基于生物信息学方法的精神分裂症炎症机制研究

目的:通过生物信息学方法研究精神分裂症涉及的炎症机制。方法:从GEO数据库中获取GSE12679基因芯片中11例精神分裂症患者和5名健康对照者背外侧前额叶皮质(DLPFC)内皮细胞转录数据,并通过生物信息学方法找出差异表达基因,通过DAVID在线数据库的基因本体(gene ontology,GO)功能注释和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)通路富集分析模块找出差异表达基因富集的功能和通路。结果:在精神分裂症患者与正常对照的DLPFC内皮细胞找到389个差异表达基因,其中145个基因表达上调,244个基因表达下调;以P0.05为标准,找到差异表达基因富集于65个GO条目以及17条KEGG通路,富集的GO条目以及KEGG通路均有涉及免疫机制,包括趋化因子、肿瘤坏死因子信号通路以及Toll样蛋白信号通路等。结论:精神分裂症的病理生理过程或许涉及炎症机制。     

颅内动脉瘤破裂关键基因的生信分析

目的 探讨颅内动脉瘤破裂的关键基因.方法 采用生信分析方法,GEO数据库下载数据集GSE13353、GSE15629、GSE54083,R语言筛选差异表达基因(DEG),WGCNA算法分析动脉瘤破裂关键基因,采用GO和KEGG分析关键基因的生物学功能,GSEA软件进行基因富集分析.应用GSE122897数据集进行验证....     

精神分裂症患者血浆外泌体微小RNA 差异表达谱及其生物信息学分析

目的:探讨精神分裂症患者及正常人群血浆外泌体微小RNA(miRNA)的差异表达，初步了解差异表达miRNA在精神分裂症病程发展中的作用。方法:采用高通量测序技术检测48例精神分裂症患者和48名健康对照者的血浆外泌体miRNA的表达水平，构建miRNA差异表达谱。预测表达差异显著的miRNA的靶基因，再对靶基因进行GO功能注释和KEGG通路分析，确定差异表达miRNA的主要生物学功能及其可能参与的信号通路。结果:与对照组相比，精神分裂症患者血浆外泌体共筛选出353个miRNA显著异常表达，其中157个表达上调，196个表达下调。通过GO富集和KEGG分析，上述差异表达的miRNAs主要涉及神经元细胞体、谷氨酸能突触、神经元间突触、突触前和突触膜等细胞组成，并主要参与轴突新生、化学突触传递调节、跨突触信号调节等生物过程，可能通过MAPK信号通路、PI3K Akt信号通路、TNF信号通路、Wnt信号通路、FoxO信号通路、多巴胺能突触及Hippo等信号通路参与精神分裂症的发生和发展过程。结论:经药治疗精神分裂症患者血浆外泌体中miRNAs存在显著的差异性表达，miRNA-206、miR-14...     

重型颅脑损伤病人外周血miRNA生物信息学分析

目的 通过生物信息学方法分析重型颅脑损伤（sTBI）病人外周血微小RNA（miRNA）的靶基因及功能。方法 从GEO数据库中检索获取sTBI病人和对照组外周血的基因芯片数据,应用生物信息学方法筛选差异表达的miRNA,并进行靶基因预测和生物学功能及信号通路分析,构建miRNA及靶基因的调控网络。结果 检索得到芯片GSE21854,筛选得到145个差异表达的miRNA,预测得到靶基因共580个。这些靶基因的功能主要为细胞增殖负性调控、转换生长因子β受体信号通路负性调控等,主要分布在Ras信号通路、转换生长因子β信号通路等。miRNA及靶基因的调控网络图显示hsa-miR-125a-5p、hsa-miR-760、hsa-miR-217、hsa-miR-199a-3p、hsa-miR-543是调控核心。结论 sTBI病人外周血存在差异性表达的miRNA,hsa-miR-125a-5p、hsa-miR-760、hsa-miR-217、hsa-miR-199a-3p、hsa-miR-543与sTBI的进展密切相关。     

基于GEO数据库的精神分裂症长链非编码基因LINC01020的筛选验证及其靶蛋白预测

目的:通过生物信息学方法识别与精神分裂症发生发展相关的长链非编码基因。方法:从GEO数据库中获取GSE17612基因芯片中28例精神分裂症患者和23名健康对照者大脑前额叶皮质(aPFC)转录数据，并通过生物信息学方法找出差异表达的长链非编码基因LINC01020,通过利用荧光定量PCR技术验证LINC01020在精神分裂症患者和健康对照者中的表达水平，通过NCBI数据库查询LINC01020的核酸序列，运用LncLocator在线网站进行亚定位预测，CatRAPID数据库进行蛋白结合位点预测，再对其靶蛋白进行蛋白网络互作分析，找出其关键蛋白。结果:精神分裂症患者aPFC内LINC01020表达上调，在精神分裂症患者外周血浆中，该基因表达水平下调，与脑组织中的表达水平呈反向联系，亚细胞定位在细胞质中，可与2064个编码蛋白发生作用，其中关键蛋白是核糖体蛋白家族。结论:LINC01020在精神分裂症脑前额叶皮质中和血浆中均有显著差异表达，与精神分裂症密切相关，定位在胞质中的LINC01020可能通过多作用位点广泛参与信使RNA转录，剪接，代谢等多种转录后调控机制参与精神分裂症的发生发展机制...     

线粒体分裂蛋白DRP1在胶质瘤中的表达及其临床意义

目的 研究线粒体分裂蛋白DRP1在胶质瘤中的表达和转录水平及其与患者预后的关系。方法 收集中国脑胶质瘤基因组图谱计划(CGGA)中mRNAseq＿325、癌症基因组图谱(TCGA)的胶质瘤数据和GEO数据库中的胶质瘤数据(GSE16011),以及适量的临床组织样本进行DRP1 mRNA与不同胶质瘤级别之间的转录分析,再进行mRNA的转录与不同级别胶质瘤之间的生存预后分析。再通过Western blot和PCR从14例Ⅳ级胶质瘤临床样本中检测DRP1的蛋白表达与mRNA转录水平。结果 (1) WHOⅡ级与Ⅲ级胶质瘤的DRP1 mRNA表达水平间的差异无统计学意义(P=0. 23),Ⅳ级胶质瘤的DRP1 mRNA表达水平显著低于Ⅱ级和Ⅲ级胶质瘤(均P 0. 05)。(2)检测14例Ⅳ级胶质瘤的临床样本发现,Ⅳ级胶质瘤的DRP1蛋白和mRNA表达水平均显著低于正常脑组织(均P 0. 05)。(3)原发性胶质瘤中DRP1的表达水平与生存时间显著相关,DRP1低表达患者的生存时间明显比高表达患者短(P 0. 000 1)。结论 线粒体分裂蛋白DRP1在胶质瘤中的表达和转录水平降低;并且胶质瘤患者的DRP1表达水平降低减少患者的生存时间。     

基于生物信息学技术探索精神分裂症发病的关键基因及诊断的生物标志物

目的 基于生物信息学分析精神分裂症发病的可能分子机制，并分析诊断精神分裂症的生物标志物。方法 选择基因表达综合数据库（GEO）中的GSE48072数据集，对31例精神分裂症患者和35名健康对照者的mRNA表达谱进行生物信息学分析。对筛选得到的差异基因进行功能富集分析。采用string数据库构建差异基因的蛋白-蛋白相互作用（PPI）网络，并通过Cytoscape软件筛选关键基因。关键基因的诊断价值通过受试者工作特征（ROC）曲线验证。结果 共筛选出82个差异基因。富集分析结果显示，差异基因主要集中在炎症、免疫调节和不饱和脂肪酸代谢中。筛选后获得CD244、GZMH、GZMA、KLRD1、GZMK 5个关键基因，ROC曲线下面积分别为0.817、0.725、0.724、0.717、0.693。结论 精神分裂症患者存在炎症通路、不饱和脂肪酸以及维生素代谢异常，CD244等5个相关基因的表达变化可作为精神分裂症发病诊断的生物学标志物。     

首发儿童精神分裂症患者脑源性神经营养因子水平及神经元凋亡研究

目的探讨首发儿童精神分裂症患者脑源性神经营养因子(BDNF)、β-微管蛋白III(Tuj-1)、胱天蛋白酶3(Caspase-3)的变化,为揭示儿童精神分裂症的病因和发病机制提供参考。方法以2015年8月-2018年3月在大理州第二人民医院就诊的符合《精神障碍诊断与统计手册(第4版)》(DSM-IV)诊断标准的儿童精神分裂症患者(n=35)为研究组,同期在大理州第二人民医院的体检儿童中随机选取健康儿童为对照组(n=30)。通过实时荧光定量逆转录-聚合酶链反应(RT-PCR)测定两组儿童血液中BDNF、Caspase-3和Tuj-1的mRNA表达水平。结果与对照组相比,研究组BDNF和Tuj-1 mRNA表达低(P0.05或0.01),Caspase-3 mRNA表达高(P0.01)。结论儿童精神分裂症患者的BDNF mRNA和Tuj-1 mRNA表达少,Caspase-3 mRNA表达多,BDNF mRNA、Tuj-1 mRNA和Caspase-3 mRNA可能与儿童精神分裂症相关。     

颞叶癫(癎)大鼠海马中miRNA表达谱的检测和分析

目的 探讨颞叶癫(癎)大鼠海马组织中miRNA分子表达谱的差异,为进一步研究相关miRNA在颞叶癫(癎)发病机制中的作用打下基础.方法 对同一父系和母系的子代大鼠,利用氯化锂-匹罗卡品化学诱导方法制备慢性颞叶癫(癎)大鼠模型.分别提取1只正常和3只颞叶癫(癎)大鼠海马组织的miRNA,采用高通量的miRNA微阵列芯片杂交,筛选颞叶癫(癎)海马组织中差异表达的内源性miRNA.结果 在大鼠海马组织中共检测到125个miRNA基因.与正常大鼠相比,颞叶癫(癎)大鼠海马组织中差异表达的miRNA有23个,其中有5个miRNA下调,18个miRNA上调.结论 与正常大鼠相比,颞叶癫(癎)大鼠海马组织中存在差异表达的miRNA分子,差异表达的miRNA分子可能参与癫(癎)的发病过程,具有潜在的研究价值.     

抗精神病药对精神分裂症患者血小板腺苷A2a受体基因表达的影响

目的 探讨未用药精神分裂症患者治疗前后血小板腺苷A2a受体(ADA2aR) mRNA表达量的变化及其与临床症状的相关性.方法 采用实时定量聚合酶链反应技术,对30例未用药精神分裂症患者(患者组)治疗前和治疗6周后进行血小板ADA2aR mRNA表达量测定,并与30名健康志愿者(对照组)进行比较;采用Pearson相关分析对患者组血小板ADA2aR mRNA表达量与精神分裂症临床症状进行相关性分析.结果 (1)治疗前,患者组血小板ADA2aR mRNA表达量(747.6±282.3)与对照组(692.7 ±286.7)比较,差异无统计学意义(P＞0.05);治疗第6周末,患者组血小板ADA2aR mRNA表达量(873.2 ±206.2)高于对照组(635.4±263.2)及患者组治疗前,差异均有统计学意义(P＜0.05).(2)患者组治疗前血小板ADA2aR mRNA表达量与病程(r=0.17)、PANSS总分(r=0.08)、阳性症状(r=-0.12)、阴性症状(r=0.08)、一般病理症状(r=0.12)均无统计学相关性(P＞0.05);治疗第6周末,患者组血小板ADA2aR mRNA表达量与病程PANSS总分(r=0.09)、阳性症状(r=-0.02)、阴性症状(r=0.26)、一般病理症状(r=-0.08)亦无统计学相关性(P＞0.05);患者组治疗前后血小板ADA2aR mRNA表达量差值与PANSS总分减分值(r=-0.31)、阳性症状减分值(r=-0.28)、阴性症状减分值(r=-0.14)、一般病理症状减分值(r=-0.11)均无统计学相关性(P＞0.05).结论 抗精神病药治疗可能对精神分裂症患者外周血小板ADA2aR基因表达产生影响,血小板ADA2aR基因表达变化可能与精神分裂症临床症状无明显联系.     

Diagnostic Difficulties and Treatment Implications

Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.     

Cognitive Dysfunction Associated with Antiepileptic Drug Therapy

Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.     

Carbamazepine Efficacy in Adults With Partial and Generalized Tonic-Clonic Seizures

Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.     

Etiologic and Preventive Aspects of Epilepsy in the Child–Bridging the Gap Between Laboratory and Clinic

Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.     

Predisposing and Causative Factors in Childhood Epilepsy

Summary: We review information from large studies of defined populations, examining the role of known factors and especially of prenatal and perinatal factors in contributing to nonfebrile seizure disorders of early childhood. We depend especially, but not exclusively, on the recently completed analyses from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, the NCPP. About 4% of children in the NCPP who had at least one non-febrile nonsymptomatic seizure by the age of 7 years had a previous seizure during acute neurologic illness, such as meningitis or during the acute illness after trauma. Many such seizures should potentially be preventable. Of children with seizures, 10% had had a neonatal seizure and 13% had had a febrile seizure. Among the hundreds of prenatal and perinatal factors explored as predictors of childhood seizure disorders, the principal predictors identified were congenital malformations of the fetus, cerebral and noncerebral; family history of certain neurologic disorders; and neonatal seizures. In agreement with the British National Child Development Study, labor and delivery factors in the NCPP appeared to contribute very little to childhood seizure disorders. Maldevelopment, rather than damage at birth to an initially intact nervous system, appeared to be the more common mechanism. Most seizure disorders of early childhood remained unexplained by the large set of prenatal and perinatal characteristics examined.     

Anticonvulsant Drugs and Cognitive Function: A Review of the Literature

Summary: Alterations of cognitive function are separate from disturbances of behavior seen in association with epilepsy. The nature of the cognitive disability may to a certain extent depend on the seizure type. Partial seizures, mainly derived from a temporal lobe focus, impair memory tasks, while generalized seizures seem to have more effect on attentional abilities. A number of studies, reviewed in this paper, suggest that anticonvulsant drugs further impair cognitive function. Maximal impairments are seen in patients receiving polytherapy: rationalization of polytherapy improves cognitive abilities. Studies in children and adults have allowed differentiation of the effects of various commonly used antiepileptic agents. Maximal cognitive deficits are seen with. phenytoin, while phenobarbital and sodium valproate induce moderate disturbances, and carbamazepine seems relatively free from such toxicity. Further research is needed on the interrelationship between types of seizure disorders, types of anticonvulsant medications, and cognitive function.     

Effects of NMD A- and AMPA-Receptor Antagonists on Different Forms of Epileptiform Activity in Rat Temporal Cortex Slices

Summary: Lowering extracellular magnesium induces different patterns of epileptiform activity in rat hippocampus and entorhinal cortex. Short recurrent epileptiform discharges in the hippocampus are stable over time, whereas seizurelike events (SLEs) in the entorhinal cortex, the subiculum, and the neighboring neocortex develop into late recurrent discharges which are not blocked by clinically employed antiepileptic drugs. We tested the sensitivity of the different epileptiform discharge patterns to. /V-methyl-D-aspartate (NMDA)- and non-NMDA-receptor antagonists. As NMDA-receptor antagonist we used dextrorphan, ket-amine, and 2-aminophosphonovalerate (2APV); as α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-receptor antagonist we employed the quinoxaline derivative glutamate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The findings show that the different patterns of epileptiform activity, including the late recurrent discharges, are sensitive to all NMDA-receptor antagonists. However, when dextrorphan was employed to suppress seizure-like events, later recurrent discharges did not develop during the remaining time course of the experiment. CNQX reversibly suppressed recurrent discharges in the hippocampus and SLEs in the entorhinal cortex. However, late recurrent discharges become insensitive to CNQX, even at a high concentration of 60 μM m. This finding suggests a prominent role for NMDA receptors in the generation of late recurrent discharges.     

The influence of comorbid depression on seizure severity

PURPOSE: To determine the relation between depressive symptoms and seizure severity among people with epilepsy. METHODS: A postal questionnaire was used to survey a nationwide community sample about seizures and depression. The Seizure Severity Questionnaire (SSQ) assessed the severity and bothersomeness of seizure components. The Centers for Epidemiological Studies-Depression scale categorized levels of depression. RESULTS: Respondents categorized as having current severe (SEV, n = 166), mild-moderate (MOD, n = 74), or no depression (NO, n = 443) differed significantly in SSQ scores (all p < 0.0001). People with SEV or MOD reported significantly worse problems than did those with NO depression for overall seizure recovery (mean, 5.3, 4.9, 4.5, respectively); overall severity (5.0, 4.5, 4.2); and overall seizure bother (5.3, 4.8, 4.4) (all p < 0.005). Cognitive, emotional, and physical aspects of seizure recovery also were rated worse among people with SEV than with NO depression (all p < 0.05). Symptoms of depression were significantly correlated with higher levels of all components of generalized tonic-clonic seizure severity (r = 0.33-0.48; all p < 0.0001), and partial seizures (r = 0.31-0.38; all p < 0.01). CONCLUSIONS: Clinically depressed people with epilepsy reported higher levels of perceived severity and bother from seizures, as well as greater problems with overall seizure recovery than did nondepressed people experiencing similar types of seizures. The pervasive influence of depressive symptoms on reports of seizure activity suggests that people with epilepsy should be screened for depression. These data highlight the importance of detecting and treating depression among people with epilepsy.     

Une phénoménologie de la dépendance à l'alcool. Une expérience primordiale de la « nostrité »

The phenomenological approach to alcoholism interestingly focuses on specific dynamics of interpersonal relationships displaying the founding of the Self from a primary “us” and its original basis in the human feast. Priorities for treatment intervention recommend to involve social setting and relationships of the patients, reaching their active participation to a motivational and long term group treatment, underlying the specific therapeutic effect of world exchanges. Biopsychosocial determination of alcoholism could be primarily based on components of interpersonal relationships. Regarding social background, drinking is one of the most famous supports for the achievement of the feast, a founding marker of present time. Taking an existential point of view, the feast appears as the heart of mankind because it presents a primary “us”, a plural state which indicates the beginning and founding of the Self from the others. During the feast, we regularly have to reach our Self from the “us” while avoiding two main dangers, drunkenness, an increase in the dizziness of upright verticality, and addiction, an opposite vertical surrender to alcohol and falling into in the alcoholic relapse, both situations imply a spatial domination and the disappearance of others. Treatment programs of alcohol addicts need to integrate the necessity of reaching the existential basic trust from the support of a group to the appropriation of the community which can be defined as an original “usness”.