大鼠颅脑损伤后亚低温治疗对Calpain及作用底物MAP-2表达的影响

目的探讨亚低温治疗对颅脑损伤后Calpain、MAP-2基因和蛋白表达的影响。方法将54只SD大鼠随机分为假手术组（n=6）、常温脑损伤组（n=24）和亚低温脑损伤组（n=24）。亚低温脑损伤组在液压打击伤后即接受持续4h的亚低温治疗。伤后6h、12h、24h和72h4个时间点分别处死3只常温脑损伤组和亚低温脑损伤组大鼠。荧光PCR、Western blot半定量检测皮质Calpain及MAP-2基因转录和蛋白的表达。结果颅脑损伤后12h及24h亚低温使Calpain mRNA表达增加（P〈0．05）,伤后6h、12h、24h和72h亚低温均可减少Calpain蛋白的升高,伤后12h及72h尤其显著（P〈0．05）。与假手术组比较,常温脑损伤组和亚低温脑损伤组MAP-2基因转录均减少（P〈0．05）;与常温脑损伤组比较,伤后6h、12h和24h亚低温可抑制MAP-2基因转录的下调,但亚低温脑损伤组MAP-2蛋白的表达均比同时间点常温组低（P〈0.05）。结论颅脑损伤后亚低温治疗的脑保护机制可能与调节Calpain蛋白的表达有关,而亚低温与MAP-2的关系还有待进一步研究。     

延迟亚低温治疗对大鼠永久性大脑中动脉阻塞后凋亡相关蛋白表达的影响

目的 研究延迟亚低温治疗对大鼠永久性脑缺血的神经保护作用以及作用机制.方法 线栓法制备永久性大脑中动脉阻塞(pMCAO)模型,随机分为3组,每组10只.亚低温治疗组(HT组)分为HT 2h组和HT 6h组,前者在pMCAO后2h给予亚低温(33±0.5℃)治疗22h,后者在pMCAO后6h给予亚低温(33±0.5℃)治疗18h.缺血对照组(NT组)在pMCAO后放置于室温(25℃).制备pMCAO模型过程中,应用激光多普勒血流监测仪监测局部大脑中动脉供血区脑血流量.持续监测直肠温度.各组大鼠均于pMCAO后24h灌注取脑制备冰冻切片,进行TUNEL染色以及Bcl-2、Bax、Caspase-3免疫组织化学染色.结果 NT组有3只大鼠死亡,亚低温治疗组无大鼠死亡.与NT组比较,HT组皮层缺血半暗带区域凋亡细胞减少,Bcl-2蛋白表达增多,Bax蛋白表达减少,Bcl-2/Bax比值升高,Caspase-3蛋白表达显著减少(P<0.05).与HT 6h组比较,HT 2h组皮层缺血半暗带区域凋亡细胞减少(P<0.05),但Bcl-2、Bax、Caspase-3蛋白表达以及Bcl-2/Bax比值均无显著性差异(P>0.05).结论 永久性脑缺血后延迟6h给予亚低温治疗18h仍然可以减少缺血后神经细胞凋亡.延迟亚低温治疗通过抑制Bcl-2基因家族蛋白介导的线粒体依赖性Caspase激活途径,抑制Caspase介导的细胞凋亡途径,从而发挥神经保护的作用.在脑缺血的治疗过程中,要尽早给予亚低温治疗,以保护更多的神经元和更好地促进神经功能的恢复.     

亚低温对重型颅脑损伤后葡萄糖代谢影响的实验研究

目的研究亚低温治疗对重型颅脑损伤大鼠血糖的影响。方法25只雄性SD大鼠随机分为三组:假手术组、常温组和亚低温治疗组。采用硬膜外自由落体打击法制作颅脑损伤模型。监测直肠温度,亚低温治疗组保持大鼠体温在33.0±1.5℃。常温组维持大鼠通常体温(为38.0±0.5 ℃)。分别于术前、术后3、8、24和48 h取血,检测血糖含量,测定其基础值及伤后动态变化。结果实验性颅脑损伤后血糖明显升高,于伤后24 h达到最高水平。常温组伤后各时段血糖值与基础值比较有显著差异(P<0.05)。亚低温治疗组伤后各时段血糖值与基础值比较无显著差异(P>0.05),但其伤后各时段血糖值与常温组各时段血糖值比较有显著差异(P<0.05),表明亚低温治疗可抑制重型颅脑损伤后高血糖反应。结论亚低温治疗可抑制颅脑损伤后高血糖反应,这有利于减轻颅脑损伤后糖代谢障碍所致脑组织的继发性损害。抑制颅脑损伤后高血糖反应可能是亚低温脑保护机制之一。     

亚低温治疗对颅脑创伤后β-淀粉样蛋白表达影响的实验研究

目的 探讨亚低温治疗对大鼠颅脑创伤( TBI)后β-淀粉样蛋白(Aβ)基因和蛋白表达的影响.方法 将60只SD大鼠分为假手术组(n=20)、常温脑创伤组(37C,n=20)和亚低温脑创伤组(32℃,n =20).建立SD大鼠液压打击致颅脑创伤模型.亚低温脑创伤组在液压打击伤后立即接受持续6h的亚低温治疗.伤后24h处死大鼠并取海马组织行HE染色,用RT-PCR、蛋白免疫印迹( Western blot)和免疫组化法检测Aβ基因转录和蛋白的表达.结果 与假手术组比较,颅脑创伤后24hAβ免疫阳性细胞数明显增加(P＜0.01),其mRNA和蛋白表达分别升高1.58和1.76倍.与常温脑创伤组比较,亚低温组Aβ免疫阳性细胞数明显减少(P＜0.01),其mRNA和蛋白表达分别下降68％和64％.结论 亚低温治疗可降低颅脑创伤后Aβ基因转录和蛋白的上调表达,通过抑制Aβ的神经毒性来发挥神经保护作用,而亚低温与Aβ的确切关系还有待进一步研究.     

亚低温治疗犬颅脑枪弹伤后局部脑组织c-jun蛋白的表达

目的 研究颅脑枪弹伤常温下及全身亚低温治疗后脑神经元c-jun蛋白表达的变化。方法 18只杂种犬,随机分为常温组(正常犬温为38.5~39.5 ℃)、亚低温组(31.5~32.5℃)。以德国小口径步枪子弹致伤犬颅脑贯通伤(PCI)模型为对象,采用免疫组化法检测两组脑组织伤后30 min、2 h、6 h弹道挫伤区、震荡区及脑干神经元中c-jun蛋白的表达。结果 全身亚低温治疗组弹道挫伤区、震荡区及脑干神经元中c-jun蛋白表达较常温组显著减少(P<0.01)。结论 颅脑枪弹伤后全身亚低温治疗能够抑制脑神经元c-jun蛋白的表达。     

重型颅脑创伤病人CSF中IL-6含量的变化及其临床意义

目的研究急性重型颅脑创伤(sTBI)病人脑脊液(CSF)中白细胞介素-6(IL-6)含量的变化及亚低温治疗对其影响与临床意义。方法80例急性sTBI患者(伤后6h内入院,GCS≤8分)随机分为亚低温(HT)组和常温(NT)组各40例,采用放射免疫法检测亚低温治疗前(伤后早期)、后不同时段CSF中IL-6的含量,同时对比两组病人的颅内压(ICP)、GlasgowOutcomeScale(GOS)计分指标并分析其间关系。结果急性sTBI病人伤后早期CSF中IL-6含量明显增高。与NT组病人比较,亚低温治疗后24h,HT组病人的ICP值和IL-6含量明显降低(P<0.05;P<0.05),并持续至复温后24h(P<0.01;P<0.01),而IL-6含量在伤后1个月时仍明显低于NT组(P<0.01)。HT组病人伤后6个月时的GOS计分明显高于NT组(P<0.05),即HT组病人的预后较好。结论sTBI病人急性期CSF中IL-6含量增高,亚低温可降低急性sTBI后的高ICP和明显抑制IL-6超表达,改善临床预后。     

大鼠液压脑损伤后皮层微血管改变与脑水肿的关系

目的探讨大鼠液压脑损伤后皮层微血管损伤情况及其与伤后脑水肿的关系。方法成年SD大鼠30只,随机分为正常组（n=6）、假手术组（n：6）、损伤组（n=18）,其中损伤组分为伤后6h、24h、72h三亚组,每亚组6只。利用液压冲击法建立大鼠颅脑损伤模型,显微镜下观察直接损伤侧和非直接损伤侧皮层微血管损伤隋况,CD34标记血管内皮细胞评价血管密度改变,干湿重法检测脑组织含水量的变化。结果大鼠皮层微血管损伤后6h可见血管支行迂曲、扩张、充血,伤后24h可见少量血栓形成,损伤后72h可见有较多血栓形成。损伤组CD34阳性细胞数明显低于假手术组和对照组（P〈0．05）,而脑组织含水量明显高于假手术组和对照组（P〈0．05）,而后两组无统计学差异（P〉O．05）。损伤组直接损伤侧皮层微血管损伤较非直接损伤组严重,而且伤后24h较伤后6、72h严重。结论颅脑损伤后脑微血管损伤为全脑性血管损伤,这可能是伤后脑水肿形成的机制之一。     

大鼠颅脑创伤后肝细胞生长因子表达变化的实验研究

目的 探讨肝细胞生长因子(HGF)在颅脑创伤后的表达趋势,为颅脑创伤治疗中的HGF干预策略提供前期研究基础. 方法 96只wistar大鼠按随机数字表法分为实验组和假手术组,实验组为液压冲击中度颅脑创伤大鼠,并分为伤后2h、6h、12h、24 h、72h、168 h、336 h组,假手术组不致伤,每组再分为两个亚组.每亚组6只,一组行HE及免疫组化染色,观察伤后病理变化及HGF的表达部位和表达量,另外一组用RT-PCR的方法 观察创伤后HGF mRNA表达情况.结果 在创伤后的大鼠大脑皮层组织中,HGF在蛋白水平以及基因水平都出现表达增高的情况.创伤边缘区HGF阳性细胞数从伤后24 h开始增多,168 h达高峰,336 h有所下降,但仍高于伤前水平,差异有统计学意义(P<0.05).HGF mRNA表达量从创伤后72 h开始增加,168 h达高峰,与假手术组比较差异有统计学意义(P<0.05). 结论 HGF作为神经营养因子和血管生长因子,可能参与了颅脑创伤后神经元的保护和组织的修复、再生.     

亚低温治疗重型颅脑损伤病人纤维蛋白原和D-二聚体的变化及其临床意义

目的观察重型颅脑损伤病人在亚低温和常温治疗状态下纤维蛋白原(Fbg)与D-二聚体(D-dimer)差异及其临床意义。方法43例单纯性、重型颅脑损伤病人随机分为亚低温治疗组和常温组,两组性别、年龄、GCS评分无显著差异。伤后5次(6h、12h、24h、48h、72h)检测Fbg和D-dimer,并记录GOS评分。结果①两组Fbg值在伤后6h、12h、24h、48h差异显著,但伤后72h两组差异不显著。两组Fbg值在伤后6h均较高,常温组升高幅度更明显。两组Fbg值在伤后12h下降,亚低温组降低程度较常温组小。②两组D-dimer在伤后6h明显升高,常温组升高更明显;其在伤后6h、12h、24h差异显著,而在伤后48h、72h差异不显著。③亚低温组GOS评分优于常温组,差异显著。结论在颅脑损伤后4h即开始实施亚低温治疗能改善伤后的高凝状态,并减轻继发纤溶亢进。亚低温治疗缓解了凝血功能紊乱,是其能起到脑保护作用和改善治疗效果的机制之一。     

rh—EPO对大鼠颅脑损伤模型脑红蛋白表达研究

目的观察重组人促红细胞生成素rh—EPO对大鼠脑损伤后皮层脑红蛋白NGB表达的影响,探讨其在脑损伤后的意义。方法78只大鼠随机分为3组：假手术组6只,单纯颅脑损伤组36只,rh—EPO干预组36只。单纯颅脑损伤组与rh—EPO干预组模型分别按照3h、6h、12h、24h、48h、72h 6个时间点随机分为6个亚组,每个亚组6只大鼠,通过免疫组化及图像分析方法,观察打击区周边皮层中脑红蛋白NGB的表达。结果单纯颅脑损伤组打击周边区NGB蛋白免疫反应阳性细胞表达较假手术组增多（P〈0．01）,在相应区域rh—EPO干预组明显高于前两组（P〈0．01）。结论rh—EPO可诱导增加大鼠脑损伤后脑红蛋白的表达。     

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.     

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.     

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.