多发性硬化患者外周血肿瘤坏死因子超家族成员LIGHT及其受体HVEM的表达

目的 为分析TNF家族成员LIGHT及其受体疱疹病毒侵入介体（herpesvirus entry mediator，HVEM）与多发性硬化（MS）的关系，尝试性地研究了MS患者外周血T细胞LIGHT和HVEM的表达。方法 用流式细胞仪检测了LIGHT和HVEM在未治疗MS、免疫抑制治疗MS、脑卒中患者以及正常对照组外周血CD4^＋、CD8^＋T细胞的表达。结果 与正常对照比较．免疫调节治疗MS患者表达HVEM的外周血单个核细胞（PBMC）、CD4^＋和CD8^＋T细胞明显增多（分别为P〈0．001、P〈0．01和P〈0．001）。LIGHT尽管在未治疗MS组CD8^＋T细胞的表达呈增高趋势．但各组间差异无显著性。结论 LIGHT上调可能与CD8^＋T细胞的表达相关，LIGHT和HVEM之间是否存在调节性反馈环路尚需探讨。     

Th1/Th2型细胞因子在实验性自身免疫性神经炎发病机制中的作用

目的 建立P2多肽诱导的实验性自身免疫性神经炎(EAN)大鼠模型,探讨Th1/Th2型细胞因子在EAN发病机制中的作用.方法 实验组用100 μg或200 μg P257-81多肽加完全弗氏佐剂(FCA)免疫Lewis大鼠,对照组单用FCA免疫,致敏后每日对大鼠进行临床评分,比较高峰期最高评分.致敏第14天测定淋巴结细胞培养液上清干扰素(IFN)-γ、IL-4及IL-10的含量,并进行坐骨神经病理学检查.结果 实验大鼠瘫痪高峰期最高评分P257-81 200 μg组(3.6±0.3)显著高于100 μg组(2.2±0.6,P＜0.01);P257-81 200 μg组大鼠病程显著长于100 μg组;IFN-γ含量,两组实验大鼠均显著高于对照组[分别为(530.6±91.7)、(806.3±132.4)和(35.0±5.9)pg/ml,均P＜0.01],而P257-81 200 μg组显著高于100 μg组(P＜0.01);IL-4和IL-10含量,P257-81 100 μg组均显著高于对照组(均P＜0.01),P257-81 200 μg组显著低于对照组(P＜0.05,P＜0.01);坐骨神经病理可见EAN急性期以炎性细胞浸润为主,P257-81 200 μg组慢性期无炎性细胞浸润,而表现为多发性局灶性脱髓鞘和神经纤维崩解未恢复.结论 EAN临床表现随致敏原P257-81多肽剂量增加而加重;在EAN急性期,IFN-γ水平与EAN临床表现大致平行;EAN疾病具有自限性可能与IL-4和IL-10水平增高有关,而疾病迁延可能与IL-4和IL-10水平降低有关.     

城乡儿童血铅含量对智力、行为、学习影响及“剂量-效应”关系的研究

目的研究城乡儿童血铅水平的差异;血铅水平对儿童智力、行为、感觉统合发育、学习成绩等影响的“剂量－效应”关系。方法随机整群抽取城市和农村1所小学三～五年级儿童各100名作为研究对象,在严格质量控制下,测定全静脉血铅含量,同时进行儿童行为、智力、儿童感觉统合能力评定并进行学习成绩评价。结果高血铅检出率为23％,其中城市儿童检出率为29％,农村儿童检出率为17％,城市儿童血铅含量高于农村儿童（P〈0．001）;高血铅组儿童行为异常检出率41．3％,非高血铅儿童行为异常检出率为10．39％,有非常显著性差异（P〈0．01）。高血铅对总智商损害：200－499μg／L组重于100～199μg／L（P〈0．001）;对语言智商的损害：200～499μg／L组重于100～199μg／L组（P〈0．01）;对操作智商损害：100～199μg／L重于〈99gg／L组（P〈0．01）。儿童感觉统合失调发生率血铅％99μg／L组、100～199μg／L、200～499μg／L组分别为7．5％、40．26％、100％。对学习成绩的影响：血铅100～199μg／L组重于血铅〈99μg／L组（P〈0．01）;当血铅在100～199μg／L,200～499μg／L时数学成绩均明显低于语文成绩（P〈0．001;P〈0．05）。结论城市在校小学生的血铅含量水平明显高于农村在校小学生的血铅含量水平;高血铅含量对操作智商损害早于言语智商;对数学成绩的影响早于对语文成绩的影响;血铅含量对智力、行为、感觉统合发育、学习成绩的影响存在明显的“剂量－效应”关系。     

36例吉兰-巴雷综合征患者免疫功能监测及预后

目的 探讨T淋巴细胞亚群及TNF-α、LI-2水平与占兰-巴雷综合征（GBS）的关系及临床意义。方法 采用APAAP、ELISA法对36例GBS患者及36例正常人进行外周血T淋巴细胞亚群及血清TNF-α、IL-2水平测定。结果 重症GBS患者外周血CD；^＋T细胞显著高于对照组（P〈0．01），CD4／CD8比例增大，GBS患者血清TNF-α水平明显高于对照组（P〈0．05），血清中IL-2高于对照组（P〈0．01）。结论 GBS患者的免疫功能处于失衡状态。外周血T淋巴细胞亚群及血清TNF-α、IL-2的测定，可直接反映恶者的病情轻重。     

T细胞疫苗接种实验性自身免疫性神经炎的实验研究

目的建立P257-81-特异性T细胞系,在实验性自身免疫性神经炎(EAN)大鼠进行T细胞疫苗接种(TCV)的实验研究。方法P257-81多肽、IL-2和抗CD3/CD28单抗包被磁珠诱导扩增P257-81-特异性T细胞及非抗原特异性T细胞,将灭活T细胞接种大鼠,检测指标包括:瘫痪高峰期最大评分比较,淋巴细胞增殖试验、CD4 T/淋巴结单个核细胞及CD4 CD25 T/CD4 T细胞百分比测定、培养液上清IFN-γ及IL-10水平测定以及坐骨神经病理学检查。结果P257-81-特异性T细胞显著扩增,2周扩增近1000倍;P257-81-特异性TCV预防组无大鼠发病;P257-81-特异性TCV治疗组大鼠病情减轻,其坐骨神经炎性细胞浸润程度显著轻于对照组(P<0.001);P257-81-特异性TCV预防组和治疗组CD4 CD25 T/CD4 T细胞百分比及培养液上清IL-10水平均显著高于其对照组,培养液上清IFN-γ水平均显著低于其对照组(均P<0.001)。结论抗原 IL-2 CD3/CD28单抗包被磁珠刺激是一种高效、可靠的扩增抗原特异性T细胞方法;P257-81-特异性TCV能预防EAN发生,并可治疗已发生的EAN,其机制可能为:使CD4 CD25 调节性T细胞/CD4 T细胞比例上调,诱导致病性CD4 Th1细胞向保护性CD4 Th2细胞转换。     

胶质母细胞瘤组织中CD4+T细胞人类白细胞抗原G受体表达简

目的探讨三种主要人类白细胞抗原G（HLA—G）受体，即CD158d、CD85j和CD85d，在胶质母细胞瘤中CD4^＋T细胞的表达情况。方法分离胶质母细胞瘤和正常脑组织中CD4^＋T细胞利用佛波酯和离子霉素进一步激活CD4^＋T细胞。利用流式细胞术分析CD4^＋T细胞三种HLA—G受体的表达。结果胶质母细胞瘤中CD4^＋T细胞表面CD158d、CD85j和CD85d的表达阳性率较正常脑组织明显升高（P〈0．05），应用佛波酯和离子霉素刺激后，这三种受体表达水平显著增高（P〈0．05）。结论胶质母细胞瘤中CD4^＋T细胞存在HLA—G受体表达的上调现象，高表达HLA—G受体可能与肿瘤中T细胞功能抑制并最终引发肿瘤的免疫逃逸有关。     

单核细胞趋化蛋白-1和调节活化正常T细胞表达分泌因子与实验性变态反应性神经炎的关系

目的 研究趋化因子单核细胞趋化蛋白-1（MCP-1）和调节活化正常T细胞表达分泌因子（RANTES）与实验性变态反应性神经炎（EAN）发病的关系，探讨EAN的免疫发病机制。方法 给Wistar大鼠足垫皮下注射兔坐骨神经匀浆建立EAN模型，用免疫组化技术检测EAN大鼠发病不同时间坐骨神经MCP-1和RANTES的表达。结果 EAN组的MCP-1表达第9d达高峰，随后逐渐下降，第15d、21d、28dMCP-1的表达与前一时间点比较差异均有显著性（均P〈0．01）；第9d、15d、21dMCP-1表达均显著高于对照组（均P〈0．001）。EAN组第9d、15d、21dRANTES表达均显著高于对照组（P〈0．01～0．001），第15d表达最高。结论 MCP-1和RANTES在EAN的发病过程中发挥了重要作用，MCP-1可能起始动作用，RANTES可能与EAN的病情进展有关。     

可诱导协同刺激分子、CD28、CD24基因多态性与多发性硬化的相关性

目的探讨可诱导协同刺激分子（ICOS）、CD28、CD24基因多态性与多发性硬化（multiple sclerosis，MS）遗传易患性的相关性。方法以来自中国汉族人群的83例确诊MS患者和110例非自身免疫性疾病的患者及健康志愿者为研究对象，利用聚合酶链．限制性长度多态性分析（PCR-RFLP）技术检测3个基因扩增产物酶切多态性。结果ICOS-2394位点TT基因型频率MS组明显高于对照组（分别为33．7％和10．9％，P〈0．01），携带T等位基因可增加MS患病危险性（OR=3．482，P〈0．01）；ICOS-2119位点携带C-等位基因MS组明显低于对照组（分别为4．8％和15．5％，P〈0．05）。CD28-372位点基因型等位基因频率分布MS组与对照组差异无统计学意义。CD24 E2＋226位点T等位基因频率MS组较对照组增多（分别为44．6％和33．2％，P〈0．05）。单倍体型关联分析显示CD24 E2＋226T等位基因分别与ICOS-2394T及ICOS-2119C联合可明显增加MS患病危险性，CD28基因多态与ICOS基因多态构成的单体型在MS和对照组中差异无统计学意义。结论中国汉族人群ICOS-2394C／T、ICOS-2119C／T及CD24E2＋226C／T多态性与Ms发病相关，两基因可能均是MS的易患基因或与易患基因相连锁。CD28-372位点多态性与MS患病无直接相关。     

脑胶质瘤免疫治疗的实验研究

目的：提纯大鼠脑胶质瘤C6细胞热休克蛋白抗原肽复合物（HAC），免疫大鼠，观察HAC的抑瘤作用。方法：彩免疫亲和层析方法提纯鼠脑胶质瘤C6细胞HAC，免疫20只大鼠为实验组，以另20只大鼠作为对照组，于免疫后1周，采用立体定向脑内接种方法，以C6细胞攻击两组大鼠，于肿瘤细胞攻击后第2周，取两组动物外周静脉血，并采20只正常动物的外周静脉血做为正常对照，测定外周静脉血淋巴细胞计数。观察饲养过程中实验动物出现的症状、体征和第四周实验动物存尖率。于第四周处死存活动物，取脑组织进行HE染色病理组织学检查，并用免疫组化方法分析脑胶质瘤浸润区T淋巴细胞分布情况。结果：实验组大鼠外周血淋巴细胞计数显高于对照组（P＜0．01）。实验组胶质瘤局部浸润的CD3＋和CD4＋细胞数均显高于对照组（P＜0．01），实验组胶质瘤局部浸润的CD8＋细胞数与对照组比较无显性差异（P＞0．05），实验组胶质瘤局部浸润T淋巴细胞CD4＋／CD8＋显高于对照组（P＜0．01）。实验组动物症状出现时间显晚于对照组动物（P＜0．05），实验组动物四周末存活率显高于对照组（P＜0．01）。结论：C6细胞中HAC可以诱导大鼠产生对C6细胞的细胞免疫，提高大鼠存活率。     

脑胶质细胞瘤病人IL-2和sIL-2R表达及细胞免疫功能变化的意义

目的 研究脑胶质细胞瘤病人外周血中自细胞介素2（IL-2）、可溶性白细胞介素2受体（sIL-2R）的表达以及红细胞免疫和T淋巴细胞亚群的变化规律．探讨它们之间的相互关系。方法 对55例脑胶质瘤病人及55例健康献血员．采用酶联免疫吸附（ELISA）法测定血清IL-2、sIL-2R含量，免疫黏附法测定红细胞免疫活性及其调节功能，链亲和素一过氧化物酶（SP）一步法测定CD3、CD4、CD8细胞数。结果 脑胶质细胞瘤组IL-2含量较对照组显著性降低（P〈0.01），sIL-2R则显著性升高（P〈0．01）；红细胞C3b受体（RBC-C3bR）、红细胞免疫调节促进因子（RFER）亦显著性降低（P〈0．01），而红细胞免疫复合物（RBC-ICR）、红细胞免疫调节抑制因子（RFm）则显著性升高（P〈0．01）；CD3、CD4细胞数显著性降低（P〈0．001），而CD8无显著性差异（P〉0．05）。结论 脑胶质细胞瘤病人存在免疫功能低下；检测血清IL-2和sIL-2R含量、红细胞免疫功能及T细胞亚群活性，对脑胶质细胞瘤病人的免疫机制研究具有重要意义。     

Epilepsy and anomalies of neuronal migration: MRI and clinical aspects

Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.     

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.     

Special Pharmacokinetic Considerations in Children

Summary: Pediatric patients have greater degrees of pharmacokinetic variability and unpredictability than adults. This variability results from the effects of pharmacogenetics, age and growth, prior and current comedication, and disease. Newborns with seizures have the least predictable dosage requirements, and their needs change as drug-eliminating mechanisms mature in the neonatal period. Infants have the highest relative capacities to eliminate antiepileptics of any age group and require the largest relative doses. In addition to age-related trends, children demonstrate the same drug-specific, pharmacokinetic phenomena that adults do, including nonlinear phenytoin elimination, nonlinear valproate binding, and autoinduction of carbamazepine. Intercurrent illness and drug interactions further modify the age-related pharmacokinetic patterns in children and make dosage requirements even more unpredictable. Recent studies have shown that febrile illness can affect drug elimination, sometimes decreasing drug levels by 50% or more. Intermittent treatment with benzodiazepines administered either orally or rectally can be an important adjunct and help minimize this type of problem for children with marginally controlled epilepsy. Intermittent benzodiazepines are also helpful for children who have febrile seizures and who need only occasional antiepileptic protection.