左旋多巴诱发异动症大鼠纹状体区P38及GAP-43表达的变化

目的　观察帕金森病(Parkinson disease, PD)大鼠经慢性间断性左旋多巴(levodopa,L- dopa)治疗后纹状体区域突触功能的变化。方法　 6 羟多巴胺 (6 OHDA)脑立体定位注射制备偏侧PD大鼠模型,复方L dopa甲酯治疗4周[按体重20 mg/(kg·d),分2次进行腹腔注射]建立异动症(levodopa induced dyskinesias,LID)大鼠模型,采用免疫组化方法检测 PD组和 LID组纹状体内突触素(synaptophysin, P38)及生长相关蛋白(growth associated protein, GAP 43)的表达。结果　 PD 大鼠损毁侧 P38 免疫反应阳性颗粒的数密度[(0. 002 1±0 000. 5)个/μm2]和面密度(0. 045±0.01)均明显高于健侧[分别为(0 .015 0±0. 000 6)个/μm2, (0 027±0 .009)](P<0 .01),GAP- 43阳性颗粒面密度(0. 015±0. 000 3)高于健侧(0. 01±0 .000 27)(P<0. 05);LID大鼠经L dopa治疗后两者表达进一步增多,与PD组大鼠损毁侧相比差异有显著性(均 P<0 .05)。结论　慢性L dopa治疗进一步促进了PD大鼠纹状体区域P38及GAP -43的高表达,可能涉及皮质纹状体病理性长时程增强的突触前机制,提示皮质 纹状体环路的突触可塑性与LID发生密切相关。     

美多巴单用及与多巴胺受体激动剂合用治疗帕金森病的临床疗效观察

目的　评定单用美多巴 (L dopa) ,L dopa与多巴胺受体激动剂 [溴麦角隐亭碱 (BM)或甲磺酸培高利特 (PM) ]合用治疗帕金森病的疗效和安全性。方法　采用多中心、开放式分组 ,单用L dopa组 4 7例 ,L dopa +BM组 4 3例和L dopa +PM组 4 8例。临床疗效采用改良Webster量表和帕金森病运动功能量表 (MDRSPD)进行治疗前后的评定。同时取血检测肝肾功能 ,血、尿常规 ,测量血压、脉搏和做心电图检查。单用L dopa组平均日用量 (5 2 3 3± 2 35 9)mg;L dopa +BM组平均日用量为L dopa(5 2 6 7± 2 4 1 3)mg ,BM(7 3± 1 5 )mg;L dopa +PM组平均日用量为L dopa(5 5 8 3± 192 9)mg,PM(0 2 35± 0 0 4 5 )mg。结果　Webster量表、MDRSPD量表的临床总有效率 ,单用L dopa组均为74 5 % ,L dopa +BM组分别为 6 9 8%和 79 1% ,L dopa +PM组分别为 77 9%和 81 3%。不良反应发生率单用L dopa组为 2 7 7% ,L dopa +BM组为 39 5 % ,L dopa+PM组为 18 8%。结论　单用L dopa ,L dopa+BM和L dopa +PM治疗帕金森病均有效 ,对于早期帕金森病可以选用单一L dopa治疗 ;对于晚期帕金森病 ,可以选用L dopa与多巴胺受体激动剂联合治疗     

左旋多巴治疗对实验性帕金森病大鼠黑质纹状体TNF—a表达的影响

目的　研究左旋多巴 (L - dopa)治疗对实验性帕金森病 (PD)大鼠黑质纹状体肿瘤坏死因子(TNF-α)表达的影响。方法　黑质定位注射 6 -羟多巴胺 (6 - OHDA )制备偏侧 PD大鼠模型 ,经 5 0～ 10 0 mg/ kg体重 L - dopa灌胃治疗 4周后 ,检测双侧额叶皮质、黑质和纹状体区域 TNF-α的表达。结果　 6 - OHDA损毁侧黑质和纹状体 TNF-α含量和阳性细胞面密度分别显著高于健侧 (均 P<0 .0 5 )。损毁侧与健侧 TNF-α含量的比率随 L - dopa治疗用量的增加而增高 ,且均显著高于对照组 (P<0 .0 5 )。结论　 L - dopa治疗进一步加剧了PD大鼠黑质纹状体区域 TNF-α的高表达。     

左旋多巴对帕金森病大鼠毒性作用的实验研究

目的　研究左旋多巴 (L dopa)对帕金森病 (PD)模型大鼠异常行为、黑质抗氧化系统、线粒体呼吸链功能和神经递质代谢的影响及其机制。方法　应用 6 羟基多巴胺 (6 OHDA)立体定向注射制作PD大鼠模型 ,给PD大鼠L dopa 2 5mg/ (kg·d)灌胃 ,共 4 5d。给药前后分别进行行为学测试 ,给药后测定黑质区谷胱甘肽过氧化物酶 (GSH Px)、丙二醛 (MDA)、活性氧 (ROS)及线粒体呼吸链酶复合体Ⅰ水平 ,测定尾状核头部多巴胺 (DA)、高香草酸 (HVA)、单胺氧化酶 B(MAO B)的水平。结果　 (1)L dopa组大鼠旋转速度给药前为(13.1± 1.5 )r/min ,给药后为 (7.2± 1.6 )r/min,给药前后比较差异有显著性 (P <0 .0 1) ;(2 )L dopa组GSH Px活性、呼吸链酶复合体Ⅰ水平降低 ,MDA含量、ROS活性升高 ,与对照组比较差异均有显著性 (均P <0 .0 1) ;(3)L dopa组MAO B活性、DA、HVA含量及DA/HVA比值与对照组比较均显著升高 (P <0 .0 5～ 0 .0 1)。结论L dopa能有效改善PD大鼠的旋转行为 ,但可加重黑质区氧化应激损伤 ,抑制线粒体呼吸链酶活性。     

应用单光子发射计算机体层摄影术研究药物滥用对人脑纹状体多巴胺转运体的损害

目的　在分子水平上研究摇头丸和海洛因滥用对人脑纹状体多巴胺转运体(DAT)的损害。方法　对健康对照组21名、摇头丸组12例、海洛因组43例进行单光子发射计算机体层摄影术检测。静脉注射显像剂99Tcm TRODAT 1剂量为740MBq/ml。计算纹状体的体积、质量、纹状体与全脑放射性比值(Ra% )和差值率(% )。结果　对照组双侧纹状体呈典型“熊猫眼”形,双侧尾状核和豆状核大致等大,DAT分布均匀、对称。摇头丸组和海洛因组纹状体的体积分别为(21 4±4 5)cm3 和(21 3±4 4)cm3,小于对照组[ ( 32 0±2 2 )cm3;P<0 01 ];质量分别为( 23 7±3 9 )g和( 22 4±3 2)g,低于对照组[ (33 6±2 6)g;P<0 01];Ra%分别为(5 9±0 8)%和(5 2±0 9)%,亦低于对照组[ (7 6±2 0)%;P<0 05],摇头丸组和海洛因组纹状体与全脑放射性比值与对照组的差值率分别是22 03%和30 74%。结论　滥用摇头丸和海洛因均破坏脑纹状体多巴胺能神经元的功能,DAT的数量、密度、分布和活性减低。     

吗啡依赖及戒断对大鼠强啡肽原mRNA表达的影响

目的　研究吗啡依赖形成及戒断对大鼠强啡肽原mRNA表达的影响。方法　将 18只Sprague Dawley雄性大鼠随机分为吗啡依赖组、吗啡戒断组和空白对照组 ,每组 6只。采用皮下注射吗啡建立大鼠吗啡依赖模型 ,初剂量为 10mg/kg ,以后每天增加 5mg/kg ,3次 /d ,连续 6天。应用放射性3 2 磷标记的三磷酸脱氧胞苷掺入标记探针法进行Northern印迹杂交技术检测三组大鼠强啡肽原mRNA的表达水平。结果　 (1)连续 6天给予吗啡 ,吗啡依赖组大鼠下丘脑 (2 3 88± 1 6 2 )、纹状体(19 87± 2 0 3)及脊髓 (13 36± 1 4 6 )的强啡肽原mRNA相对含量分别低于对照组 (分别为 34 36±1 4 6、31 2 4± 2 83和 2 7 6 0± 2 89;均P <0 0 1) ,海马 (2 9 6 7± 3 2 3)强啡肽原mRNA相对含量高于对照组 (2 5 87± 1 74 ,P <0 0 5 ) ;(2 )给予纳洛酮处理 6 0min后 ,下丘脑 (10 2 2± 1 2 2 )、纹状体(5 90± 0 84 )、脊髓 (2 99± 0 4 8)强啡肽原mRNA的相对含量低于吗啡依赖组 (均P <0 0 1) ,而垂体强啡肽原mRNA(2 6 72± 1 79)却高于吗啡依赖组 (11 6 0± 2 2 4 ,P <0 0 1)。结论　慢性给予吗啡可影响大鼠强啡肽原mRNA的表达 ,从而参与吗啡依赖形成和戒断反应。     

多巴胺转运体显像对老年人帕金森病早期诊断价值的研究

目的 :探讨99mTc TRODAT 1SPECT多巴胺转运体 (DAT)显像对老年帕金森病 (PD)早期诊断的价值。方法 :对 2 9例老年PD患者 ,12例老年健康志愿者行99mTc TRODAT 1SPECTDAT断层显像 ,利用感兴趣区技术测定纹状体与小脑部位DAT比值。结果 :老年早期PD患者 (Hoehn Yahr分级Ⅰ级 )起病肢体对侧纹状体DAT特异性摄取 (左侧 :1 2 5± 0 10 ,右侧 :1 3 2± 0 0 6) ,与正常老年人 (左侧 :1 74± 0 13 ,右侧 :1 69± 0 0 8)相比 ,有显著性的降低 (P <0 0 1)。结论 :99mTc TRODAT 1SPECTDAT显像有助于老年PD的早期诊断。     

依达拉奉对帕金森病大鼠多巴胺转运体保护作用的研究

目的探讨依达拉奉对帕金森病(PD)大鼠多巴胺转运体(DAT)的保护作用。方法PD模型组大鼠,分为依达拉奉大剂量(3.0mg/kg)组、中剂量(1.0mg/kg)组、小剂量(0.3mg/kg)组及生理盐水组(对照组),每天两次腹腔注射治疗两周,停药1周后,用γ放射性计数仪测定双侧纹状体、大脑皮质、小脑DAT含量,计算脑组织ID值。结果大剂量组右侧纹状体放射性计数(0.47±0.06)、中剂量组(0.37±0.02),与对照组(0.25±0.01)相比差异有显著性(均P<0.05),大、中、小剂量组和未治疗组左侧脑组织放射性计数与右侧相应部位比较差异均有显著性(均P<0.05)。结论大剂量依达拉奉可增强脑组织的抗氧化能力,以纹状体最为显著。     

脱氢表雄酮硫酸盐对老年大鼠学习、记忆功能的促进作用

探讨脱氢表雄酮硫酸盐 (DHEAS)对老年大鼠迷宫光亮分辨反应的学习能力和记忆保存的影响。将2月龄年轻雄性 SD大鼠 30只 ,2 2月龄老年雄性 SD大鼠 2 8只 ,分别随机分为对照组和实验组。实验组给予DHEAS 2 0 mg/kg,对照组给予等量 5%葡萄糖 ,均腹腔注射。然后分别作 Y迷宫光亮分辨反应的学习能力测试 ,1 2 d后以同样方法检查大鼠的记忆保存能力。结果提示 :1学习能力测试 ,2 2月龄老年大鼠的 Y迷宫光亮分辨学习达到标准的训练次数为实验组 (2 0 .8± 4.3)次 ,对照组 (34.8± 6.1 )次 ,两组间差别非常显著(P<0 .0 5) ;年轻大鼠实验组 (2 3.6± 2 .8)次 ,对照组 (2 0 .4± 4.1 )次 ,两组间差别无显著性。 2记忆保存测试 ,老年大鼠达到标准所需次数为实验组 (3.0± 1 .7)次 ,对照组 (1 4.2± 2 .1 )次 ,差别非常显著 (P<0 .0 1 ) ;年轻大鼠实验组 (2 .1± 0 .7)次 ,对照组 (1 0 .3± 2 .8)次 ,差别非常显著 (P<0 .0 1 ) ;老年大鼠实验组与年轻大鼠实验组的学习能力、记忆保存比较无显著差别 (P>0 .0 5)。由此可见脱氢表雄酮硫酸盐对老年大鼠的学习能力和记忆功能有提高作用     

结核性脑膜炎的脑神经损害与脑脊液免疫球蛋白、白蛋白的关系

目的　分析结核性脑膜炎 (TM)的脑神经损害的特征 ,及其与脑脊液 (CSF)免疫球蛋白 (Ig)和白蛋白 (Alb)的关系。方法　将确诊的 4 8例TM患者分为两组 :无脑神经麻痹TM组 (A组 ,30例 )和有脑神经麻痹TM组 (B组 ,18例 ) ,用速率散射比浊法测定其CSFIg和Alb的含量。结果　B组中展神经受损最多 ,为 10例 (5 5 6 % ) ,其次为动眼神经受损 (6例 )。视神经、听神经损害分别为 4例、2例 ;B组CSF蛋白含量明显高于A组 (P <0 0 0 1) ,CSFIgG、IgM、Alb含量 :A组分别为 (135 7± 4 1 4 )mg/L、(12 4± 3 3)mg/L及 (5 6 6 5± 2 71 8)mg/L ,B组分别为 (197 2± 4 5 1)mg/L、(36 7± 5 8)mg/L及 (813 3± 2 84 5 )mg/L ,两组比较差异均有显著性 (均P <0 0 0 1)。结论　TM常有脑神经损害 ,且与血 脑屏障破坏、CSFIg和Alb升高有关     

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.