Inhibiting 5-hydroxytryptamine receptor 3 alleviates pathological changes of a mouse model of Alzheimer's disease

Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In this study,we found that 5-hydroxytryptamin receptor 3A subunit(HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice(an Alzheimer’s disease model) and patients with Alzheimer’s disease.To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques,we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model.Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons.These results suggest that HTR3A-positive interneurons may partially contribute to the generation of Aβ peptides.We treated 5.0-5.5-month-old model mice with tro pisetron,a HTR3 antagonist,for 8 consecutive weeks.We found that the cognitive deficit of mice was partially reversed,Aβ plaques and neuroinflammation we re remarkably reduced,the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice.These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer’s disease and inhibiting HTR3 partly reve rses the pathological changes of Alzheimer’s disease.

清渣汤对玫瑰痤疮模型小鼠皮损组织VEGF、TLR2、KLK5表达的影响

目的:观察清渣汤口服对玫瑰痤疮模型小鼠皮损组织血管内皮生长因子(VEGF)、Toll样受体2(TLR2)、激肽释放酶5(KLK5)表达的影响。方法:7周龄健康雄性小鼠36只,用随机数字表法将其分为6组:清渣汤高剂组、中剂组、低剂组、阳性对照组(多西环素片)、模型对照组、正常对照组,每组6只。除正常组外,其余各组均进行玫瑰痤疮造模。造模24 h后给药,模型组给予0.2 mL生理盐水灌胃,清渣汤3剂组分别给予25 mg/kg(低剂量组)、50 mg/kg(中剂量组)和100 mg/kg(高剂量组)清渣汤灌胃,阳性对照组给予30 mg/kg盐酸多西环素溶液灌胃,每日1次,共给药4周。免疫组化法检测皮损部位皮肤组织VEGF、TLR2、KLK5蛋白表达水平。结果:模型组小鼠皮损组织VEGF、TLR2、KLK5蛋白表达较正常组明显增强(P<0.01);与模型组比较,阳性对照组和清渣汤高、中、低剂量组小鼠皮损组织VEGF、TLR2、KLK5蛋白表达减弱(P<0.05)。结论:清渣汤能够抑制玫瑰痤疮小鼠模型皮损部VEGF、TLR2、KLK5蛋白表达水平,从而减轻炎症反应。

Effects of 5-hydroxytryptamine Receptor on the Reaction of the Lower Esophageal Sphincter Under the Electrical Field Stimulation

In the first and second parts of this study,5-hydroxytryptamine(5HT)receptors,including 5-HT3 and 5-HT4 with the highest expression level,were found in clasp and sling fibres of the lower esophageal sphincter(LES).Specific 5-HT3 and 5-HT4 receptor agonists can induce the contraction effect of clasp and sling fibres of the LES while specific 5-HT7 receptor agonists showed no effects.In the study of this part,the in-vitro muscle tension measurement technology and EFS methods were used to detect the effect of the selective 5-HT receptor antagonist on the clasp and sling fibres of the in-vitro LES under the electrical field stimulation(EFS),and further to ensure the effect of 5-HT receptor in the LES neuroregulatory pathway,and deeply explore the effect of 5-HT receptor in the systolic and diastolic function regulation of the LES.

Effects of 5-HT2B, 5-HT3 and 5-HT4 receptor antagonists on gastrointestinal motor activity in dogs

AIM:To study the effects of 5-hydroxytryptamine(5-HT)receptor antagonists on normal colonic motor activity in conscious dogs.METHODS:Colonic motor activity was recorded using a strain gauge force transducer in 5 dogs before and after 5-HT2B,5-HT3 and 5-HT4 receptor antagonist administration.The force transducers were implanted on the serosal surfaces of the gastric antrum,terminal ileum,ileocecal sphincter and colon.Test materials or vehicle alone was administered as an intravenous bolus injection during a quiescent period of the whole colon in the interdigestive state.The effects of these receptor antagonists on normal gastrointestinal motor activity were analyzed.RESULTS:5-HT2B,5-HT3 and 5-HT4 receptor antagonists had no contractile effect on the fasting canine terminal ileum.The 5-HT3 and 5-HT4 receptor antagonists inhibited phaseⅢof the interdigestive motor complex of the antrum and significantly inhibited colonic motor activity.In the proximal colon,the inhibitory effect was dose dependent.Dose dependency,however,was not observed in the distal colon.The 5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity.CONCLUSION:The 5-HT3 and 5-HT4 receptor antagonists inhibited normal colonic motor activity.The5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity.

Role of 5-hydroxytryptamine type 3 receptors in the regulation of anxiety reactions

5-Hydroxytryptamine(5-HT)type 3 receptor(5-HT_(3)R)is the only type of ligand-gated ion channel in the 5-HT receptor family.Through the high permeability of Na+,K+,and Ca2+and activation of subsequent voltage-gated calcium channels(VGCCs),5-HT_(3)R induces a rapid increase of neuronal excitability or the release of neurotransmitters from axon terminals in the central nervous system(CNS).5-HT_(3)Rs are widely expressed in the medial prefrontal cortex(mPFC),amygdala(AMYG),hippocampus(HIP),periaqueductal gray(PAG),and other brain regions closely associated with anxiety reactions.They have a bidirectional regulatory effect on anxiety reactions by acting on different types of cells in different brain regions.5-HT_(3)Rs mediate the activation of the cholecystokinin(CCK)system in the AMYG,and theγ-aminobutyric acid(GABA)“disinhibition”mechanism in the prelimbic area of the mPFC promotes anxiety by the activation of GABAergic intermediate inhibitory neurons(IINs).In contrast,a 5-HT_(3)R-induced GABA“disinhibition”mechanism in the infralimbic area of the mPFC and the ventral HIP produces anxiolytic effects.5-HT_(2)R-mediated regulation of anxiety reactions are also activated by 5-HT_(3)R-activated 5-HT release in the HIP and PAG.This provides a theoretical basis for the treatment of anxiety disorders or the production of anxiolytic drugs by targeting 5-HT_(3)Rs.However,given the circuit specific modulation of 5-HT_(3)Rs on emotion,systemic use of 5-HT_(3)R agonism or antagonism alone seems unlikely to remedy anxiety,which deeply hinders the current clinical application of 5-HT_(3)R drugs.Therefore,the exploitation of circuit targeting methods or a combined drug strategy might be a useful developmental approach in the future.

Distribution of serotonin 5-HT_(2A) and 5-HT_7 receptors in the Onuf’s nucleus of the rat spinal cord

BACKGROUND：Motoneurons from the Onuf’s nucleus of the spinal cord, which innervate the striated muscle of the pelvic floor, play an important role in erection, ejaculation, and urine control. Serotonin （5-hydroxytryptamine, 5-HT） regulates motoneuron activity from the Onuf’s nucleus of the spinal cord. However, few studies exist that describe 5-HT receptor distribution in the Onuf’s nucleus. In addition, the nature of the effects of 5-HT receptor on the innervating striated muscle of the pelvic floor is controversial. OBJECTIVE： To investigate the distribution of serotonin 5-HT2A and 5-HT7 receptors in motoneurons of Onuf’s nucleus in the spinal cord of male rats, and to analyze the relationship of 5-HT2A and 5-HT7 receptor to central modulation of urogenital function. DESIGN, TIME AND SETTING： The neural morphology experiment was performed at the Ultramicro-structure Laboratory of Reproductive Medicine, Basic Medical College, Chongqing Medical University, China from April to December 2007. MATERIALS： Ten adult, Sprague Dawley rats （eight males and two females） were randomly divided into gender control group （n = 4, 50% male and 50% female） and a retrograde tracing group （n = 6, 100% male） Recombinant pseudorabies virus （PRV-152） was provided by Professor LW Enquist from Princeton University, USA. Rabbit anti-5-HT2A and 5-HT7 receptor antibodies were purchased from Diasorin, France. METHODS： In the gender control group, the spinal L5-6 segments were harvested, sliced, and then incubate antibodies specific against 5-HT2A or 5-HT7 receptors for immunohistochemical staining. In the retrograde tracing group, PRV-152 was separately injected into the right ischiocavernosus （ischiocavernosus subgroup, n = 3） and the right external urethral sphincter （external urethral sphincter subgroup, n = 3）. Four days after injection, L5-6 segments were harvested, sliced, and incubated with antibodies specific against 5-HT2A or 5-HT7 receptors for double-labeling immunofluorescence staining. MAIN OUTCOME MEASURES： Distribution analysis of 5-HT2A and 5-HT7 receptors in Onuf’s nucleus utilizing optical or laser confocal microscopy. RESULTS： 5-HT2A receptor immunoreactivity was revealed primarily in the medial region of the dorsolateral nucleus of Onuf’s nucleus. 5-HT7 receptor expression was observed in the lateral part of the dorso-lateral nucleus. 5-HT2A and 5-HT7 receptor expressions in the Onuf’s nucleus were significantly greater in male rats, compared to female rats. Double-labeling immunofluorescence demonstrated that 5-HT2A recepto were distributed primarily in the surrounding motoneurons innervating the ischiocavernosus, and 5-HT7 receptors were primarily expressed in motoneurons innervating the external urethral sphincter. CONCLUSION： Motoneurons innervating the ischiocavernosus and external urethral sphincter are located primarily in the medial and lateral region of the dorsolateral nucleus of L5-6 segments. The 5-HT2A receptor-innervating ischiocavernosus may be preferentially involved in the regulation of sexual reflex, and the 5-HT7 receptor-innervating external urethral sphincter may mainly join in regulating micturition reflex.

The 5-HT2c receptor gene Cys23Ser polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation

It has been postulated that the persistent short intravaginal ejaculation latency time （IELT） of men with lifelong premature ejaculation （LPE） is related to 5-hydroxytryptamine （HT）2c receptor functioning. The aim of this study was to investigate the relationship of Cys23Ser 5-HT2c receptor gene polymorphism and the duration of IELT in men with LPE. Therefore, a prospective study was conducted in 64 Dutch Caucasian men with LPE. Baseline IELT during coitus was assessed by stopwatch over a 1-month period. All men were genotyped for Cys23Ser 5-HT2c receptor gene polymorphism. Allele frequencies and genotypes of Cys and Ser variants of 5-HT2c receptor gene polymorphism were determined. Association between Cys/Cys and Ser/Ser genotypes and the natural logarithm of the IELT in men with LPE were.investigated. As a result, the geometric mean, median and natural mean IELT were 25.2, 27.0, 33.9s, respectively. Of all men, 20.0%, 10.8%, 23.1% and 41.5% ejaculated within 10, 10-20, 20-30 and 30-60s after vaginal penetration. Of the 64 men, the Cys/Cys and Ser/Ser genotype frequency for the Cys23Ser polymorphism of the 5-HT2c receptor gene was 81% and 19%, respectively. The geometric mean IELT of the wildtypes （Cys/Cys） is significantly lower （22.6s; 95% CI 18.3-27.8s） than in male homozygous mutants （Ser/Ser） （40.4s; 95% CI 20.3-80.4s） （P = 0.03）. It is concluded that Cys23Ser 5-HT2c receptor gene polymorphism is associated with the IELT in men with LPE. Men with Cys/Cys genotype have shorter IELTs than men with Ser/Ser genotypes.

Association between Low-density Lipoprotein Receptor-related Protein 5 Polymorphisms and Type 2 Diabetes Mellitus in Han Chinese:a Case-control Study

Objective To investigate the association between low-density lipoprotein receptor-related protein 5 （LRPS） variants （rs12363572 and rs4930588） and type 2 diabetes mellitus （T2DM） in Han Chinese. Methods A total of 1842 T2DM cases （507 newly diagnosed cases and 1335 previously diagnosed cases） and 7777 controls were included in this case-control study. PCR-RFLP was conducted to detect the genotype of the two single nucleotide polymorphisms （SNPs）. Odds ratios （ORs） and 95% confidence intervals （95% CIs） were calculated to describe the strength of the association by logistic regression. Results In the study subjects, neither rs12363572 nor rs4930588 was significantly associated with T2DM, even after adjusting for relevant covariates. When stratified by body mass index （BMI）, the two SNPs were also not associated with T2DM. Among the 3 common haplotypes, only haplotype ~ was associated with reduced risk of T2DM （OR 0.820, 95% CI 0.732-0.919）. In addition, rs12363572 was associated with BMI （P〈0.001） and rs4930588 was associated with triglyceride levels （P=0.043） in 507 newly diagnosed T2DM cases but not in healthy controls. Conclusion No LRP5 variant was found to be associated with T2DM in Han Chinese, but haplotype TT was found to be associated with T2DM.

Roles of 5-HT2 receptors in effects of DOM,ketamine and methamphetamine on prepulse inhibition in Sprague Dawley rats

OBJECTIVE Prepulse inhibition(PPI)of the acoustic startle response provides a measure of sensorimotor gating system mecha⁃nisms,which is known to be impaired in schizo⁃phrenia patients.We assessed the effects of the 5-HT2A/2C receptor agonist(±)2,5-dimethoxy-4-methylamphetamine(DOM),the NMDA receptor antagonist ketamine,the dopamine receptor ago⁃nist methamphetamine(Meth)on PPI and the startle magnitude in SD rats.METHODS AND RESULTS Systemic administration of the three compounds all dose-dependently reduced PPI.However,as far as startle magnitude,only DOM at the doses of 3 mg·kg-1 reduced that,while both ketamine and Meth did not change the startle magnitudes.Furthermore,to determine whether 5-HT2A receptor mediate this effect,the non-spe⁃cific 5-HT2 receptor antagonist cyproheptadine,specific 5-HT2A receptor antagonist ketanserin and specific 5-HT2C receptor antagonist SB242084 were tested.Cyproheptadine,ketan⁃serin and SB242084 did not alter startle ampli⁃tude by themselves in SD rats and only ketanserin slightly increased PPI at higher dose(3 mg·kg-1).PPI impairment induced by DOM was restored by pretreatment of cyproheptadine(1 mg·kg-1)and ketanserin(1 mg·kg-1),while not by pretreat⁃ment of SB242084(1 mg·kg-1).Damage of PPI induced by ketamine and Meth was not reversed by cyproheptadine(1 and 5 mg·kg-1).CONCLU⁃SION The receptor mechanisms underlying the disruption of PPI caused by DOM,ketamine and Meth were different from each other,at least 5-HT2A receptor was not the junction receptor for which the three chemicals acted.

ENHANCEMENT OF DNA SYNTHESIS IN CULTURED ADULT RAT HEPATOCYTES BY 5-HT THROUGH STIMULATION OF 5-HT_2RECEPTOR

Hepatocytes were isolated from livers of adult male SpragueDawley rats and cultured in Williams'E Medium with 3 H thymidine. The effect of 5hydroxytryptamine (5HT) was investigated through adding various concentrations (10-810-3 mol/L) of 5HT to the hepatocyte cultures in the presence or absence of epidermal growth factor (EGF) and insulin. The involvement of 5HT2 receptor was examined by adding a 5HT2 receptor antagonist, ketanserin (10-6 mol/L), to some of the cultures containing 5HT. The increment of DNA synthesis was measured by 3 H thymidine incorporation. The results showed that 5HT2 (10-6 mol/L) significantly (P<005) increased the amount of DNA synthesis induced by EGF and insulin in the cultured adult rat hepaptocytes. The effect of 5HT in enhancing DNA synthesis began to appear at a concentration between 10-7 and 10-6 mol/L and reached maximum at concentrations of 10-4 mol/L. The enhancement of DNA synthesis by 5HT was significantly (P<005) antagonized by ketanserin, suggesting that this effect of 5HT was mediated by 5HT2 receptor subtype.

Role of 5-HT2A Receptors in Immunomodulation in Animal Models of Aggressive Behavior

Serotonin 5-HT2A receptors are playing an important role in the pathophysiology of aggressive behaviors and in the control of immune function. In the present study, we analyzed the effects of activation and blockade of 5-HT2A receptors with selective ligands on the immune response formation in animals with aggressive behaviors induced by genetic factors (rats selected for the increased aggressiveness toward human) or by chronic social stress (mice of the CBA/Lac strain engaged in 10 days of social confrontations). Activation of 5-HT2A receptors with DOI at 1.0 mg/kg reduced the immune response level both in aggressive rats and mice compared to the corresponding vehicle-treated groups, while DOI administration did not alter the immune reaction in nonaggressive animals. The blockade of 5-HT2A receptors with ketanserin at 1.0 mg/kg resulted in immunostimulation both in mice of the CBA strain not subjected to social stress (the controls) and in nonaggressive rats selected for elimination of aggressiveness. On the other hand, its administration to CBA mice demonstrating offensive aggression enhanced the immune reaction, while the same dose of ketanserin did not modify the immune response level in rats with genetic predisposition to the increased defensive aggression. Thus, our data suggest that the role of 5-HT2A receptors in immunomodulation depends on the specific type of aggression that may be taking into account in the treatment of some neuropsychiatric disorders with the antipsychotic drugs and antidepressants targeting 5-HT2A receptors.

血清TGR5 mRNA和BNIP3 mRNA在急性心肌梗死患者中的表达水平及临床意义

目的 探究血清G蛋白偶联胆汁酸受体5(TGR5)mRNA与Bcl-2/腺病毒QE1B-19kDa相互作用蛋白3(BNIP3)mRNA在急性心肌梗死(AMI)患者中的表达水平情况,以及二者对于术后心脏不良事件(MACE)发生的预测价值。方法 选取首都医科大学门头沟教学医院2018年1月至2020年1月收治的98例进行经皮冠状动脉介入术(PCI)的AMI患者[AMI患者包括急性非ST段抬高型心肌梗死(NSTEMI)46例与急性ST段抬高型心肌梗死(STEMI)52例]为研究组,另选取同期90例体检健康者作为对照组。采用实时荧光定量PCR(qRT-PCR)检测血清TGR5 mRNA和BNIP3 mRNA表达水平,根据PCI术后随访结果将研究组分为MACE组(46例)和非MACE组(52例)。收集两组患者临床资料,采用Pearson法分析术后MACE组血清TGR5 mRNA与BNIP3 mRNA表达水平的相关性,采用受试者工作特征(ROC)曲线分析血清TGR5 mRNA和BNIP3 mRNA对于术后AMI患者MACE发生的预测价值,采用Logistic回归分析AMI患者术后MACE发生的影响因素。结果 研究组血清TGR5 mRNA表达水平显著低于对照组,血清BNIP3 mRNA表达水平显著高于对照组,差异有统计学意义(P<0.05);术后MACE组左心室射血分数(LVEF)、TGR5 mRNA表达水平显著低于非MACE组,血清肌酐(SCr)、红细胞分布宽度(RDW)、Killip分级Ⅲ+Ⅳ级比例、BNIP3 mRNA表达水平显著高于非MACE组,差异有统计学意(P<0.05);经Pearson相关性分析,血清TGR5 mRNA与BNIP3 mRNA表达水平呈负相关(r=-0.543,P<0.05);ROC曲线分析显示,血清TGR5 mRNA预测AMI患者MACE发生的曲线下面积(AUC)为0.704(95%CI:0.601~0.808),血清BNIP3 mRNA预测AMI患者MACE发生的AUC为0.762(95%CI:0.696~0.883),血清TGR5 mRNA与BNIP3 mRNA联合预测AMI患者术后MACE发生的AUC为0.867(95%CI:0.783~0.932),优于二者单独预测(Z_(二者联合-TGR5)=2.346,Z二者联合-BNIP3=1.715,P=0.019、0.043);Logistic回归分析结果显示,TGR5 mRNA、BNIP3 mRNA、RDW是AMI患者术后MACE发生的影响因素(P<0.05)。结论 TGR5 mRNA在AMI患者血清中呈低表达水平,BNIP3 mRNA在AMI患者血清中呈高表达表达,二者对于预测术后MACE发生具有重要意义。

糖尿病大鼠胃肠功能紊乱时β_2-肾上腺素能受体与5-羟色胺受体表达的变化

目的 探讨糖尿病胃肠功能紊乱大鼠胃肠道自主神经病变的靶位。 方法 应用四氧嘧啶 糖尿病大鼠模型 ,对其胃肠道多个部位的 β2 肾上腺素能受体 (β2 AR)与 5 羟色胺受体 (5 HTR)的数量进行免疫组化检测。 结果 糖尿病大鼠胃窦与结肠的 5 HTR显著增多 ;糖尿病大鼠黏膜内分泌细胞的 β2 AR在肠道均有减少。 结论 胃肠道的 β2 AR与 5 HTR的数量在糖尿病胃肠功能紊乱时发生了改变 ,这种改变很可能是糖尿病胃肠功能紊乱的发病基础。

中国傣族、景颇族人群中与艾滋病相关的CCR5△32、CCR2b-64I、SDF1-3′A等位基因多态性分布

为了调查HIV 1感染相关的等位基因CCR5△32、CCR2b 64I、SDF1 3′A在我国云南省德宏州傣族景颇族人群中的频率和多态性分布,此课题以101例傣族和113例景颇族人群为研究对象,应用PCR、PCR RFLP(聚合酶链反应 限制性片段长度多态性)分析方法进行检测,计算突变基因频率;并对其群体分布、性别分布进行统计学分析。结果表明,中国傣族景颇族人群中未发现CCR5△32等位基因突变;傣族CCR2b 64I、SDF1 3′A基因突变频率分别为0.2130和0.2030,景颇族CCR2b 64I和SDF1 3′A基因突变频率分别为0.1637和0.1770;与中国汉族人群相比较,傣族和景颇族中SDF1 3′A突变频率较低(P值分别为0.0322和0.0021);两个民族的CCR2b 64I和SDF1 3′A等位基因群体分布符合Hardy Weinberg平衡,在性别之间分布无显著差异。中国傣族景颇族人群的CCR2b 64I等位基因的突变频率与汉族人相似,SDF1 3′A等位基因的突变频率比汉族人低,此两种突变基因在艾滋病发病过程中的影响值得进一步研究。由于未发现CCR5△32基因突变,中国傣族景颇族人群对HIV 1感染可能有较大的遗传易感性。

5-羟色胺2A受体基因多态性与利培酮治疗中国首发精神分裂症患者疗效关联(英文)

背景 5-羟色胺2A受体基因已经证实为精神分裂症的候选易感基因，因为阐明其作为非典型抗精神病药物重要作用靶点减轻阴性症状已引起业界倍加关注。本研究试图探讨：（1）5-HT2A受体基因T102C多态性在不同临床亚型之间等位基因和基因型频率的关系，（2）5-H12A受体基因T102C在利培酮高剂量组和低剂量组之间基因型和等位基因分布频率的关系，（3）5-H12A受体基因T102C多态性在治疗有效组与无效组之间的基因型和等位基因分布频率的关系，（4）5-羟色胺2A受体T102C基因多态性是否与中国首发精神分裂症患者利培酮疗效有关。方法 对201例精神分裂症初发期患者分别进行利培酮治疗[3～5mg／d，平均（3．2±1．3）mg／d]，疗程8周。采用聚合酶链式反应扩增与限制性片段长度多态性（PCR-RFLP）技术检测5-H12A受体基因T102C多态性。以临床亚型将精神分裂症患者划分为偏执型、瓦解型、未定型和其他型，分析不同临床亚型等位基因和基因型频率的差异；按服用利培酮剂量划分低剂量组（〈4mg／d）和高剂量组（≥4mg／d），经比较利培酮高剂量组和低剂量组的5-H12A受体基因T102C基因型和等位基因分布频率差异性；同时以阴性和阳性症状量表（PANSS）总减分率〉50％有效，≤50％为无效以分析治疗有效组与无效组之间的基因型和等位基因分布频率差异有无显著性；以PANSS评定患者治疗前及治疗后2周、4周、6周和第8周末的精神症状，比较5-H12A受体T102C各基因亚型与年龄、发病年龄、PANSS总分值、阳性症状基线分、阴性症状基线分、一般病理症状基线分、PANSS总减分率、阳性症状减分率、阴性症状减分率和一般病理症状减分率的差异。结果 5-H他A受体T102C基因型在患者组分布频率均符合H-W平衡定律（P〉0．05）；不同临床诊断亚型精神分裂症患者等位基因和基因型频率无显著性差异（χ^2=0．415，P=0．937；χ^2=1．705，P=0．941）；高剂量组与低剂量组之间的基因型和等位基因分布频率差异均无显著性（χ^2=2．402，P=0．301；χ^2=2．465，P=0．116）；治疗有效和无效组的基因型和等位基因分布频率的差异无显著性（χ^2=1．995，P=0．369；χ^2=1．939，P=0．164）；各基因型亚组的年龄、发病年龄及其病程差异均无显著性（P均大于0．05）；但基因亚组A1／A1的治疗前PANSS总分（χ^2=4．076，P=0．018）和阴性症状分（χ^2=3．946，P=0．021）以及治疗结束PANSS总分减分率（χ^2=4．036，P=0．019）和阴性症状减分率（χ^2=3．876，P=0．022）均显著高于A1／A1及A1／A1基因型。结论 （1）首发精神分裂症患者不同临床亚型5-H12A受体基因T102C基因型和等位基因频率无显著差异。（2）利培酮高剂量组和低剂量组5-H12A受体基因T102C基因型和等位基因分布频率没有显著性差异。（3）治疗有效组与无效组之间5-H12A受体基因T102C基因型和等位基因分布频率也无显著性差异。（4）5-H12A受体T102C A1／A1基因亚型可能影响中国首发精神分裂症患者对利培酮的治疗效应。

5-HTR4和GABRG2基因多态性与精神分裂症关系

目的探讨5-羟色胺4受体基因(5-HTR4)和γ-氨基丁酸-γ2受体基因(GABRG2)基因多态性与精神分裂症的关系。方法在95个中国北方汉族精神分裂症患者和他们的健康父母组成的核心家系中,以聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法对5-HTR4基因rs888957(C/T碱基改变)和GABRG2基因rs211014(T/G碱基改变)单核苷酸多态性(SNP)进行检测。应用基于家系的连锁不平衡方法分析基因型数据。结果(1)5-HTR4基因rs888957及GABRG2基因rs211014基因型频率的分布均符合Hardy-Weinberg平衡;(2)传递不平衡检验(TDT)结果提示,5-HTR4基因rs888957及GABRG2基因rs211014与精神分裂症无连锁及关联;(3)UNPHASED双位点单体型分析结果显示,rs888957-rs211014单体型系统与精神分裂症无关联(P>0.05);(4)5-HTR4基因的rs888957位点等位基因分布与精神分裂症的阳性症状钟情妄想相关联(P<0.01)。GABRG2基因的rs211014位点等位基因分布与精神分裂的阳性症状冲动伤人行为相关联(P<0.05)。结论5-HTR4基因rs888957位点及GABRG2基因rs211014位多点态性可能与精神分裂症无关,但不能排除5-HTR4基因及GABRG2基因其他SNPs与精神分裂症相关联。

曲妥珠单抗联合奥沙利铂、5-氟尿嘧啶治疗HER-2/neu高表达晚期胃癌的临床疗效观察

目的观察曲妥珠单抗联合奥沙利铂、5-氟尿嘧啶治疗HER-2/neu高表达晚期胃癌的临床疗效与安全性。方法选择2009年10月—2011年4月收治的晚期胃癌患者84例为研究对象,随机分为观察组(44例)与对照组(40例),对照组给予奥沙利铂联合5-氟尿嘧啶化疗方案,观察组在此基础上加用曲妥珠单抗,2组均化疗4个周期,并进行24个月随访观察,对比2组化疗结束后临床疗效、化疗期间药物毒性反应及24个月内存活情况。结果(1)2组化疗结束后1个月,观察组总体有效率为63.6%,KPS评分为(79.6±6.4)分,均高于对照组的42.5%和(75.8±5.7)分,HER-2细胞外定量(28.4±6.6)μg/L低于对照组的(31.5±7.2)μg/L,差异均有统计学意义(P<0.05)。(2)观察组心脏毒性、发热或寒战、皮疹发生率显著高于对照组(分别为15.9%vs 2.5%、25.0%vs 10.0%、29.5%vs 7.5%),差异均有统计学意义(P<0.05)。(3)观察组化疗结束后24个月平均生存率为(43.5±7.1)%,平均存活时间为(16.9±3.1)个月,均高于对照组的(39.7±5.8)%和(14.6±2.8)个月,差异有统计学意义(P<0.05)。结论对HER-2/neu高表达晚期胃癌患者在行奥沙利铂联合5-氟尿嘧啶化疗基础上使用曲妥珠单抗,能明显提高临床疗效,延长患者存活时间;同时需密切监测曲妥珠单抗的药物毒性尤其是心脏毒性。

TLR-2和TLR-5在弥漫大B细胞淋巴瘤组织中的表达及临床意义

目的探讨Toll样受体-2(TLR-2)和Toll样受体-5(TLR-5)在弥漫大B细胞淋巴瘤(DLBCL)组织中的表达及其临床意义。方法采用免疫组化法检测60例DLBCL组织标本中TLR-2和TLR-5的表达,以21例反应性淋巴结增生组织为对照组,并分析TLR-2和TLR-5表达与DLBCL临床病理特征的关系。结果 TLR-2在DLBCL组织中的阳性表达率为78.3%,在对照组中为28.5%,差异有统计学意义(P<0.05);TLR-2表达与年龄、性别和ECOG评分无关,与临床分期、乳酸脱氢酶水平、B症状、IPI、免疫亚型以及结外受累有关。TLR-5在DLBCL中的阳性表达率为26.6%,在对照组中为23.8%(P>0.05);TLR-5表达与各临床病理特征无关。结论 TLR-5与DLBCL临床特征无关;TLR-2可能参与了DLBCL的发生和发展,有望作为判断其预后的生物学指标。

5-羟色胺2A受体基因多态性与糖尿病血管舒张功能的关联

用PCR-RFLP方法检测79例T2DM患者与84例健康正常人的5-HT2AR基因1438A/G多态性,用彩色多谱勒超声测定肱动脉反应性充血后以及含服硝酸甘油后血管内径的变化。T2DM组GG型者血清5-HT水平显著升高(P<0.01),NO水平显著降低(P<0.05),内皮依赖性血管舒张功能减弱(P<0.05)。结果说明5-HT2AR基因1438位碱基纯合突变可能与T2DM血管舒张功能减弱有关。

LRP5基因多态性与绝经后妇女2型糖尿病伴骨质疏松症的相关性研究

目的探讨上海地区绝经后2型糖尿病和骨质疏松症妇女的低密度脂蛋白受体相关蛋白5基因多态性与骨密度、骨代谢、糖代谢的关系。方法选取上海市普陀区无亲缘关系的绝经后汉族妇女354例,其中骨质疏松组(A组)90例、2型糖尿病组(B组)96例、2型糖尿病伴骨质疏松组(C组)90例、健康老年对照组(D组)78例。运用双能X线骨密度仪检测腰椎(L2-4)及股骨颈骨密度,同时检测骨代谢指标:BALP、TRACP-5b;糖代谢指标:Hb A1c、FINS。应用基因测序技术检测LRP5基因A1330V位点多态性。采用协方差分析校正年龄、绝经年限、体重指数后比较LRP5基因多态性与骨密度的相关性。结果 A组LRP5基因A1330V位点CC型与CT/TT型相比腰椎骨密度增高(P<0.05),经年龄、绝经年限、BMI校正后仍有显著差异(P<0.01);D组LRP5基因A1330V位点多态性与Hb A1c相关(P<0.05),CC型较CT/TT型Hb A1c高,经年龄、绝经年限、BMI校正后无统计学意义(P>0.05)。结论上海地区汉族绝经后骨质疏松症妇女LRP5基因型与腰椎骨密度相关,提示LRP5基因可能是上海地区汉族绝经后骨质疏松症妇女的易感基因。2型糖尿病患者BMD增高,可能与BMI、胰岛素水平增高有关。LRP5基因可能不是上海地区绝经后2型糖尿病妇女的易感基因。