颅内动脉狭窄与HLA-DQA1、DQB1基因多态性关系研究

目的 探讨白细胞抗原(HLA)-DQA1、DQB1基因多态性与颅内动脉狭窄的关系.方法 运用聚合酶链反应-序列特异性引物(PCR-SSP)方法 对自2006年7月至2007年3月天津医科大学总医院神经内科收治的15例缺血性卒中伴颅内动脉中重度狭窄患者(简称狭窄组)、49例缺血性卒中且无动脉狭窄患者(简称无狭窄组)和52例健康体检者(对照组)进行HLA-DQA1和DQB1基因多态性分型. 结果 狭窄组DQA1*0501和DQB1*0501出现频率增高,与其它2组比较差异有统计学意义(P<0.05);而无狭窄组与对照组相比,DQA1*0301和DQB1*0301频率增高,差异有统计学意义(P<0.05). 结论 DQA1*0501和DQB1*0501是缺血性卒中伴颅内动脉狭窄易感基因,DQA1*0301和DQB1*0301为缺血性卒中易感因素.     

家族性重症肌无力临床特点及其与人类白细胞抗原DQA1基因多态性的相关性研究

目的探讨家族性重症肌无力(MG)的临床特点及其与人类白细胞抗原(HLA)DQA1基因多态性的相关性。方法对15例家族性、36例散发性MG患者的临床特点进行研究,并运用聚合酶链反应序列特异性引物(PCR SSP)对HLA DQA1基因多态性进行分型。结果与散发性MG相比,家族性MG患者发病年龄较早(两者分别为18 7、34 4岁,P=0 006),病情较轻,预后较好;与散发MG组及健康对照组比较,家族性MG患者的DQA1 0301基因频率增高(三者分别为40 0%、19 4%和20 2% ),差异有统计学意义(P<0 05),这种差异在眼肌型的患者中同样存在,但未发现患者性别与DQA1相关。结论家族性MG有其独特的临床特点,DQA1 0301是家族性尤其是眼肌型MG的易患基因,提示家族性MG与散发MG可能有着不同的免疫遗传机制。     

人类白细胞抗原-DQB1等位基因多态性与我国南方汉族人群多发性硬化的相关性研究

目的探讨人类白细胞抗原(HLA)-DQB1基因多态性与我国南方汉族人群多发性硬化(MS)的相关性。方法采用基因测序的方法(SBT)对42例南方汉族MS患者及48名健康对照者进行HLA-DQB1等位基因的检测,并比较MS组与健康对照组之间等位基因型频率的差异。结果共检测到15种HLA-DQB1等位基因片段,其中DQB1*0502等位基因频率MS组(35.7%)显著高于健康对照组(8.9%)(P=0.0018,Pc=0.027,OR=4.29);DQB1*0303等位基因频率MS组(19.0%)低于健康对照组(39.6%)(P=0.04,OR=0.48),但差异经校正后无统计学意义。HLA-DQB1*0601和DQB1*0602等位基因频率在MS组患者与健康对照组之间差异无统计学意义。结论我国南方汉族人群MS与HLA-DQB1*0502等位基因有关,而与HLA-DQB1*0601和DQB1*0602等位基因无关。     

深圳汉族人群HLA-Cw，-DQB1基因座等位基因的多态性

背景：HLA复合体是极其复杂的遗传系统，对其多态性的研究在法医学个体识别和亲权鉴定、群体遗传学、移植免疫、疾病相关等医学领域有重要的应用价值。 目的：了解HLA-Cw，-DQB1基因座的等位基因在深圳汉族人群中的分布规律。 设计、时间及地点：样本基因型的统计学分析，于2007-01/2008-06深圳市血液中心免疫遗传研究室完成。 材料：样本来自中国造血干细胞捐献者资料库深圳地区志愿捐献者，使用EDTA-K2抗凝管采集外周血。 方法：采用聚合酶链式反应-序列测定方法对深圳地区226名无关供者HLA-Cw，-DQB1基因座的2，3外显子进行序列测定与分析。等位基因频率采用直接计数法计算，Hardy-Weinberg平衡检验采用x2检验。 主要观察指标：样本HLA-Cw，-DQB1基因座的基因型。 结果：226个样本中共检测到25个Cw等位基因。其中Cw*0102，Cw*0702的频率最高（0.1881），其他频率较高的等位基因依次为Cw*0304，Cw*0302，Cw*0401及Cw*0801，Cw*0303，Cw*0602。该位点基因型观察值与期望值经χ2检验符合Hardy-Weinberg平衡定律（x2=116.00，u=1.78, ν=91，P > 0.05）。226个样本中共检测到17个DQB1等位基因。其中DQB1*0301占绝对优势，其基因频率为0.2124。其他频率较高的等位基因依次为DQB1*0303，DQB1*0601，DQB1*0502，DQB1*0602，DQB1*0302，DQB1*0401。该位点基因型观察值与期望值经χ2检验符合Hardy-Weinberg平衡定律（x2=101.34，u=0.78,ν=91，P > 0.05）。经计算HLA-Cw位点的杂合度为0.887 8，个体识别力为0.976 9，非父排除率为0.773 1，多态性信息含量为0.875 7；HLA-DQB1位点的杂合度为0.889 4，个体识别力为0.976 2，非父排除率为0.753 3，多态性信息含量为0.965 9。 结论：深圳汉族人群HLA-Cw及DQB1基因座是高度杂合、具有较高鉴别力和丰富信息含量的遗传标记，能较好地反映群体遗传特征。     

眼肌型重症肌无力临床特点及其与HLA-DQ基因多态性相关研究

目的探讨眼肌型重症肌无力(OMG)的临床特点及其与人类白细胞抗原(HLA)DQA1、B1基因多态性的相关性。方法运用聚合酶链反应方法-序列特异性引物(PCR-SSP)对26例OMG、60例全身型MG(GMG)和93名健康对照(对照组)的HLA-DQA1、B1基因多态性进行分析。结果 OMG发病年龄(24.38岁)早于GMG(31.28岁;P=0.039),女性OMG发病年龄(22.21岁)亦早于女性GMG(32.92岁;P=0.016)。OMG组DQB1*0501等位基因频率(29%)明显高于GMG组(16%,P0.05,OR=2.16,95%CI为0.99~4.68)和对照组(11%,P0.01,OR=3.19,95%CI为1.50~6.76);GMG组DQA1*0501(24%,P0.05,OR=1.96,95%CI为1.09~3.53)、DQB1*0301(23%,P0.01,OR=2.55,95%CI为1.35~4.84)等位基因频率高于对照组(分别为14%、10%);OMG和GMG组DQA1*0103等位基因频率(分别为4%、5%)均低于对照组(16%)(分别P=0.02,OR=0.21,95%CI为0.048~0.90;P=0.003,OR=0.27,95%CI为0.11~0.68);DQB1*0601等位基因频率(分别为6%、7%)也均低于对照组(17%)(分别P=0.047,OR=0.31,95%CI为0.09~1.05;P=0.01,OR=0.36,95%CI为0.16~0.81)。结论 OMG患者,尤其是女性OMG患者发病年龄早于GMG患者。DQB1*0501可能是OMG患者的易感基因。     

HLA-DQA1基因与我国重症肌无力患者的关联性

HLA Ⅱ类基因在发生自身免疫过程中起重要作用。1988年本组血清学分析上海地区44例重症肌无力(MG),发现HLA-DR9频率显著增高,无胸腺瘤的眼肌型患者HLA-B46频率增高。本文报告用多聚酶链反应(PCR)限制片段长度多态性(RFLP)分型技术,从DNA水平分析探讨HLA-DQA1基因与我国MG患者的关联性。     

HLA-DRB1基因型与多发性硬化易患性的关系

目的：探讨HLA基因型与多发性硬化（MS）易患者的关系。以及临床表现与基因型的关系。方法：30例MS患者（包括2对双生子患者）、40名健康对照组，应用序列特异性引物聚合酶链反应（PCR－SSP）方法进行HLA－DRB1基因分型，对2个双生子家系进行家系分析。结果：单卵双生子？（经遗传标记确定）同患MS，病变均累及大脑，脑干和脊髓，基因型为HLA－DRB1＊09＊14．1。异卵双生子之一为复发缓解型视神经脊髓炎，基因型为DRB1＊01＊12，其未患病双生子妹妹为DRB1＊17＊12。根据病变部位。30例MS中视神经脊髓炎型和西方型各15个。脊髓（70．0％），和视神经（56．7％）是最常见病变累及部位。DR15的等位基因频率在MS组无显著增高，但DR12等位基因频率在MS中显著升高（10／30vs 4/40,P=0.0157)，分层分析显示视神经脊髓炎患者中DR12等位基因频率升高，差异有极显著意义（8／15vs 4/40,P=0.0019,RR=5.33)。结论：单卵双生子与异卵双生子的患病一致性差异表明，遗传因素在MS发病中起一定作用。DR12可能是部分视神经脊髓炎型MS的易患基因，关联基因的差异可能是东西方MS临床表现和病变部位不同的原因之一。     

CTLA-4基因-1722位点多态性与重症肌无力的相关性研究

目的 研究细胞毒性T淋巴细胞相关抗原4(CTLA-4)基因上游启动子区域-1722位点多态性与重症肌无力(MG)患者的相关性及其与患者临床表型之间的关系.方法 应用聚合酶链反应(PCR)-限制性片断长度多态性(RFLP)方法,对166例MG患者和233名健康对照者CTLA-4基因启动子区域-1722位点进行多态性检测.结果 与健康对照组相比,MG患者中CTLA-4基因-1722位点CC基因型频率明显增高(P<0.01),C等位基因明显高于健康对照组(P<0.01).患者不同性别、合并胸腺瘤否、临床分型、发病年龄等不同组之间分型差异无统计学意义.结论 CTLA-4基因-1722位点CC基因型与MG明显相关,有必要对CTLA-4基因位点多态性进行进一步研究.     

IL-17A基因rs8193037和rs1974226位点多态性与重症肌无力的相关性研究

目的探索IL-17A基因rs8193037及rs1974226位点多态性与重症肌无力(MG)的易感性和严重程度的相关性。方法本研究共纳入480例MG患者及487例健康对照组,采用SNPscanTM多重SNP分型技术对IL-17A基因rs8193037及rs1974226位点进行基因分型,比较等位基因频率在MG组及各亚组(发病年龄、胸腺情况、AChR抗体、首发受累范围、发病后2 y间最严重时受累范围及严重程度)的分布。在共显性及加性遗传模型下比较基因型频率。结果 IL-17A基因rs8193037和rs1974226位点的等位基因和基因型频率在MG整组、各亚组和对照组均无显著性差异。结论未发现IL-17A基因rs8193037及rs1974226位点多态性与MG的易感性和严重程度有关。     

HLA-DQB1等位基因多态性与新疆人群重症肌无力的相关性研究

目的探讨HLA-DQB1基因多态性与新疆人群重症肌无力(MG)的相关性。方法采用基因测序的方法对120例新疆地区MG患者及120例健康对照者进行HLA-DQB1等位基因的检测,并比较MG组与对照组之间等位基因型频率的差异。结果共检测出14种HLA-DQB1等位基因片段,其中DQB1*05:03等位基因频率MG组显著高于健康对照组(OR=2.818,P=0.002),而DQB1*02:01:01、DQB1*06:02等位基因频率显著低于对照组(OR=0.179,P=0.006;OR=0.511,P0.001)。DQB1*04:01:01、DQB1*05:03等位基因频率在MG汉族组显著高于对照汉族组(OR=4.000,P=0.009;OR=3.077,P=0.006),DQB1*02:01:01、DQB1*06:02等位基因频率MG汉族组显著低于对照汉族组(OR=0.358,P=0.002;OR=0.207,P0.001)。MG维吾尔族组与对照维吾尔族组相比DQB1等位基因频率差异无统计学意义。结论新疆MG患者可能和HLA-DQB1*05等位基因有关,DQB1*04:01:01可能与汉族人群MG相关。MG患者中缺乏DQB1*06:02、DQB1*02:01:01,可能在新疆人群中起保护作用。     

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.