血清IL-6在小鼠单纯疱疹病毒I型复发感染中的意义

目的探讨血清中IL-6在小鼠单纯疱疹病毒I型复发感染中的意义。方法将单纯疱疹病毒I型潜伏感染的小鼠用过热作为应激原,诱发病毒的复发感染。以免疫组化检测病毒抗原的表达观察病毒活化;用放射免疫的方法检测血清中IL-6水平的变化。结果热应激后,疱疹病毒潜伏感染小鼠的部分三叉神经节细胞出现HSV-1抗原阳性表达,12～24hOD值达高峰,之后下降。小鼠血清IL-6水平也出现升高,12h为峰值,24h后开始下降,持续48h。与对照组比较差异有统计学意义(P<0.05)。结论IL-6能够诱发单纯疱疹病毒-Ⅰ型的复发感染。     

IL-6在小鼠单纯疱疹病毒Ⅰ型潜伏与再激活感染中的表达及意义

目的探讨细胞因子IL-6在小鼠三叉神经节单纯疱疹病毒I型(HSV-1)潜伏与再激活感染时的表达及其意义。方法用角膜划痕法建立Balb/c小鼠HSV-1潜伏感染模型,紫外线角膜照射诱发疱疹病毒的再激活。免疫组织化学法检测小鼠三叉神经节病毒抗原和IL-6的表达,Mias2000图像分析系统测定其平均光密度值。结果HSV-1潜伏感染组小鼠三叉神经节细胞周围卫星细胞出现IL-6的弱表达,其OD值高于对照组(0.198±0.025 vs 0.145±0.017,P<0.05);再激活感染组小鼠三叉神经节IL-6的表达在2d达高峰,其OD值高于同一时间点单纯紫外线照射组(0.282±0.047 vs 0.230±0.040,P<0.05),同时三叉神经节单纯疱疹病毒抗原的表达在2~4d也达最高值。结论IL-6是一多功能的细胞因子,对于HSV-1潜伏感染的维持以及病毒再激活的发生和病毒的清除都起重要作用。     

小鼠单纯疱疹病毒Ⅰ型脑内潜伏感染的实验研究

目的:探讨单纯疱疹病毒Ⅰ型(HSV-Ⅰ)F株初次感染后在脑内是否形成潜伏感染。方法:用角膜划痕法给Balb/c小鼠接种单纯疱疹病毒Ⅰ型F株,6周后用免疫组化法检测脑组织不同部位及三叉神经节HSV-1抗原的表达,聚合酶链反应(PCR)方法分别检测小鼠脑的颞叶、脑干、小脑及三叉神经节疱疹病毒DNA片段。结果:病毒接种6周后,小鼠三叉神经节、脑组织的不同部位未检测到HSV-1抗原的表达;三叉神经节、脑的颞叶、脑干和小脑均检测到了疱疹病毒DNA片段。结论:单纯疱疹病毒除了可以在三叉神经节建立潜伏感染外,脑组织也是其建立潜伏感染的部位之一。     

三叉神经根区粘连蛛网膜组织中IL-6的表达及意义

目的探讨原发性三叉神经痛(TN)患者三叉神经根区粘连的蛛网膜组织中白细胞介素-6(IL-6)表达对单纯疱疹病毒Ⅰ型(HSV-1)的影响,并进一步探讨HSV-1感染与TN的关系。方法首先采用PCR方法检测TN患者三叉神经根区粘连的蛛网膜、无粘连的蛛网膜组织中HSV-1特异性基因片段,再用免疫印迹法分别检测上述组织中抗原的表达,从而确定病毒感染状态,将其重新划分为HSV-1潜伏感染组、增殖感染组、未感染组,再用酶联免疫吸附测定法分别定量检测三组蛛网膜标本组织和患者血清中IL-6水平。结果 HSV-1增殖感染组的蛛网膜组织中IL-6水平[(324.64±14.28)pg/g]高于潜伏感染组[(232.75±19.17)pg/g],潜伏感染组也高于未感染组[(93.54±14.08)pg/g],且均有统计学差异(P<0.01);血清中IL-6水平三组之间无明显差异(P>0.05)。结论 IL-6是HSV-1增殖感染过程中的重要介质。HSV-1的增殖感染可能诱发或加重三叉神经根区蛛网膜的粘连,蛛网膜组织可能也是HSV-1的潜伏基地。HSV-1感染可能是继血管压迫之外造成三叉神经根区蛛网膜粘连继而引发TN的另一重要因素。     

小鼠单纯疱疹病毒Ⅰ型脑内潜伏感染LAT基因的表达及意义

目的　观察小鼠单纯疱疹病毒 I型 (HSV - 1)脑内潜伏感染时潜伏相关转录子 (L AT)在脑组织与三叉神经节 (TG)表达的差异 ,探讨 HSV - 1脑内潜伏再激活感染的发病机制。方法　用颅内病毒接种法给 Balb/ c小鼠接种单纯疱疹病毒 I型 F株 ,建立 HSV- 1脑内潜伏感染模型 ,病毒接种 8周后半定量 RT- PCR方法分别检测小鼠三叉神经节和脑的颞叶、小脑、脑干 L AT m RNA的表达。结果　小鼠三叉神经节和脑的不同部位均有 L AT m RNA的表达 ,三叉神经节、颞叶、小脑和脑干的半定量值分别为 :0 .6 86 0、0 .4 2 2 3、0 .3915和 0 .4 4 72。三叉神经节的半定量值高于脑的其它部位 (P<0 .0 5 )。结论　三叉神经节与脑组织 L AT m RNA表达水平的差异可能是两者病毒潜伏再激活感染发生机制不同的原因之一。     

小鼠单纯疱疹病毒性脑炎主要免疫反应特性研究

目的 了解单纯疱疹病毒性脑炎(HSE)小鼠的主要免疫反应特性.方法 Balb/c小鼠颅内注射HSV1病毒制造HSE模型,脑组织切片观察病理变化,流式细胞仪检测CD11b、CD40、MHCⅠ、MHCⅡ抗原表达水平,RT-PCR检测脑内细胞因子(IL-2、IL-4、IL-10、TNF-α)mRNA表达水平.结果 HSE小鼠脑组织片状坏死出血.HSE小鼠表达CD11b、CD40、MHC 、MHC 增加,TH1型细胞因子(IL-2、TNF-α)、TH2型细胞因子(IL-4、IL-10)显著增高.结论 小胶质细胞感染后被激活、增殖,MHC增加以发挥抗原提呈作用;CD40表达将进一步激活小胶质细胞,促进TH1及TH2型细胞因子分泌.     

免疫增强药物对单纯疱疹病毒性脑炎预后的影响

目的:检测细胞因子IL-2、IL-10、TNF-α在单纯疱疹病毒性脑炎(HSE)中的表达和变化。探讨具有免疫增强作用的药物干预(利比、黄芪)对小胶质细胞细胞因子分泌及对HSE疾病预后的影响。方法:使用逆转录-聚合酶链反应(RT-PCR)检测颅内感染单纯疱疹病毒I型(HSVⅠ)的小鼠在感染后及使用具有免疫增强作用的药物治疗后各细胞因子变化及观察脑组织切片HE染色后的病理变化。结果:HSVⅠ感染后出现脑内出血坏死性的病理改变,各细胞因子均明显上升;各用药组治疗好转后脑内病理变化改善,IL-2保持稳定、IL-10继续升高,TNF-α显著下洚。结论:具有免疫增强作用的药物可调节小胶质细胞分泌细胞因子的动态平衡,改善HSE的预后。     

白细胞介素-2基因佐剂对单纯疱疹病毒糖蛋白D DNA疫苗的免疫增强作用

目的探讨自细胞介素-2（IL-2）基因佐剂对单纯疱疹病毒Ⅰ型（HSV—Ⅰ）糖蛋白D（gD）DNA疫苗的免疫调节作用。方法将表达HSV—Ⅰ gD基因的DNA疫苗质粒IRES-gD以及HSV-Ⅰ gD与IL-2基因共表达的重组质粒IRES-gD-IL-2分别注入BALB／c鼠股四头肌，检测特异性抗体和中和抗体的产生情况，并于第3次注射后14d用滴度100组织培养半数感染量（TCID50）的HSV—Ⅰ病毒感染小鼠，观察小鼠的生存情况。结果IRES-gD组和IRES-gD-IL-2组均可刺激小鼠产生抗HSV—Ⅰ gD的特异性抗体和中和抗体，抗体滴度随免疫次数增加而升高IRES-g D-IL-2组小鼠产生的抗体及中和抗体滴度明显高于IRES-gD组，两组小鼠的生存率差异无统计学意义。绪论IL-2基因佐剂可促进HSV—Ⅰ gD DNA疫苗诱导抗体的产生，并具有免疫增强作用。     

HCV感染小鼠小胶质细胞后TLR7 mRNA和IL-6表达

目的通过观察丙型肝炎病毒(HCV)感染小鼠小胶质细胞BV2后Toll样受体(TLR)7 mRNA及白细胞介素(IL)-6水平的动态变化,探讨HCV对中枢神经系统(CNS)的免疫发病机制。方法用20%(体积分数)的HCV阳性血清感染BV2细胞,在感染后6、12、244、8 h收集细胞,应用实时荧光定量PCR(RT-qPCR)和ELISA法检测TLR7 mRNA和IL-6表达,同时设空白对照组和正常血清组。结果 3组BV2细胞中均有TLR7 mRNA表达;HCV阳性血清感染BV2细胞后TLR7 mRNA表达随时间延长而逐渐增高,其中在12、24、48 h时表达水平均较其他两组增高(P<0.05)。IL-6表达在HCV阳性血清组也逐渐增高,48 h时与空白对照组、正常血清组48 h时比较差异有统计学意义(P<0.05)。结论 BV2细胞可以表达TLR7 mRNA,HCV感染能上调BV2细胞TLR7 mRNA和IL-6表达。TLR7可能参与了HCV对CNS的病理生理过程。     

细胞因子IL-2、IL-10、TNF-α在小鼠单纯疱疹病毒性脑炎中的表达

目的检测细胞因子IL-2、IL-10、TNF-α在单纯疱疹病毒性脑炎(HSE)中的表达和变化,探讨细胞因子IL-2、IL-10、TNF-α在HSVE发病机制中的作用.方法使用逆转录-聚合酶链反应(RT-PCR)检测颅内感染单纯疱疹病毒1型(HSV1)的小鼠在感染后及使用无环鸟苷(ACV)治疗后细胞因子IL-2、IL-10、TNF-α变化及病理变化.结果HSV1感染后出现脑内出血坏死性的病理改变,IL-2、IL-10、TNF-α均明显上升;无环鸟苷治疗好转后脑内病理变化改善,IL-2保持稳定,IL-10继续上升,TNF-α显著下降.结论在小鼠HSVF急性期TH1型及TH2型反应同时被激活,发挥抗病毒作用,并以TH1型反应为主;在HSVE恢复期以TH2型反应为主,并抑制体内免疫反应的扩大;3种细胞因子的动态变化反映出机体免疫调节的动态平衡,并可反映HSVE的预后,早期应用ACV治疗HSVE确有极其明显的抗病毒治疗作用.     

Diagnostic Difficulties and Treatment Implications

Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.     

Cognitive Dysfunction Associated with Antiepileptic Drug Therapy

Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.     

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.     

Carbamazepine Efficacy in Adults With Partial and Generalized Tonic-Clonic Seizures

Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.     

Etiologic and Preventive Aspects of Epilepsy in the Child–Bridging the Gap Between Laboratory and Clinic

Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.     

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.     

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.     

Predisposing and Causative Factors in Childhood Epilepsy

Summary: We review information from large studies of defined populations, examining the role of known factors and especially of prenatal and perinatal factors in contributing to nonfebrile seizure disorders of early childhood. We depend especially, but not exclusively, on the recently completed analyses from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, the NCPP. About 4% of children in the NCPP who had at least one non-febrile nonsymptomatic seizure by the age of 7 years had a previous seizure during acute neurologic illness, such as meningitis or during the acute illness after trauma. Many such seizures should potentially be preventable. Of children with seizures, 10% had had a neonatal seizure and 13% had had a febrile seizure. Among the hundreds of prenatal and perinatal factors explored as predictors of childhood seizure disorders, the principal predictors identified were congenital malformations of the fetus, cerebral and noncerebral; family history of certain neurologic disorders; and neonatal seizures. In agreement with the British National Child Development Study, labor and delivery factors in the NCPP appeared to contribute very little to childhood seizure disorders. Maldevelopment, rather than damage at birth to an initially intact nervous system, appeared to be the more common mechanism. Most seizure disorders of early childhood remained unexplained by the large set of prenatal and perinatal characteristics examined.     

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.