大鼠脑缺血区局部炎症和细胞免疫反应的研究

目的了解大鼠脑缺血区局部炎症和细胞免疫的形态和位置,探讨其与缺血性脑损伤的病理关系.方法用免疫组化方法观察大鼠大脑皮质缺血区的单核/巨噬细胞、小胶质细胞和T淋巴细胞的形态分布和浸润时程及其相关免疫分子的表达.结果脑缺血3 d后,巨噬细胞激活抗原1(ED1)阳性细胞聚集于大脑皮质缺血性半暗带区;脑缺血1周时,其数量显著增加,并迁移到脑缺血中央区,此变化持续到脑缺血后2周.脑缺血后3 d,缺血性半暗带区内的OX42阳性细胞发生肥大和增生性改变,并持续到脑缺血后2周.OX6阳性细胞在半暗带区呈分支状,而在脑缺血中央区为圆形的阿米巴样细胞.阳性细胞在脑缺血后3 d出现,脑缺血1周时,其形态和数量变化最显著,并持续到脑缺血后2周.在脑缺血3 d时,大量白细胞分化抗原(CD3)阳性细胞聚集于大脑皮质缺血性半暗带区,以血管壁及其周围为主.脑缺血1周时数量最多,并迁移到脑缺血中央区.脑缺血后2周时,阳性细胞稍减少.结论脑缺血诱导单核/巨噬细胞、小胶质细胞和T淋巴细胞在大脑皮质缺血区聚集和激活,并表达相关的免疫分子,提示脑缺血启动了脑组织局部炎症和免疫反应,此可能与缺血性脑损伤有关.     

局灶脑缺血再灌注后成年大鼠大脑MyT1表达变化

目的 探讨脑缺血再灌注后成年大鼠大脑MyT1表达变化及其意义.方法 以线栓法制作成年SD大鼠局灶性脑缺血再灌注模型(阻塞90min再灌注1,7,14d);用免疫荧光组织化学法检测脑缺血再灌注成年大鼠早期大脑梗死中心区、梗死周边区和缺血对侧区MyT1阳性细胞数量.结果 (1)脑缺血再灌注后各时间点梗死中心区MyT1阳性细胞数明显减少;(2)脑缺血再灌注后梗死周边区MyT1阳性细胞数从脑缺血后第1天开始增加;脑缺血后7d和14d时,各组大鼠MyT1阳性细胞增加数较之对照组大鼠有显著的差别.结论 成年SD大鼠脑缺血再灌注后梗死周边区MyT1表达显著增加,可能参与了少突胶质前体细胞的发育过程,调节髓鞘蛋白基因的转录,参与缺血性脑损伤的修复过程.     

川芎嗪对脑缺血保护作用的实验研究

白细胞、单核／巨噬细胞与脑血管病的发生、发展和预后密切相关。白细胞、单核／巨噬细胞在脑梗死区的浸润使脑损伤加重,而缺血区微血管内皮细胞粘附分子的表达,是白细胞和单核细胞浸润的先决条件。中药川芎嗪具有抗血小板聚集、扩张小血管和改善微循环的作用。最近的研究报道,其对白细胞和小胶质细胞的浸润及激活有明显的抑制作用。为此,我们观察了川芎嗪对实验大鼠脑缺血区血管内皮细胞粘附分子（ICA－1）mRNA和蛋白质的表达以及对脑缺血时单核／巨噬细胞浸润的影响,探讨川芎嗪在脑缺血病理损伤中的作用及其机制。资料：Ⅱ级雄性S…     

大鼠脑缺血再灌注时小胶质细胞或巨噬细胞的活化与增殖

目的 研究脑缺血再灌注时小胶质细胞/巨噬细胞的活化与增殖。方法 阻塞大鼠大脑中动脉2h再灌注0.5-48h制成脑缺血模型，以免疫组化与凝集素（GSI-B4）组化法观察小胶质细胞/巨噬细胞在脑组织的分布及形态特点。结果 0.5h时，呈现有大量形态各异的GSI-B4阳性小胶质细胞与巨噬细胞，随后下降；12-48h，数量再次且持续增高，并呈不同的形态，视前区，杏仁皮质核浅层及其脑膜有阳性巨噬细胞，3-48h，在缺血区有CD45阳性的活化小胶质细胞；缺血再灌注各组，室管膜及室管膜下层有PCNA强阳性细胞，杏仁核，杏仁皮质核，视前区及其软脑膜有PCNA强阳性细胞；有PCNA与CD45双标阳性的细胞。结论 缺血再灌注时，不同区域小胶质细胞形态呈明显的异形性，外源性巨噬细胞可能来自血单核细胞的浸润，脑膜巨噬细胞和室管膜及室管膜下层细胞的增生，浸润和迁移；CD45是小胶质细胞活化的标志。     

大鼠持续脑缺血后星形胶质细胞的时空分布及其变化

目的 本实验研究星形胶质细胞在持续脑缺血后的时空分布及其变化。方法 选用SD雄性大鼠54只，随机分为分成假手术组和手术组。手术组又按缺血时间（3、6、12、24及48 h）分为5个亚组。假手术组和每亚组各9只大鼠。采用颈内动脉线栓加环扎法复制大鼠持续脑缺血模型，相应时间点灌注取脑，常规固定包埋切片，HE和TdT介导的dUTP缺口末端标记（TUNEL）、胶质纤维酸性蛋白（GFAP）染色。结果 随着持续脑缺血时间的延长，中心区神经细胞及星形胶质细胞的数量逐渐减少，缺血边缘区凋亡的神经细胞数量逐渐增多，而星形胶质细胞在12 h达到最低点之后，数量逐渐增多，并呈空泡状改变。结论 在持续缺血12 h之后，缺血中心区与半暗带区星形胶质细胞数量变化不一致，在半暗带其数量逐渐增多，提示星形胶质细胞在缺血后的不同阶段，其作用可能不同。     

成年大鼠脑创伤后脑组织碱性成纤维细胞生长因子表达的变化

目的:研究液压冲击性脑损伤后成年大鼠脑组织碱性成纤维细胞生长因子(bFGF)表达时程和空间分布的变化。方法:制作液压冲击性脑损伤模型,免疫组织化学法动态检测内源性bFGF的变化。结果:在正常脑组织中,bFGF免疫活性低水平表达,且主要位于胶质细胞核及神经元细胞质中。液压冲击伤后bFGF免疫活性增强,聚集核周边。此外,部分bFGF免疫活性聚集于神经元周围间隙中半定量分析显示液压冲击伤后3d,大脑皮质bFGF阳性细胞数量较正常对照组升高4.8倍;伤后7 d,bFGF免疫活性达高峰,伤后30 d消失。结论:液压冲击伤后,损伤的胶质细胞和神经元暂短地合成bFGF,并以旁分泌和自分泌形式起作用。     

NBQX对脑缺血再灌注后成年大鼠大脑少突胶质前体细胞的保护作用

目的 探讨脑缺血再灌注后成年大鼠大脑少突胶质前体细胞的变化及MK-801和NBQX对其保护作用.方法 以线栓法制作成年SD大鼠局灶性脑缺血再灌注模型(阻塞90min再灌注1d、7d和14d),分别向其大脑皮质缺血区立体定向注射5mmol/L 的MK-801和50 mmol/L的NBQX各1μl,用免疫荧光组织化学法检测脑缺血再灌注后成年大鼠早期大脑梗死中心区、梗死周边区和缺血对侧NG2和O4阳性细胞数量.结果 脑缺血再灌注后成年大鼠大脑皮质梗死中心区NG2 和O4阳性细胞逐渐减少, NBQX组大鼠NG2和O4阳性细胞数减少的幅度较少.脑缺血再灌注后梗死周边区NG2和O4阳性细胞数逐渐增加,NBQX组大鼠增加更明显,而MK-801组与生理盐水组无明显差别.结论 成年SD大鼠脑缺血再灌注后梗死周边区少突胶质前体细胞增多.NBQX对少突胶质前体细胞早期的缺血性损伤有保护作用.     

缺血再灌流时胶质源性神经营养因子在大鼠脑组织的分布特点

目的 观察大鼠脑缺血再灌流时胶质源性神经营养因子（GDNF）在脑组织的分布特点，及其在缺血性脑损伤中的作用。方法 阻断大鼠大脑中动脉（MCA）血流2小时，再灌流0．5－48小时制成局灶性脑缺血模型，HE染色评价缺血性脑损伤的组织学特点，免疫组化法观察GDNF在脑组织的分布特点。结果 再灌流0．5小时组有灶性缺血区，24小时组面积最大，包括视前区、纹状体和皮质。再灌注6小时组开始出现神经元不可逆变性，24小时组梗死形成。再灌注0．5小时组，缺血区皮质神经元GDNF弱阳性，缺血周边区中等阳性；再灌流3－48小时组，缺血区神经元GDNF阴性。再灌流48小时组视前区的梗死周边区巨噬细胞GDNF呈强阳性。GDNF阳性细胞计数显示缺血区各实验组与正常组相比均减少（均P＜0．01）；24小时和48小时组分别与0．5小时组和3小时组相比，GDNF阳性细胞数减少（分别P＜0．01）。结论 缺血性脑损伤时，变性死亡的神经元GDNF不表达，存活的神经元和活化的小胶质细胞或巨噬细胞的GDNF表达增加。     

实验性脑缺血再灌流后不同时程热休克蛋白基因表达的变化

为探讨脑缺血再灌流后热休克蛋白(HSP70)基因表达的变化,采用原位杂交和免疫组化方法检测了脑缺血2h再灌流后不同时程应激蛋白—热休克蛋白(hsp70)mRNA和蛋白表达的变化。结果显示再灌流后早期即可见hsp70mRNA的蛋白表达增加,以18～24h阳性染色最强,HSP70阳性细胞主要分布于缺血周围半暗带区,提示HSP70蛋白表达增加可抵御缺血性脑损伤,对神经元具有保护作用。     

受体介导的1-磷酸鞘氨醇信号通路在局灶性脑缺血损伤中作用

目的探讨1-磷酸鞘氨醇(sphingosine 1-phosphate,S1P)受体亚型S1P3在局灶性脑缺血再灌注过程中的作用及其机制,为其作为药物靶点应用到脑缺血再灌注损伤的治疗提供理论依据。方法大脑中动脉闭塞法制备局灶性脑缺血再灌注的小鼠模型。用特异性S1P3拮抗剂CAY10444干预来评测S1P3在脑缺血再灌注中的作用。通过计算药物干预前后脑梗死体积、神经组织学评分和神经退行性变指标评估各组脑损伤程度。采用HE染色以及通过Iba1和Brd U/Iba1免疫组织化学染色方法观察和分析小胶质细胞的活化、形态转化和增殖情况。结果 CAY10444抑制S1P3后显著降低MCAO诱导的脑梗死体积、神经功能缺损以及神经退行性变评分和程度。MCAO术后当S1P3活性受到抑制时,Iba1免疫阳性细胞的数量显著减少,脑缺血的核心区和周边区域活化的小胶质细胞数量均明显减少,同时,缺血核心区的小胶质细胞由阿米巴样形状恢复为分枝状形态。在MCAO后MCAO组脑缺血区小胶质细胞增殖明显,表现为Brd U/Iba1双免疫阳性细胞增多。与MCAO组相比,抑制S1P3后Brd U/Iba1双免疫阳性细胞的数量减少。结论 S1P3是缺血再灌注脑损伤的致病介质,其机制可能是其参与调节了小胶质细胞活化和炎症发生,这为把S1P3作为脑缺血再灌注损伤的治疗靶点提供了依据。     

Classification of methods in transcranial Electrical Stimulation (tES) and evolving strategy from historical approaches to contemporary innovations

Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.     

Hepatic Considerations in the Use of Antiepileptic Drugs

Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.     

Vascular Malformations and Epilepsy: Clinical Considerations and Basic Mechanisms

Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.     

Neonatal Seizures: Problems in Diagnosis and Classification

Summary: The clinical identification of neonatal seizures is critical for the recognition of brain dysfunction; however, diagnosis is often difficult because of the poorly organized and varied nature of these behaviors. Current classification systems are limited in their ability to communicate motor, autonomic, and electroencephalo-graphic features of seizures precisely and to provide a basis for uniform effective diagnosis, therapy, and determination of prognosis. Recent investigations of neonates, utilizing bedside electroencephalographic/polygraphic/ video monitoring techniques, have provided the basis for improved diagnosis and classification of seizures in the newborn. These studies have demonstrated that not all clinical phenomena currently considered to be seizures require electrocortical epileptiform activity for their initiation or elaboration. In addition, the specific clinical character of the phenomena considered to be seizures, the clinical state of the infant, and the character of the EEG indicate the probable pathophysiological mechanisms involved and suggest probable etiologies, prognosis, and therapy. Similarities between animal models that demonstrate reflex physiology and neonates with motor automatisms and tonic posturing suggest that these clinical behaviors may not be epileptic in origin but, rather, primitive movements of progression and posture mediated by brainstem mechanisms. Although not all clinical behaviors currently considered to be neonatal seizures may have similar pathophysiological mechanisms, they are clinically significant because they all indicate brain dysfunction.     

Valproate Monotherapy in the Management of Generalized and Partial Seizures

Summary: For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.     

Carbamazepine Efficacy and Utilization in Children

Summary: Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmacokinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.     

Un nouveau cadre conceptuel de travail pour la psychiatrie

In an attempt to place psychiatric thinking and the training of future psychiatrists more centrally into the context of modern biology, the author outlines the beginnings of a new intellectual framework for psychiatry that derives from current biological thinking about the relationship of mind to brain. The purpose of this framework is twofold. First, it is designed to emphasize that the professional requirements for future psychiatrists will demand a greater knowledge of the structure and functioning of the brain than is currently available in most training programs. Second, it is designed to illustrate that the unique domain which psychiatry occupies within academic medicine, the analysis of the interaction between social and biological determinants of behavior, can best be studied by also having a full understanding of the biological components of behavior.     

Clobazam for Treatment of Intractable Epilepsy: A Critical Assessment

Summary: Clobazam (CLB), a 1,5-benzodiazepine, is a remarkably effective add-on drug for individual patients with refractory partial epilepsy. CLB has an excellent safety record. As with all benzodiazepines used for treating epilepsy, sedation and withdrawal effects, together with the development of tolerance, limit its usefulness. Recent efforts to prevent or reverse tolerance with intermittent administration of CLB or periodic injection of a benzodiazepine antagonist, flumazenil, are encouraging and justify further investigations.     

La passion de Torquemada et le terrorisme islamique : quelques points de comparaison

This original research compares the doctrinal, psychopathological and operational standpoints of the 15th century Spanish Inquisition (Torquemada) with those of radical Islamism from 1988 to 2005 (Al-Qaeda). The following are reviewed: (a) the main texts codifying the procedure for conducting the criminal investigation of a Holy Office trial (Directorium inquisitorum); (b) the life and work of the grand inquisitor Tomás de Torquemada (1420–1498); (c) the psychopathological relations between passion (passionate psychoses, passionate idealism, paranoid personality) and fanaticism; (d) “the madmen, the enlightened and the criminals” of Islamic terrorism; (e) the cognitive and emotional motives for engagement in the jihadist radicalization of young people; (f) the common principles of monotheistic fanaticism (Inquisition, Al-Qaeda) and the particular dogmas of Islamic terrorism in our time; (g) the operating modes of the Inquisition and the Jihadist holy war. The author concludes that the rigour and seriousness of the inquisitorial judicial procedure, which was precise, individual and personalized, contrasts with the revolutionary pamphlets of Al-Qaeda, which only provide broad guidelines for the modus operandi of the fight against infidels, who are usually random victims.