均同样显著高于对照组（P〈0．05），但TAO组与无眼病组相比亦差异无统计学意义（P=0．075）。③TAO组按甲状腺眼病分级分成5＋6级、4级和3级，3组进行比较发现，3组之间GG基因型频率及G等住基因频率相比差异均无统计学意义（P〉0．05）。结论CTLA-4基因可能是广东地区汉族人群中TAO的易感候选基因。     

血管紧张素转换酶基因及CD14基因多态性与变应性鼻炎的关系

目的：通过对血管紧张素转换酶（ACE）基因插入／缺失的多态性及CD14／-159C／T基因的多态性分析，探讨其在变应性鼻炎发病中的作用。方法：采用聚合酶链反应（PCR）扩增及限制性内切酶片段多态性（PCR—RFLP）分析方法测定60例变应性鼻炎患者和40例健康对照者的ACE基因型和CD14／-159C／T基因型的分布情况，并采用相关统计学方法对结果进行分析。结果：（1）ACE等位基因I、D频率在变应性鼻炎组和对照组的分布差异有统计学意义（xz=17．37，P〈0．01）。等位基因D与变应性鼻炎高度相关（OR=3．46，95％CI=1．92—6．23，P〈0．01）。（2）CD14／-159C／T等位基因C、T频率在变应性鼻炎组和对照组的分布差别具有统计学意义（xz=14．53，P〈0．01），等位基因C与变应性鼻炎高度相关（OR=3．1，95％CI=1．75—5．47，P〈0．01）。2组基因型（CC型、CT型、TT型）频率的分布比较差别也有统计学意义（x^2=11．77，P〈0．01）。结论：ACE基因多态性与CD14基因的多态性是影响变应性鼻炎的重要候选基因，其中ACE的D等位基因与CD14—159C／T的C等位基因与变应性鼻炎相关。     

蛋白S基因（PROS1）2148A／G多态性和血浆蛋白S水平与下肢深静脉血栓形成关系的研究

目的探讨蛋白S基因（PROS1）2148A／G多态性频率分布和血浆蛋白S水平与下肢深静脉血栓形成（Lowerextremity deep venous thrombosisLEDVT）啦关系。方法用PCR—RFLP分析基因频率分布,ELISA法分析血浆蛋白S水平,对122例LEDVT组和138啻l健康人对照组进行研究。结果等位基因A在对照组及LEDVT组分布频率分别为0．554和0．422（P〈0．01）。GG和AG基因型的个体发生LEDVT的风险分别是AA基因型个体的3．342和1．869倍（ORGG=3．342,95％CI为1．051～10．875;ORAG＝1．869,95％CI为0．857～3．992）。对照组和LEDVT组中总蛋白S（tPS）水平分别为23．32±5．30μg／ml和17．20±4．02μg／ml（P〈0．01）,游离蛋白S（IPS）水平分别为9．61±2．50μg／ml和6．72±1．55μg／ml（P〈0．01）。在对照组和LEDVT组中,A等位基因携带者的tPS、fPS水平均高于非携带者。分别为23．98±5．50μg／ml和20．45±3．65μg／ml（P〈0．01）,18．31±4．02μg／ml和15．15士3．95μg／ml（P〈0．01）;10．01±3．03vg／ml和7．89±2．01μg／ml（P〈0．01）,7．13±1．58μg／ml和5．97±1．31μg／ml（P〈0．01）。结论（PROS1）2148A等位基因与血浆蛋白S水平具有相关性,血浆蛋白S水平低下是LEDVT的危险因素,蛋白S蛋白S基因（PROS1）2148A／G多态性可能为福建地区人群LEDVT的危险因素。     

IL-10 基因多态性及血清水平与颅内动脉瘤发病的关系

目的 分析白细胞介素（IL）-10 基因启动子区－ 1082G/A、－ 819C/T 单核苷酸多态性（SNP）及血清 IL-10 水平与颅内动脉瘤（IAs）发病的关系。 方法 运用 PCR 及 DNA 直接测序的方法, 检测 206 例 IAs 患者（IAs 组）和 187 例非 IAs 患者（对照组）的 IL-10 基因启动子区 SNP 位点, － 1082G/A、－ 819C/T 的基因型频率和等位基因频率, χ2检验分析 IAs 组和对照组之间的差异; 采用 ELISA 法检测血清中 IL-10 水平, t 检验分析 2 组之间的差异。 结果 IL-10 基因启动子区－ 1082G/A 位点的 GG 基因型和 GA＋ AA 基因型, 以及 G 等位基因和 A 等位基因频率比较, IAs 组较对照组 GA＋ AA 基因型以及 A 等位基因频率更高, 差异均有统计学意义（P < 0.01）, GA＋ AA 基因型（OR 值为 4.137, 95%CI 2.476~6.914）和 A 等位基因（OR 值为 3.368, 95%CI 2.476~4.583）携带者有更高的 IAs 发病风险; IL-10 基因启动子区－ 819C/T 位点的 CC 基因型和 CT＋ TT 基因型以及 C 等位基因和 T 等位基因频率比较, IAs 组较对照组 CT＋ TT 基因型以及 T 等位基因频率更高, 差异均有统计学意义（P < 0.01）, CT＋ TT 基因型（OR 值为 3.393, 95% CI 1.952~5.900）和 T 等位基因（OR 值为 3.764, 95%CI 2.730~5.192）携带者有更高的 IAs 发病风险。 IAs 组血清 IL- 10 水平低于对照组（P < 0.01）。 结论 IL-10 基因启动子区 SNP 影响 IL-10 表达,IL-10 基因启动子区－ 1082G/A、－ 819C/T 多态性与 IAs 的发病有关。     

RANTES 基因多态性与结核性脓胸发病风险的关系

目的：探讨河北地区受激活调节正常 T 细胞表达和分泌因子（regulated upon activation normal T cell ex－pressed and secreted factor,RANTES）基因－403G／A 和－28C／G 单核苷酸多态性（SNP）与结核性脓胸的关系。方法采用聚合酶链反应－限制性片段长度多态性（PCR－RFLP）方法检测300例结核性脓胸患者和300例对照人群RANTES基因－403G／A 和－28C／G 的基因型。结果 RANTES 基因－403G／A SNP 基因型频率和等位基因频率在结核性脓胸组和正常组间差异有统计学意义（ P ＝0．004和 P ＝0．008）,与 GG 基因型相比,携带 AG ＋AA 基因型可增加结核性脓胸发病风险（OR ＝1．40395％,CI ＝1．015～1．939）。 RANTES 基因－28C／G SNP 基因型频率和等位基因频率在结核性脓胸组和正常组间差异无统计学意义（ P ＝0．128和 P ＝0．064）,与 CC 基因型相比,携带 CG ＋GG 基因型与结核性脓胸发病风险无关（OR ＝1．31495％,CI ＝0．891～1．936）。结论 RANTES 基因－403G／A SNP 可能与结核性脓胸的发病风险有关,即携带 AG ＋AA 基因型增加结核性脓胸发病风险;RANTES 基因－28C／G SNP 可能与结核性脓胸发病风险无关。     

eIF3a 2554G>A基因多态性对肺癌患者铂类药物化疗敏感性的影响

目的elF3a在基因转录和翻译过程中起重要的调控作用,近年来研究发现elF3a蛋白在肺癌组织中具有高表达。本研究检测elF3a基因2554G7A此位点的突变,研究这些突变与肺癌发生的易感性以及与肺癌患者化疗药物敏感性的关系。方法在湘雅医院收集肺癌患者和健康对照者血液标本。用半巢式聚合酶链式反应连接的限制性片段长度多态性分析法对16号外显子的2554G〉A进行分型,分析该基因多态性与肺癌易感性及肺癌患者对铂类药物化疗敏感性的相关性。结果elF3a2554G〉A突变在肺癌中的突变频率为10．9％,其中鳞癌突变频率为10．9％,腺癌为5．9％,小细胞癌为13．4％;健康人群中突变频率为15．3％。在肺癌患者中,elF3a2554G〉A三种基因型GG、GA和AA的频率分别为78．8％、20．6％和0．6％。而健康对照者中,GG、GA和AA三种基因型的频率分别为72．9％、23．5％和3．5％。经非条件logistic回归平衡了性别、年龄和吸烟史后,GA、AA、GA＋AA基因型患肺癌的危险性与GG基因型相比均无统计学意义,相对于GG基因型,GA型患肺癌（OR=0．83,95％CI：0．49～1．41）,AA型患肺癌（OR=0．18,95％cI：0．02-1．59）,GA＋AA基因型（OR=0．76,95％CI：0．45～1．27）。小细胞肺癌组GG基因型患者的化疗有效率低于GA基因型（65.0%-75.0%）,而非小细胞肺癌组GG基因型患者的化疗有效率高于GA＋AA基因型（24.3％W16．7％）。结论elF3a2554G〉A基因多态性与肺癌的发生无明显相关性。在小细胞肺癌和非小细胞肺癌中．elF3a2554G〉A不同基因型的个体具有不同的铂娄化疗疗效．     

单核细胞趋化蛋白-1-2518A／G基因多态性与肺癌分型关系的研究

目的：（1）研究贵州地区汉族人群中单核细胞趋化蛋白‐1（MCP‐1）‐2518A／G位点是否存在基因多态性;（2）探讨MCP‐1‐2518A／G基因多态性与肺癌及其分型的相关性。方法收集2013年3－12月在我科住院治疗的无血缘关系的肺癌患者（实验组）90例,根据肿瘤组织病理学类型分为非小细胞肺癌（NSCLC ）和小细胞肺癌（SCLC）,同时收集同期健康体检者（对照组）32例。通过运用聚合酶链式反应‐限制性片段长度多态性（PCR‐RFLP）技术对MCP‐1‐2518A／G的基因型进行检测。结果（1）贵州地区汉族人群中MCP‐1‐2518A／G存在基因多态性,健康人群中三种基因型（AA、AG、GG）的分布频率分别为：6．2％、46．9％、46．9％;实验组为：26．7％、46．6％、26．7％;（2）实验组和对照组中MCP‐1‐2518A／G 三种基因型分布差异具有统计学意义,AA基因型个体患肺癌的相对风险度高（OR＝5．455,P＝0．015）,GG基因型个体患肺癌的相对风险度低（OR＝ 0．412,P＝0．035）,携带A等位基因的个体患肺癌的相对风险是携带G等位基因个体的2．368倍;（3）从组织学类型来看,NSCLC患者AA基因型和GG基因型分布频率在两组间差异具有统计学意义,AA基因型个体患NSCLC的相对风险度高（OR＝7．174,P＝0．004）,GG基因型个体患病的相对风险度低（OR＝0．408,P＝0．043）,SCLC患者各基因型患病的相对风险度与对照组差异无统计学意义。结论（1）贵州地区汉族人群中存在MCP‐1‐2518A／G基因多态性;（2）MCP‐1‐2518A／G基因多态性与肺癌的发病有相关性,A等位基因可能是肺癌发病的易感基因;（3）MCP‐1‐2518A／G基因多态性与NSCLC的发病有相关性,与SCLC的发病无相关。     

氯氮平在体内代谢与细胞色素P450 1A2-2964位点多态性的关系

目的：探讨氯氮平在精神分裂症患者体内代谢和细胞色素P450 1A2－2964位点多态性关系，指导临床对不同患者合理使用氯氮平。方法：采用固定剂量给药，用高效液相色谱法（HPLC）测定血药浓度，用限制性片段长度多态性（RFLPs）分析基因型。结果：吸烟组和非吸烟组之间比较，吸烟组血浆氯氮平浓度低，去甲氯氮平／氯氮平比值高（P＜0．05，P＜0．01），P450 1A2-2964位点等位基因G的频率为0．75，A的频率为0．25，在非吸烟患者中，去甲氯氮平／氯氮平在w/w基因型与非w/w基因型(w/m m/m)之间无显著的统计学意义（P＞0．05），在吸烟患者中，w/w基因型去甲氯氮平／氯氮平要高于非w/w基因型（P＜0．05），在吸烟患者和非吸烟患者中w/w基因型之间比较，吸烟患者的去氯氮平／氯氮平明显高于非吸烟患者（P＜0．01）；而非w/w基因型之间无显著的统计学意义（P＞0．05），结论：吸烟能诱导P450 1A2的活性。P450 12-2964位点等位基因均为G（w/w)时诱导能力最强，发生G→A突变时，诱导能力降低，分析患者P450 1A2 G－2964A的多态性，对合理使用氯氮平有意义。     

海洛因依赖和μ阿片受体A118G多态性的关联：Meta分析

目的：探讨汉族人群中海洛因依赖和μ阿片受体基因（OPRM1）A118G多态性的关联。方法：检索PubMed，CNKI，维普等数据库，搜集有关汉族人群海洛因依赖和A118G多态性关联研究的相关文献，然后进行Meta分析。结果：A118G基因型G／G在海洛因依赖组和对照组之间的比较中，异质性检验无显著性差异（P=O．49），遂选用固定效应模型，合并OR=0．90（95％CI，0．64—1．25），效应检验结果提示没有显著性差异（P=0．51）；A118G等位基因G在海洛因依赖组和对照组之间的比较中，异质性检验存在显著性差异（P=0．03），则选用随机效应模型，合并OR=0．94（95％CI，0．71—1．23），效应检验结果提示不存在显著性差异（P=0．63）。结论：汉族人群海洛因依赖与A118G多态性的基因型和等位基因不存在关联性。     

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.