慢病毒介导bFGF基因修饰的骨髓基质细胞对脑梗死后血管新生的影响

目的探讨慢病毒介导碱性成纤维细胞生长因子（basic fibrobla stgrowth factor,bFGF）基因修饰的骨髓基质细胞（bone marrow stromal cells,BMSCs）对脑梗死后血管新生的影响。方法利用慢病毒载体介导bFGF基因修饰BMSCs,获得稳定转染bFGF的BMSCs。脑梗死后1d立体定向移植至梗死灶周围。在MCAO术前及术后1、3、7、14d进行神经功能评分。术后14d股静脉注射异硫氰酸荧光素右旋糖酐（FITC-dextran）标记微血管,结合共聚焦显微镜和3DDoctor3．5版软件分析梗死灶周围区微血管的直径、面积及血管分支数目。结果bFGF-BMSCs组术后3d神经功能恢复明显优于对照组与BMSCs组（P〈0．05）,BM—SCs组和bFGF-BMSCs组术后7d及14dmNSS评分显著低于对照组（P〈0．05）,而且bFGF-BMSCs组神经功能恢复好于BMSCs组（P〈O．05）。bFGF-BMSCs组微血管直径、分支数目及面积显著性高于对照组（P〈0．01）和BMSCs组（P〈0．05）。结论bFGF修饰的B^假瞄能更好地促进脑梗死后神经功能恢复及血管新生。     

HIF-1α基因修饰神经干细胞移植对大鼠损伤脊髓NF200和GFAP表达的影响

【摘要】目的研究低氧诱导因子-1α（HI-1α）基因修饰的神经干细胞移植对大鼠脊髓损伤后神经丝蛋白200（NF200）和胶质纤维酸性蛋白（GFAP）表达的影响及意义。方法采用电控脊髓损伤打击装置制作大鼠脊髓损伤模型。按随机数字表将120只SD大鼠平均分为4组：假手术组（Sham组）,单纯损伤组（SCI组）,神经干细胞组（NSC组）和HIF-1α基因修饰NSC组（HIF—NSC组）。应用免疫组化法检测受伤脊髓中HIF-1α、NF200和GFAP的表达。结果HIF-NSC组中HIF-1αt免疫阳性细胞平均光密度值比其他各组各时间点均高（P〈O．01）,且表达高峰延迟至移植后14d;除第1天外,HIF—NSC组NF200表达比SCI组和NSC组明显增高（P〈0．05）,移植后28dNF200免疫阳性轴突数目也比SCI组和NSC组明显增多（P〈0．01）;移植后7d、14d、28dGFAP免疫阳性细胞面积均比SCI组和NSC组明显减少（P〈0．01）。结论HIF-1α基因修饰NSC移植可引起HIF-1α在损伤脊髓内有效表达,且能明显的促进NF200的表达,并能在脊髓损伤的后期抑制GFAP的表达。这提示HIF-1α基因修饰的NSC移植可减少受伤脊髓中胶质细胞的增生和胶质疤痕的形成,促进轴突再生。     

颈交感神经干离断对局灶性脑缺血再灌注后大鼠海马iNOS表达的影响

目的采用颈交感干离断（TCST）模拟星状神经节阻滞，观察其对局灶性脑缺血再灌注损伤（CIRI）大鼠脑梗死容积及海马诱导型一氧化氮合酶（iNOS）表达等的影响，并探讨其脑保护作用的机制。方法将大鼠随机分成实验组（A组）、对照组（B组）和假手术组（C组）；采用线栓法行大脑中动脉栓塞（MCAO）制作大鼠局灶性CIRI模型，A组于TCST后即行MCAO，2h后再恢复灌注；B组为单纯CIRI组；C组仅完成与A组相似的手术步骤但不造成MCAO、不行TCST；再灌注24h后观察各组大鼠神经行为学评分、脑梗死容积及海马iNOs的表达变化。结果A组大鼠脑梗死容积和神经行为学评分均低于B组（P〈0．05）；与A组、C组相比，B组大鼠海马iNOS的表达增加（P〈0．05），而A组与C组间无显著差异（P〉0．05）。结论TCST可通过下调大鼠海马iNOS的表达而对局灶性CIRI发挥脑保护作用。     

侧脑室注射质粒pLXSN介导bcl-2基因对大鼠脑梗死及BDNF影响的研究

目的 研究大鼠短暂大脑中动脉闭塞（MCAO）模型经侧脑室注射质粒pLXSN介导bcl-2基因后，该基因对脑梗死及脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）表达的影响。方法取135只Wistar大鼠随机分配为3组,每组45只．对照组为脑室注射生理盐水和空质粒两组．治疗组为脑室注射Bcl-质粒pLXSN介导bcl-2基因。以改良线栓法制备短暂缺血2h脑梗死模型。每组分别于缺血后3、6、24、48、72h为时间点。分别测量梗死体积变化以及BDNF蛋白的表达。结果MCAO后24、48、72h．梗死体积治疗组显著小于对照组（P〈0．05）；3、6h时间点无显著变化（P〉0．05）。MCAO后24、48、72h。治疗组Bcl-2和BDNF蛋白的表达较对照组显著增加（P〈0．01）．而3、6h时间点无显著改变（P〉0．05）。结论脑室注射质粒pLXSN介导bcl-2基因对短暂脑缺血有治疗作用．并可增加BDNF表达。上调BDNF表达所起的神经保护作用可能是短暂脑缺血后bcl-2基因的治疗作用机制之一。     

血管紧张素Ⅱ-1型受体拮抗剂对自发性脑出血大鼠脑组织中VEGF含量的影响

目的研究血管紧张素Ⅱ-1型受体（AT1R）拮抗剂对脑出血后脑组织中血管内皮生长因子（VEGF）含量和脑水肿的影响及其神经保护作用。方法140只雄性大鼠按随机数字表法分为正常对照组,脑出血组和治疗组。脑出血组和治疗组大鼠建立脑出血模型,治疗组给予氯沙坦灌胃。各组动物均参与盲法改良神经功能损伤严重程度评分（mNSS）评定神经功能。正常对照组于24h后,治疗组和脑出血组脑出血24h、48h和72h后测定脑组织中VEGF含量和脑组织含水量。结果脑出血后24h,48h和72h治疗组和脑出血组的mNSS评分显著高于正常对照组（P〈0．01）。脑出血后各时间点治疗组mNSS评分显著低于脑出血组相应的各时间点的mNSS评分（P〈0．05）。脑出血后24h、48h和72h,脑出血组和治疗组脑组织含水量和VEGF含量均显著高于对照组（P〈0．05）。脑出血组脑出血后各时间点脑组织中VEGF含量均高于治疗组（P〈0．05）。结论ATlR拮抗剂对自发性脑出血后脑组织中VEGF的表达有抑制作用,同时也减轻了脑水肿,并对神经功能有保护作用。     

VEGF表达对大鼠坐骨神经嵌压性损害的神经保护作用

目的 探讨血管内皮细胞生长因子（VEGF）的表达对周围神经嵌压症病理损伤和神经功能损害的保护作用。方法 将80只SD大鼠按体重随机分层分组制作坐骨神经嵌压性损害的动物模型，取嵌压后第12小时、72小时、7天与第4周的大鼠坐骨神经，分别采用免疫组化与病理学、电生理学的方法检测VEGF水平与病理变化、神经传导速度、脊髓神经元计数等，并将各项检测结果进行对比，运用正常对照组、模型组、前列地尔组和盐酸丁咯地尔组采用SAS统计软件9．1．3进行方差分析统计处理。结果 （1）嵌压大鼠坐骨神经后，除正常对照组外12h起各组背根神经节细胞VEGF表达开始增加，72h达到高峰后开始下降，一周时接近正常水平。正常对照组只轻度表达。与正常对照组比较，其余各组各时段背根神经节细胞VEGF表达水平均显著增加（P〈0．05），前列地尔组和盐酸丁咯地尔组较模型组为优（P〈0．05）、表达的数量增加、持续时间延长。（2）嵌压大鼠坐骨神经4周后，正常对照组正常，其余各组病理变化、脊髓神经元计数均明显较正常对照组差（P〈0．01）；而前列地尔组和盐酸丁咯地尔组第4周时上述诸项结果虽较正常对照组差（P〈0．05），但均较模型组为优（P〈0．05）。（3）嵌压大鼠坐骨神经4周时，正常对照组正常，其余各组大鼠坐骨神经传导速度均明显较正常对照组差（P〈0．01）；而前列地尔组和盐酸丁咯地尔组第4周时上述诸项结果虽较正常对照组差（P〈0．05），但均较模型组为优（P〈0．05）。（4）VEGF表达增加组之病理改变减轻、神经功能恢复增加。结论对于周围神经嵌压性损害，VEGF表达的增加可减轻周围神经病理损害、提高神经传导速度、促进周围神经损伤的修复。     

骨髓间充质干细胞自体移植治疗大鼠脑冷冻伤的实验研究

目的探索骨髓间充质干细胞（MSCs）对脑损伤的治疗作用。方法将Wistar大鼠自体骨髓MSCs在体外扩增并经Brdu标记后，通过颈内动脉注射将其植入冷冻伤脑水肿动物体内，从组织化学和神经功能评分两个方面观察骨髓MSCs自体移植的治疗作用。实验动物分为4组；A组给予常规治疗；B组给予干细胞自体移植；C组在进行干细胞自体移植的同时给予神经节苷脂和丹参注射液治疗；D组在干细胞自体移植前给予罂粟碱开放血脑屏障。结果经颈内动脉注射的Brdu标记的大鼠自体骨髓MSCs细胞可向脑损伤区域迁移。B、C、D组Brdu阳性细胞的数量和神经功能恢复的程度均高于A组（P〈0．05）。与B组相比，C组未增加Brdu阳性细胞的数量，但是神经功能恢复的程度明显升高（P〈0．05）。D组Brdu阳性细胞的数量、神经功能恢复的程度均高于B组（P〈0．05），但神经恢复的程度与C组相比无明显差异（P〉0．05）。结论骨髓间充质干细胞可以通过循环系统向脑损伤区迁移而发挥其治疗作用。     

BDNF和神经干细胞联用对穹隆海马伞切割鼠基底前脑p75NGFR阳性神经元数及其形态学的影响

目的研究神经干细胞（NSC）和脑源性神经营养因子（BDNF）联合治疗对穹隆海马伞切割鼠基底前脑p75^NGFR阳性神经元厦其形态学的影响。方法切断SD大鼠左侧穹隆海马伞模拟AD大鼠模型，利用无血清培养技术获得新生SD鼠的海马NSC。基底前脑注射NSC，同时侧脑室注射BDNF,4周后行免疫组化结合图象分析技术观察各组大鼠基底前脑p75^NGFR阳性神经元厦其形态学变化。结果损伤组大鼠p75^NGFR阳性神经元数在内侧隔核（MS）和斜角带（VDB）较正常组明显下降（P〈0．01）；移植组细胞数较损伤组有改善（P〈0．05）；与正常组相比较，联合组免疫阳性神经元数无显著下降（P〉0．05）。形态学参数测试结果显示，p75^NGFR阳性神经元的面积、周长在4组中的改变类似p75^NGFR阳性神经元数。结论NSC和BDNF联用较单独使用BDNF或NSC更好地增加p75^NGFR阳性神经元数及其形态学参数。     

依达拉奉对急性脑梗死患者神经元特异性烯醇化酶变化的影响

目的观察依达拉奉对急性脑梗死患者的神经元特异性烯醇化酶（NSE）变化的影响及评价其对脑梗死的治疗效果。方法选择76例急性脑梗死患者在治疗前、治疗第3d和治疗1周后血清NSE变化和神经功能缺损评分变化。结果急性脑梗死常规治疗组和依达拉奉治疗组治疗前血清NSE均高于正常对照组（P〈0．01），依达拉奉治疗第3d时，患者血清NSE浓度明显下降，低于常规治疗组。神经功能缺损评分低于常规治疗组（P〈0．05）。结论依达拉奉有保护脑神经元作用，并能有效改善急性脑梗死的神经功能缺损。     

抑制 p53 通路促进移植神经干细胞在脑缺血区的存活简

目的探讨一种提高移植神经干细胞（neural stem cells,NSC）在脑缺血区存活的方法。方法原代培养胚胎NSC并鉴定。采用改良Longa线栓法成功制作60只大鼠大脑中动脉阻塞模型,随机分为3组：对照组（n=12）、NSC移植组（n=24）和NSC＋P53抑制剂（pifithrin—α,PFT—α）移植组（n=24）。以上3组在脑梗死模型建立24h后,分别于脑内特定部位注射等量DMEM／F12培养液、NSC悬液和NSC＋PFT-α悬液。细胞移植12h、24h和7d后行免疫荧光染色,检测P53蛋白表达和移植NSC的存活情况。结果移植后12h,NSC移植组P53蛋白主要表达在移植细胞的细胞核,而NSC＋PFT-α移植组P53蛋白的表达主要位于移植细胞的细胞质。移植后7d,NSC＋PFT-α移植组NSC的存活数为（18．20±2．69）／高倍镜视野,NSC移植组为（13．06±3．20）／高倍镜视野,两组间比较差异具有统计学意义（P〈0．05）。结论NSC移植联合PFT-α对提高移植细胞的存活率有重要意义。     

Treatment Considerations in Anticonvulsant Monotherapy

Summary: The long-standing practice of polypharmacy in treating epilepsy is giving way to use of monotherapy. Monotherapy can improve seizure control as well as reduce the risk of serious idiosyncratic reactions, dose-related side effects, and complex drug interactions. Monotherapy also offers improved compliance and cost-effectiveness. The basis of monotherapy is accurate diagnosis and assessment of the patient's seizure type(s), followed by selection of a single appropriate anticonvulsant drug. Many patients currently treated with multiple anticonvulsants can be successfully converted to monotherapy with a carefully monitored program in which troublesome and redundant drugs are gradually withdrawn from the therapeutic regimen.     

Dextromethorphan: Cellular Effects Reducing Neuronal Hyperactivity

Summary: Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and an-tiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N -methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.     

Pediatric Epilepsy Surgery

Summary: The use of implantable arrays of epidural electrodes has made it possible to carry out extraoperative electrocorticography (ECoG) and functional localization in the awake child. This has permitted cortical excisions that are determined by criteria similar to those obtained during surgical procedures performed under local anesthesia in adults. In addition, the method also permits simultaneous ECoG and video monitoring during the child's symptomatic seizures, providing additional important localizing information that is impractical to obtain in operations under local anesthesia. We report our experience with 75 children, ages 5 months to 15 years, whom we have managed with epidural electrode arrays. The method of extraoperative ECoG is described and illustrative cases are presented to demonstrate its feasibility and utility in children. In addition, we call attention to gliomas as a common cause of chronic focal seizures in children. Of 49 children undergoing resection and followed for from 1 to 14 years (mean of 5.8 years), 32 (65%) are either seizure free or have had a significant reduction in seizure frequency that has unambiguously improved their quality of life. The results are analyzed further by relating the surgical outcome to each of the pathologic entities that caused the seizures. This analysis reveals the variety of neurological conditions that commonly cause intractable focal seizure disorder in children and distinguishes those pathologic entities in which the seizure disorder is apt to respond to surgical intervention from those that will not.     

Un nouveau cadre conceptuel de travail pour une psychiatrie revisitée ? Introduction à deux articles de E. Kandel

In two articles which appeared in the American Journal of Psychiatry and that were subsequently translated for Évolution Psychiatrique, E. Kandel examines the bases for a reinterpreted psychiatry that is prepared to confront the major challenge of the 3rd millenium: that of insight into the mind and brain. This requires a major reorganization of the discipline, which involves a reinvestment of the scientific approach and a critical  assessment of the data provided by psychoanalytical psychiatry and cognitive neurosciences. Seven concepts have therefore been proposed for interactive re-examination: consciousness, the unconscious, memory, emotion, development, desire, impulse. The dynamic relations existing between genetics and the environment allow one to see how evolutions are possible from actions at different levels, both psychotherapeutic and pharmacological. Imaging and other techniques provide additional objective information to the process of human interaction which remains the basis of psychiatry. A common framework for psychiatry and the neurosciences, a reconsideration and renewal of the psychoanalytical approach are both possible and necessary.     

Opioids and the developing organism: A comprehensive bibliography, 1984–1988

A comprehensive bibliography of the literature concerned with opioids and the developing organism for 1984-1988 is presented. Utilized with companion papers (Neurosci. Biobehav. Rev. 6:439-479; 1982; 8:387-403; 1984), these articles cover the clinical and laboratory references beginning in 1875. For the years 1984, 1985, 1986, 1987, and 1988, a total of 877 citations were recorded. A series of indexes accompanies the citations in order to make the literature more accessible. These indexes are divided into clinical and laboratory topics, and subdivided into such topics as the type of opioid explored and the general area of biological interest (e.g., physiology).     

La biologie et le futur de la psychanalyse : un nouveau cadre conceptuel de travail pour une psychiatrie revisitée

The American Journal of Psychiatry has received a number of letters in response to my earlier “Framework” article (1). Some of these are reprinted elsewhere in this issue, and I have answered them briefly there. However, one issue raised by some letters deserves a more detailed answer, and that relates to whether biology is at all relevant to psychoanalysis. To my mind, this issue is so central to the future of psychoanalysis that it cannot be addressed with a brief comment. I therefore have written this article in an attempt to outline the importance of biology for the future of psychoanalysis.     

Facteurs de risque environnementaux à la schizophrénie

Schizophrenia is currently a major concern, its prevalence being estimated at around 1% and its social consequences being severe. The elucidation of the pathophysiology of the disease is difficult due to the great variability of clinical expressions, the instability of the clinical symptoms during the evolution and the absence of reliable biological markers. The existence of a familial aggregation in schizophrenia is well known, the risk of presenting the disease for first-degree relatives of patients being 5 to 10 times higher than the risk observed in the general population. The genetic component was further confirmed by twin and adoption studies. Although the concordance for the disease is higher (40 to 70%) among monozygotic twins as compared with dizygotic twins (15%) it does not reach 100%, which implies that environmental factors modulate the effects of the genotype. However, the role of these factors and especially their interaction with genetic factors remain unclear but the implications of some specific environmental factors are well documented by recent research data. The current literature on sex differences in schizophrenia is consistent. Several studies have suggested that male and female patients may differ in age at the onset and expression of clinical symptoms. Complications during pregnancy or birth-giving may increase the risk of developing schizophrenia later in life. The major complications are oxygen deprivation during pregnancy, bleeding, maternal malnutrition or infection (exposure to influenza, for example). A low birth weight is associated with an increased risk of schizophrenia. Psychoses are more common among people living in an urban environment and among those born during winter months. Schizophrenia is probably more prevalent in people who are living promiscuously, are subject to toxic abuse, poor nutrition and stress but here more precise data are needed. Moreover, immigrants have a higher risk of developing psychotic disorders. In addition, head traumas are associated with an increased risk of schizophrenia. Though they are contentious, some studies suggest that substance abuse (cannabis use in European countries) is related to the development of schizophrenia, especially in people with genetic vulnerability. Moreover, substance misuse may worsen the symptoms. If the environment is sufficiently stressful, people with a high genetic vulnerability will develop some degree of mental illness, including schizophrenia. Conversely, a less stressful or a protective environment may decrease the risk of its onset in persons with a predisposition to schizophrenia.     

Introduction: Goals

Summary: Epilepsy is characterized by recurrent seizures. Many epilepsies with focal seizures as well as convulsive generalized seizures respond satisfactorily to antiepileptic drugs (AEDs) that reduce repetitive firing (e.g., phenytoin, carbamazepine, and valproate) or that augment GABA_A-mediated inhibition (e.g., phenobarbital and benzodiazepines). A number of drugs presently under development, such as NMDA receptor antagonists, loreclezole, losigamone, meth-ysticine, and dextromethorphan, are promising in acute animal models of otherwise drug-resistant convulsant activity. As a result of recent studies in both experimental models and surgically resected human epileptic brain, the prospects for development of AEDs have significantly improved. Several new AEDs recently have reached the commercial market or are in experimental or clinical trials. A comparative presentation of the standing of the new AEDs with respect to their efficacy and side effects is necessary, but still very difficult. Because initial experience with new AEDs is restricted to populations with severe drug-resistant epilepsy, the crucial question whether potential new AEDs can alter prognosis is not yet definitively answered. There is a clear need to compare the effects of standard AEDs and new AEDs in naive patients and over longer follow-up periods. Moreover, because of the strong desire to develop antiepileptic therapy that directly treats the primary etiology of a given epileptic syndrome , or modifies the neurobiological processes that cause recurrent seizures, better experimental epilepsy models for chronic epilepsy and further clinical studies are necessary to increase the knowledge on the pathophysiology of distinct epileptic syndromes. In this respect, studies on the differences between responders and nonresponders to a given AED treatment are extremely valuable.