局部亚低温对大鼠脑出血后基质金属蛋白酶-9及血脑屏障通透性的影响

目的探讨局部亚低温对大鼠自体血注入法脑出血模型基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)mRNA及蛋白表达的影响以及局部亚低温减轻脑出血后水肿的可能机制。方法雄性Wistar大鼠240只,随机分为脑出血(ICH)组和脑出血加局部亚低温(ICH H)组。每组分为对照、脑出血后6h、24h、72h、5d、7d共6个亚组,ICH H组于注血后立即给以4h的局部亚低温治疗,各亚组分别进行血脑屏障(BBB)通透性、脑水含量的检测以及应用RT-PCR及Western印记对MMP-9进行测定。结果ICH组大鼠脑内注血后6h开始出现脑组织水含量(P<0.01)及BBB通透性(P<0.05)的显著增加,二者在72h达到高峰,然后逐渐消退,ICH组MMP-9蛋白表达量与脑含水量和血脑屏障通透性呈正相关(r=0.88和r=0.96),ICH组MMP-9 mRNA表达量也与脑含水量和血脑屏障通透性呈正相关(r=0.78和r=0.85)。ICH H组大鼠脑组织水含量、BBB通透性以及MMP-9蛋白的表达与ICH组各时间点相比较,明显降低,而MMP-9 mRNA的表达与ICH组相比仅有轻度下降。结论脑出血后MMP-9的变化与BBB通透性和脑水肿密切相关,局部亚低温可以抑制脑出血后MMP-9蛋白表达的增加以及脑水肿的形成。提示局部亚低温可能通过影响MMP-9的变化来抑制脑出血后的水肿形成。     

亚低温对大鼠局灶性脑缺血再灌注后MMP-9表达和细胞凋亡的影响

目的 通过研究亚低温对大鼠局灶性脑缺血再灌注后基质金属蛋白酶-9(MMP-9)表达和细胞凋亡的影响,探讨亚低温脑保护的可能机制.方法 将雄性SD大鼠39只分为假手术组、常温缺血组和缺血期亚低温组.制作大脑中动脉阻塞(MCAO)模型,缺血2h再灌注48h,HE染色观察各组大鼠脑组织形态学改变;采用TTC染色法观察梗死体积;TUNEL法检测细胞凋亡;免疫组化法检测MMP-9表达.结果 亚低温减轻脑缺血组织病理学损伤,明显缩小脑梗死体积(P<0.05).常温下缺血侧脑组织可见大量TUNEL阳性细胞和MMP-9免疫阳性细胞,主要位于皮质缺血半暗带区.亚低温减少脑缺血后TUNEL阳性细胞数目(P<0.05),明显下调MMP-9蛋白表达(P<0.05).结论 亚低温可能通过下调脑缺血再灌注后MMP-9表达,抑制细胞凋亡,从而发挥确实的脑保护作用.     

bFGF对脑缺血再灌注大鼠ICAM-1表达及脑组织含水量的影响

目的探讨bFGF对局灶性缺血再灌注大鼠脑组织含水量及脑组织ICAM-1水平的影响。方法SD大鼠48只,随机分为假手术组（n=16）、缺血再灌注组（n=16）和bFGF组（n=16）。应用线栓法制作大鼠局灶性脑缺血再灌注模型,大脑中动脉阻塞1h再灌注损伤24h,bFGF组伤后即刻一次性经腹腔注射bFGF（10g／kg）,假手术组和损伤组以相同方法给予0．9％的生理盐水。采用干湿法检测各组大鼠脑组织含水量,采用伊文思蓝（evansblue,EB）法检测脑毛细血管通透性,采用免疫组化法检测大鼠脑组织ICAM-1水平。结果与假手术组比较,缺血再灌注组脑含水量、脑皮质EB含量及ICAM-1表达显著增加（P〈0．05）,与缺血再灌注组比较,bFGF组脑含水量、脑皮质EB含量及ICAM-1表达较模型组显著性降低（P〈0．05）。结论ICMA-1表达增加是脑缺血再灌注后脑水肿形成和缺血性损伤的重要原因之一,减少ICAM-1表达和脑组织含水量推测是bFGF脑保护作用机制之一。     

急性局灶性脑挫裂伤后大鼠血脑屏障改变的实验研究

目的:研究急性局灶性脑挫裂伤后大鼠血脑屏障的改变及对脑水肿的影响。方法:采用Feeney's自由落体撞击法建立急性局灶性脑挫裂伤模型。每组6只测量伤侧脑组织伊文思蓝(Evans Blue,EB)含量、脑组织含水量。每组3只电镜观察微血管内皮细胞超微结构改变。结果:急性局灶性脑挫裂伤后24h脑组织含水量为(79.79±0.83)%,与正常对照组(78.68±0.63)%相比有明显差异(P<0.01),脑损伤后6h脑组织中EB含量为(362.12±28.16)ug/g,与正常对照组(11.89±2.28)ug/g相比有明显差异(P<0.01);脑损伤后30min,微血管内皮细胞有轻度受损迹象,伤后3h毛细血管腔内有微绒毛形成,伤后6h微绒毛增多,伤后24~72h毛细血管腔明显狭窄。结论:脑含水量的变化与脑组织中EB含量变化不同步,BBB的开放先于脑水肿的形成。BBB的开放与微血管的机械性损伤、内皮细胞吞饮小泡增加、内皮细胞紧密连接中断有关,也与早期缺血、缺氧关系密切。     

孕酮对局灶脑缺血再灌注大鼠血—脑脊液屏障变化的影响

目的探讨孕酮（PROG）减轻缺血/再灌注（I/R）时脑水肿的机制。方法采用大鼠局灶性脑I/R模型,分光光度计定量测定大脑中动脉阻塞(MCAO)2h再灌注22h后脑皮层伊文思蓝（EB）含量的变化及PROG的影响。结果MCAO侧EB含量I/R组为5.89±1.37μg/g湿重,溶剂（DMSO)组为5.03±2.70μg/g湿重,PROG组为2.07±0.96μg/g湿重;PROG组显著低于I/R组和DMSO组（P<0.05）。结论PROG显著降低缺血2h再灌注22h时血-脑脊液屏障（BBB）的通透性,这可能是其减轻I/R时脑水肿的机制之一。     

实验性脑出血灶周MMP-9的表达与脑水肿的关系

目的探讨脑出血（ICH）后出血灶周脑组织MMP-9表达的动态变化,分析其与脑水肿的关系。方法健康雄性Sprauge-Dawley（SD）大鼠56只,分为正常组（8只）和手术组（48只）,手术组选择出血后12、24、48、72、96、120h共6个时间点,每点各8只。在脑立体定向仪下采用自体动脉血注入尾状核法制备脑出血模型。用免疫组化法和RT-PCR法检测MMP-9的表达水平;用干湿重法测量脑含水量（BWC）;用测定渗出脑血管外的EB量来评价BBB的通透性,电镜观察神经元形态变化。结果ICH灶周脑组织MMP-9的表达在48h达峰值,脑水肿于72h达峰值,两者呈正相关（r=0．698,P〈0．01）。电镜观察到血管周围水肿,神经元水肿。结论MMP9参与了ICH后灶周脑组织水肿的过程,诱导或加重脑水肿。     

亚低温治疗大鼠缺血性脑水肿研究

目的研究亚低温对延迟时间窗再灌注的局灶脑缺血大鼠缺血性脑水肿的治疗作用。方法 SD雄性大鼠96只,线栓法制作大脑中动脉闭塞模型后随机分为缺血3 h组、缺血6 h组、缺血9 h组(每组各30只),分别在造模3 h、6 h和9 h后拔出线栓,使大脑中动脉再灌注。各缺血组按照再灌注后是否给予亚低温治疗及亚低温持续时间分为常温、亚低温3 h和亚低温5 h三个亚组,每个亚组有10只大鼠。另设假手术组6只。缺血组大鼠在再灌注24 h后处死取脑,假手术组在术后24 h处死取脑,干-湿重法测定各组缺血侧脑组织含水量并进行比较。结果与假手术组比较,缺血组缺血侧脑组织含水量明显增高。缺血3 h组中3 h亚低温和5 h亚低温亚组的缺血侧脑组织含水量与缺血3 h常温组比较,差异有统计学意义(79.39%±2.44%vs82.16%±1.50%,P0.05;79.20%±1.55%vs 82.16%±1.50%,P0.05)。其余各缺血组中经过亚低温治疗的大鼠与常温亚组的脑组织含水量无统计学差异。结论亚低温可减轻缺血早期(3 h)再灌注的脑组织水肿,保护缺血脑组织,而对晚期(6 h和9 h)再灌注的缺血性脑水肿无论亚低温时间长短均无明显保护作用。     

亚低温对大鼠缺血再灌注后脑梗死体积和神经功能及ICAM-1的影响

目的研究亚低温对缺血脑组织的保护作用及对缺血区炎症反应的影响。方法制作大鼠大脑中动脉脑缺血模型,观察亚低温治疗对大鼠脑梗死灶体积、神经功能和缺血脑组织细胞间黏附分子-1(ICAM-1)表达的影响。结果亚低温组和常温组大鼠脑梗死体积占全脑体积的百分比分别为(22.95±2.69)和(30.83±2.67),神经功能评分分别为(1.43±0.25)和(1.97±0.30)分,ICAM-1表达的阳性血管数分别为(29.04±4.59)和(51.94±5.93),差异均有显著性意义。结论亚低温对缺血脑组织具有保护作用,对炎症级联反应的抑制是其发挥脑保护作用的重要机制之一。     

大鼠脑出血周边组织MMP-9、TIMP-1表达对脑水肿的影响

目的:研究大鼠脑出血周边组织基质金属蛋白酶系(MMPs)的成员明胶酶-9(MMP-9)和内源性基质金属蛋白酶抑制物(TIMP-1)表达对脑水肿的影响。方法:Wister大鼠50只随机分为对照组、出血组,各组又分为6、24、48、72、120h等5个时间点。测定脑组织含水量、脑组织示踪剂伊文思蓝(EB)含量和MMP-9、TIMP-1表达。结果:出血后脑组织含水量在72h、EB含量在48h、MMP-9和TIMP-1表达在48h达到高峰,血脑屏障(BBB)在各时间点均有破坏。结论:出血后MMP-9表达可导致BBB通透性增加,TIMP-1通过抑制MMP-9的表达减轻脑水肿。     

糖尿病大鼠缺血-再灌注对脑组织核转录因子-κBp65和基质金属蛋白酶-9表达的影响

目的观察糖尿病大鼠缺血-再灌注后脑组织核转录因子-κBp65和基质金属蛋白酶-9的表达及意义。方法89只Wistar大鼠随机分为正常对照组、假手术组、缺血-再灌注组和糖尿病缺血-再灌注组，采用腹腔注射小剂量链脲佐菌素诱发形成糖尿病大鼠模型，线栓法复制大鼠大脑中动脉缺血-再灌注模型；应用免疫组织化学方法分别检测再灌注0h、6h、12h及24h脑组织标本中核转录因子-κBp65和基质金属蛋白酶-9的表达水平。结果糖尿病缺血-再灌注组和缺血-再灌注组大鼠核转录因子-κBp65和基质金属蛋白酶-9主要表达于缺血周边区。糖尿病缺血-再灌注组大鼠再灌注0h、6h、12h及24h核转录因子-κBp65阳性细胞百分率分别为（24．68±4．19）％、（53．37±7．86）％、（72．38±7．24）％和（60．66±5．02）％，与缺血-再灌注组同-时限相比差异有统计学意义（P〈0．01）；基质金属蛋白酶-9阳性血管数分别为（0．83±0．81）支、（2．44±1．61）支、（5．08±2．11）支和（3．63±1．60）支，与缺血-再灌注组同一时限比较，再灌注0h组间差异无统计学意义（P〉0．05），而再灌注6h和12h组间差异有统计学意义（P〈0．01），其中24h组基质金属蛋白酶-9阳性表达低于12h组（P〈0．05）。缺血周边区脑组织核转录因子-κB065与基质金属蛋白酶-9的表达具有明显的时间相关性。结论糖尿病大鼠缺血-再灌注后，脑组织对核转录因子-κBp65和基质金属蛋白酶-9的表达水平升高且表达时间提前，这可能是糖尿病加重脑缺血-再灌注损伤的机制之一。     

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.