抗精神分裂症药物诱发迟发性运动障碍与COMT基因多态性的关联性分析

目的:通过分析中国北方汉族人群中精神分裂症患者COMT基因多态性Val158Met 分布,研究COMT基因多态性与精神分裂症及迟发性运动障碍(TD)发生的关系.方法:采集356例并发TD的精神分裂症患者( TD组)、419例不发生TD的精神分裂症患者(非TD组)及471例正常健康人 (正常对照组)的全血样本,提取基因组DNA,应用TaqMan探针检测COMT基因多态性Val158Met基因型和等位基因的分布.结果:正常对照组与精神分裂症组比较,基因型与等位基因频数分布差异均无统计学意义(χ2=3.08,df=3,P=0.21;χ2=2.067,df=2,P=0.15).TD组与正常对照组比较,基因型与等位基因频数分布差异均无统计学意义(χ2=1.857,df=3,P=0.40;χ2 =1.281,df=2,P=0.26).非TD组与正常对照组比较,基因型与等位基因频数分布差异均无统计学意义(χ2=2.505,df=3,P=0.29;χ2=1.709,df=2,P=0.19).TD组与非TD组比较,基因型与等位基因频数分布差异均无统计学意义(χ2=0.021,df=3,P=0.99;χ2=0.013,df=2,P=0.91).结论:精神分裂症的发生与COMT基因多态性Val158Met无关联性,精神分裂症患者并发TD与COMT基因多态性Val158Met无关联性.     

Tim-3基因4个SNP位点多态性与宁夏地区回族人群类风湿性关节炎易感性的关联性分析

目的:探讨宁夏地区回族人群中Tim-3基因4个单核苷酸多态性(SNP)位点多态性与类风湿性关节炎(RA)易感性的关联性,为RA的早期预防提供理论依据.方法:采用序列特异性引物聚合酶链式反应(SSP-PCR)及限制性片段长度多态性(PCR-RFLP)2种方法检测113例RA患者及111例健康个体Tim-3基因-574、-882、-1541和4259共4个位点的单核苷酸多态性.结果:宁夏回族健康人群和RA患者中,Tim-3基因-574、-882、-1541基因型频数和等位基因频数的分布差异均无统计学意义(P>0.05),4259位点基因型和等位基因频数分布差异有统计学意义(P<0.05),RA患者组G等位基因频数(6.36%)显著高于健康组(1.58%).结论:宁夏回族人群Tim-3基因-574、-882、-1541和4259位点存在单核苷酸多态性变异,其中4259T>G的变异与宁夏回族人群RA发生有关.     

雄激素受体基因E211G》A多态性与汉族女性青春期后痤疮的关联性分析

目的:探讨雄激素受体(AR)基因E211 G>A单核苷酸多态性与汉族女性青春期后痤疮的关联性,为汉族女性青春期后痤疮发病遗传学研究奠定基础.方法:将女性青春期后痤疮患者79例和正常女性志愿者80例分为女性青春期后痤疮组和女性正常对照组,采用PCR技术扩增出AR-E211 G>A基因多态位点的片段,用限制性内切酶StuⅠ进行酶切,产物在2%琼脂糖凝胶上电泳,确定G>A基因的3种基因型,即GG、GA、AA,观察两组基因型频数和等位基因型频数分布的差异.结果:女性青春期后痤疮组GA+AA基因型频数低于对照组(P=0.028,OR=0.937,95% CI=0.885～0.992).女性青春期后痤疮组A等位基因频数低于对照组(P=0.029,OR=0.968,95% CI=0.941～0.996).结论:AR-E211 A等位基因的存在使青春期后女性患痤疮的风险性明显降低.     

ADAMTS-1基因多态性与母猪产仔数的关系

用PCR-RFLP方法对118 头大长杂交母猪的ADAMTS-1基因进行分型,并分析了ADAMTS-1不同基因型母猪的产仔数差异.结果表明,在所检测的大长杂交猪群体中,基因A为0.56,基因B为0.44;不同基因型间产仔数表现出AB＞BB＞AA的趋势,AA型与BB型以及AB对猪的产仔数和产仔活数差异不显著.     

纯血马和百色马IGF1R基因蛋白编码区序列的多态性分析

[目的]研究纯血马和百色马IGF1R基因成熟蛋白编码区序列的多态性,为揭示马矮小性状的分子机理和马的分子育种提供理论参考.[方法]采集纯血马和百色马的血样各57份,按常规酚仿法抽提DNA.利用DNA混合池和PCR产物直接测序的方法检测IGF1R基因的多态位点,利用PCR-RFLP技术分析这些多态位点在纯血马和百色马中的基因型及其频率分布.[结果]在马IGF1R基因的第2、第5和第16外显子上存在4个多态位点,其中突变179 627 T→C为纯血马和百色马共有,且两者在基因型频率上差异不显著;突变212 077 G→A为纯血马所独有;突变406 T→C和212 110 G→A为百色马所独有.[结论]马IGF1R基因的多态位点可能与百色马的矮小和纯血马的高大有关.     

抵抗素-420C/G基因多态性与中国东北地区汉族人群2型糖尿病大血管病变相关性分析

目的:研究中国东北地区汉族人群抵抗素(RETN)-420C/G基因单核苷酸多态性(SNPs)的等位基因、基因型频率分布及其与2型糖尿病(T2DM)大血管病变之间的关系.方法:应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法对180例样本[T2DM并发大血管病变组60例,单纯T2DM组60例,正常对照(ND)组60例],进行基因分型及频率测定.结果:T2DM并发大血管病变组及单纯T2DM组等位基因频率及CC/GC+GG基因型分布与ND组比较差异均有统计学意义(P＜0.01);T2DM并发大血管病变组等位基因频率及CC/GC+GG基因型分布与单纯T2DM组比较差异亦有统计学意义(P<0.05),T2DM并发大血管病变组GC+GG基因型频率明显高于单纯T2DM组.结论:RETN-420C/G基因多态性与中国东北地区汉族人群T2DM及其大血管病变的发生有相关性.     

A neural systems theory of schizophrenia and tardive dyskinesia

Some systems ideas applied to individual persons are used to try to explain symptoms of schizophrenia and a syndrome of uncontrolled fragments of movement which sometimes occurs as a side effect of chronic, antipsychotic drug therapy. The behavior of normal organisms may be conceptualized in three echelons of control, with each successively higher echelon organizing, by selective disinhibition, semiautonomous, spontaneous fragments of activity which comprise the next lower echelon. It is hypothesized that schizophrenia involves a deficiency of inhibition by the frontal cortex, first echelon, on the corpus striatum, second echelon. This results first in insufficiently integrated fragments of behavior, and second in premature associative linkages among active elements. First echelon control develops as a normal person matures and gradually loses some of the playful activities of childhood. It is hypothesized that by disrupting certain aspects of activity in the corpus striatum, neuroleptic drugs reduce schizophrenic symptoms but also reduce the capacity of the second echelon to inhibit and integrate the smaller behavioral fragments wired into lower parts of the brain, third echelon. This results in uncontrolled movements. Though many researchers already favor the hypothesis that neuroleptic drugs act on the corpus striatum, the broader theory presented here is new and depends in large part on general living systems considerations. Emphasis is on conceptual decomposition of the integrated behavior of a whole organism into less complex subsystems. Individually, these have neither too much nor too little complexity to yield a plausible model. Some experimental predictions and predictions about possible therapies are made from the theory.     

Handedness and the risk of tardive dyskinesia

1. We investigated whether contractile responses evoked by 5-HT1D receptor agonists were influenced by the endothelium (E) and nitric oxide (NO) in the rabbit isolated saphenous vein. 2. Saphenous vein rings were set up for isometric tension recording in oxygenated (5% CO2 in O2) Krebs solution (pH 7.4) containing (10(-6) M): idazoxan (1), indomethacin (10), ketanserin (0.1), prazosin (10), and N(omega) nitro-L-arginine methyl ester (L-NAME; 0 or 10), a NO synthase inhibitor. In some experiments, the E was removed mechanically. 3. 5-Hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT) and sumatriptan (Sum) contracted rabbit saphenous vein rings in the potency order (pD2 range) of 5-CT(7.2-7.6) > 5-HT(6.2-7.1) > Sum(5.0-5.8), irrespective of the presence or absence of the E or L-NAME (n = 9-37 per group) indicating that the potencies of the 3 agonists were not significantly affected by either the E or L-NAME. 4. Efficacy, as assessed by the maximal contractile response (Emax), was significantly greater for Sum compared to 5-HT and 5-CT with intact E irrespective of the presence (77 +/- 3, 62 +/- 3, and 50 +/- 3 mN respectively; P < 0.05 Sum versus 5-HT and 5-CT) or absence (26 +/- 3, 14 +/- 4, and 13 +/- 2 mN respectively; P < 0.05 Sum versus 5-HT and 5-CT) of L-NAME. In E-denuded rings, the Emax values were all higher than in E-intact rings and did not differ between the 3 agonists (36 +/- 4, 37 +/- 4, and 36 +/- 5 mN for Sum, 5-HT and 5-CT, respectively; P > 0.5 between the 3 agonists) indicating that an endothelium-derived relaxing factor (EDRF) counteracted the constrictor activities of the 5-HT1D receptor agonists and raising the possibility that a component of the Sum-induced contractile responses was E-dependent. Without E, the presence of L-NAME did not significantly affect the Emax values of the 3 agonists (41 +/- 4, 41 +/- 5, and 41 +/- 4 mN for Sum, 5-HT, and 5-CT respectively; P > 0.5 between the 3 agonists) indicating that the NO synthase inhibited was of endothelial origin. 5. Potentiation of the Emax of the 3 agonists by L-NAME was significantly albeit partially reversed by L-arginine (10(-2) M) indicating that NO synthase was indeed inhibited by L-NAME. Furthermore, in the presence of E, potentiation of Emax of the 3 agonists by L-NAME was mimicked by methylene blue (10(-5) M) providing further evidence that NO was involved in the attenuation by the E of the contractile responses induced by the 5-HT1D receptor agonists. 6. In the presence of an intact E and L-NAME, contractile responses elicited by 5-HT and Sum were competitively antagonized by the non-selective 5-HT1D receptor antagonist, methiothepin (pA2: 9.4 and 8.8; slopes: 0.66 and 0.81, respectively) and the highly selective 5-HT1D receptor antagonist, GR 127935 (pA2: 9.0 in each case; slopes: 1.04 and 0.93, respectively) indicating that contractions were mediated through activation of a single population of 5-HT1D receptors. Contractile responses elicited by 5-CT were also competitively antagonized by methiothepin and GR 127935, but non parallel rightward shifts of the concentration-response curves were observed suggestive of the involvement of additional but as yet unidentified receptors in mediating the 5-CT-induced responses. 7. In conclusion, the efficacy, but not the potency, of 5-HT, 5-CT and Sum in evoking 5-HT1D receptor-mediated contractile responses are subject to a substantial inhibitory influence of the E and of an EDRF (probably NO).     

Association study between schizophrenia and dopamine D3 receptor gene polymorphism

Crocq et al. [1992: J Med Genet 29:858-860] reported the existence of an association between schizophrenia and homozygosity of a BalI polymorphism in the first exon of the dopamine D3 receptor (DRD3) gene. In response to this report, further studies were conducted; however, these studies yielded conflicting results. In the present study, we examined 100 unrelated Japanese schizophrenics and 100 normal controls to determine any association between this polymorphism and schizophrenia. Results suggest that neither allele nor genotype frequencies of the DRD3 gene in the schizophrenics as a whole are significantly different from those of the controls. Further, we found no association between any allele or genotype and any clinical subtype based on family history of schizophrenia and age-at-onset. A significantly high frequency of homozygosity of a dopamine D3 receptor gene allele was not observed in the schizophrenics as a whole, or in clinical subtypes. Our results suggest that an association between the dopamine D3 receptor gene and schizophrenia is unlikely to exist.     

The effect of clozapine on preexisting tardive dyskinesia

Since the 1950s, the main treatment for schizophrenia has been the use of neuroleptic therapy. However, these medications may produce tardive dyskinesia in those patients who require prolonged neuroleptic treatment. With the advent of clozapine, patients with preexisting tardive dyskinesia began therapy and their symptoms did not worsen--and, in many cases, their symptoms improved dramatically. In this study, the mean Abnormal Involuntary Movement Scale (AIMS) scores from baseline to 6 months are compared for 12 patients in a private partial hospitalization program for schizophrenia. The findings reveal a drastic decrease in AIMS scores after 1 month of clozapine therapy and a steady decrease in scores throughout the 6 months of analysis.     

Neuroleptic-induced acute extrapyramidal syndromes and tardive dyskinesia

Neuroleptic drug-induced acute extrapyramidal symptoms and later-onset tardive dyskinesia are major limitations to these valuable drugs. Each of these disorders can be described by special risk factors that include patient characteristics, drug factors, and temporal considerations. The limitations that derive from these motor side effects have been one of the major reasons propelling the search for neuroleptic drugs that are free of these side effects. Strategies for managing the acute and late-onset extrapyramidal syndromes are presented. Significantly more research is needed, however, on all these disorders before a unified and cohesive explanation can account for these seemingly disparate syndromes. New medications, which effectively treat schizophrenia and are free of acute extrapyramidal syndromes and tardive dyskinesia, will be a giant step forward in patient care and our knowledge of the mechanisms controlling both mental function and motor control.     

Genetic relationship between dopamine transporter gene and schizophrenia: linkage and association

This experiment was aimed at comparing the sensorimotor correlates of fimbria-fornix lesions made with either a classical aspiration technique that also removes part of the overlying cortical structures, or an electrolytic one that does not encroach upon these cortical structures. About 4 months after lesion surgery, Long-Evans female rats which had sustained an aspiration or an electrolytic fimbria-fornix lesion at the age of 90 days were tested to measure their beam-walking performance as an index for their sensorimotor capabilities. We found that after an aspiration lesion, the rats presented sensorimotor deficits which did not occur after an electrolytic lesion. After having found that electrolytic lesions of the fimbria and the fornix produced neurochemical deficits (in the dorsal hippocampus) and cognitive alterations close to those resulting from aspiration lesions, it is concluded from the present experiment that the electrolytic lesion technique is an interesting alternative to an aspiration technique, essentially because the former does not induce the sensorimotor deficits due to the partial damage that an aspiration technique produces in the medial parietal cortex. As the electrolytic lesion technique may minimize the risk of introducing a sensorimotor bias in the accuracy of cognitive evaluations, the present result might be of interest to neuroscientist using a fimbria-fornix lesion paradigm in order to investigate the efficacy of drugs, grafts or other treatments on the recovery from cognitive deficits.