人星形细胞瘤TGF—α表达与血管形成的研究

目的探讨TCF-α在人脑星形细胞瘤中表达，研究其在肿瘤血管形成中的作用。方法用SP免疫组化法检测50例人脑星形细胞瘤标本中TCF-α蛋白表达；用抗CD34相关抗原单克隆抗体免疫组化染色显示肿瘤组织微血管，并以微血管密度（miemvessel density，MVD）测定肿瘤血管生成。结果实验组50例人脑星形细胞瘤TGF-α表达总阳性率64％（32／50）；总MVD38.88±19．13，显著高于正常脑组织组9．30±3．74（P〈0．01）。随着人脑星形细胞瘤级别增高，MVD数值呈现增高趋势。TGF-α与MVD呈显著线性正相关性（r=0．869，P〈0．01））。结论TGF-α在人脑星形细胞瘤中高表达，可能参与人脑星形细胞瘤的血管形成．     

Survivin、Bcl-2和PTEN在人脑星形细胞瘤中的表达及相关性研究

目的 研究人脑星形细胞瘤中survivin、bcl-2和PTEN的表达情况及相关性，探讨其与星形细胞瘤的发展、临床病理参数之间的关系。方法 应用免疫组织化学Elivision二步法检测实验组与正常对照组标本中survivin、bcl-2和PTEN的表达。结果 survivin、bcl-2和PTEN在不同级别星形细胞瘤中的阳性表达率有显著性差异（P〈0．01）。随着星形细胞瘤病理分级的增加，survivin和bcl-2表达的阳性率及表达强度渐增（P〈0．01），PTEN表达的阳性率及表达强度渐减（P〈0．01）。survivin和bcl-2的表达之间存在正相关关系（P〈0．01）；survivin、bcl-2与PTEN的表达均存在负相关关系（P〈0．01）。结论 在人脑星形细胞瘤中，survivin、bcl-2高表达和PTEN相对低表达，说明三者可能参与人脑星形细胞瘤的病理发展。     

人脑星形细胞肿瘤中FHIT、PCNA蛋白表达关系的研究

目的研究人脑星形细胞肿瘤中FHIT、PCNA蛋白的差异表达，探讨它们与病理分级之间的关系。方法应用免疫组化SP法检测了50例星形细胞肿瘤中不同级别的FHIT、PCNA蛋白的表达水平，以10例非肿瘤脑组织作对照。结果非肿瘤脑组织FHIT、PCNA蛋白阳性表达率分别为100％，0％，星形细胞肿瘤中FHIT、PCNA蛋白阳性表达率分别为40％，86％；尽管在星形细胞肿瘤中FHIT、PCNA蛋白表达总体差异有统计学意义（P〈0．05），但Ⅲ级与Ⅳ级比较差异无统计学意义（P〉0．05）；经统计学分析FHIT、PCNA蛋白呈显著负相关（P〈0．01）。结论FHIT、PCNA蛋白的表达可能与星形细胞肿瘤的恶性程度有关，星形细胞肿瘤中FHIT、PCNA蛋白表达之间的显著负相关，提示FHIT蛋白可能对细胞增殖具有负性调控作用。     

TP、MVD在人脑星形胶质细胞瘤中的表达及意义

目的探讨脑星形胶质细胞瘤组织胸苷磷酸化酶（TP）和微血管密度（MVD）的表达及其与星形细胞瘤的病理分级关系。方法选取病例50例，记录病例年龄、性别、组织学类型、病理分级。正常脑组织病例5例，鼠抗人单克隆抗TP抗体选取乳腺炎石蜡标本1例（阳性对照）。鼠抗人单克隆抗CD34抗体选取扁桃体炎石蜡标本1例（阳性对照）。将上述符合条件病例蜡块每例切片3张，利用免疫组化技术SP法检测它们TP、CD34的表达。结果5例正常尸检脑组织TP表达均阴性（-）；高级别星形胶质细胞瘤TP阳性表达率及微血管密度（MVD）值明显高于低级别星形胶质细胞瘤（WHOⅠ-Ⅱ级）（P〈0．05）。且口表达与MVD明显正相关（r=0．692，P〈0．05）。结论TP及MVD可以作为星形胶质细胞瘤恶性程度病理分级及判定预后的参考指标。     

14-3-3β在人脑星形细胞瘤中的表达及意义

目的探讨14-3-3β在人脑星形细胞瘤中表达与肿瘤病理分级的关系。方法采用免疫组化法检测14-3-3β亚型在80例人脑星形细胞瘤和10例正常脑组织标本中的表达水平。结果在正常脑组织中，14-3-3蛋白6亚型只表达于神经元胞体和突起，在胶质细胞中未见表达。母亚型在人脑星形细胞瘤的表达阳性率及免疫反应评分（IRS）分别为60％、1．86±1．83。Ⅰ～Ⅳ级脑星形细胞瘤中β亚型表达阳性率分别为40％（8／20）、50％（10／20）、70％（14／20）和80％（16／20）。Ⅰ～Ⅳ级脑星形细胞瘤中β亚型IRS分别为0．88．4±0．27、1．15±0．28、2．19±0．37和3．23±0．47。不同恶性级别的脑星形细胞瘤中，14．3-3蛋白β亚型的阳性表达率无显著差异，但其IRS有显著差异（P〈0．05）。结论14-3-3β在人脑星形细胞瘤中高表达，且随着星形细胞瘤病理级别的增高而表达增强，14-3-3蛋白β亚型在脑星形细胞瘤的发生过程中具有重要作用。     

14-3-3蛋白在星形细胞瘤中的表达及意义

目的探讨14-3-3蛋白在星形细胞瘤中的表达与肿瘤病理分级和预后间的关系。方法采用免疫组化ABC法检测10例正常脑组织和67例确诊并有随访的人脑星形细胞瘤石蜡标本中14-3-3蛋白的表达情况。分析14-3-3蛋白的表达与肿瘤恶性程度及预后间的关系。结果在正常脑组织标本中，14-3-3蛋白主要表达于神经元胞体和突起，而在少数的胶质细胞中仅见其弱表达。绝大部分星形胶质细胞瘤中可见14-3-3蛋白阳性表达，其阳性表达率为：Ⅱ级76．5％（13／17），Ⅲ级76．2％（16／21），Ⅳ级79．3％（23／29）。不同恶性级别的星形细胞肿瘤中，14-3-3蛋白的阳性表达率无显著差别（P〉0．05），但14-3-3蛋白表达的强度和范围有随肿瘤的恶性度增高而增加的趋势（P〈0．05）。52例14-3-3蛋白阳性表达患者的生存期明显短于15例14-3-3蛋白表达阴性的患者（P〈0．01）。结论14-3-3蛋白在人脑星形细胞瘤中的表达上凋与肿瘤的恶性程度及预后相关。14-3-3蛋白有望成为星形细胞瘤基因治疗的新靶点。     

脑胶质瘤低氧诱导因子-1α的表达及其意义

目的 探讨低氧诱导因子-1α在脑胶质瘤中的表达及其意义。方法60例脑胶质瘤标本中Ⅰ级11例（毛细胞型星形细胞瘤8例、脉络丛乳头状瘤2例、黏液乳头状型室管膜瘤1例）；Ⅱ级20例（弥漫型星形细胞瘤11例、少突胶质细胞瘤5例、室管膜瘤2例、多形性黄色瘤型星形细胞瘤2例）；Ⅲ级21例（间变性星形细胞瘤12例、间变性少突胶质细胞瘤6例、间变性室管膜瘤3例）；Ⅳ级8例（均为胶质母细胞瘤）。采用免疫组织化学方法检测胶质瘤标本中低氧诱导因子-1α的表达变化，并与胶质瘤体积及患者年龄、性别进行统计学分析。结果（1）胶质瘤组织低氧诱导因子-1α表达呈阳性反应，主要位于细胞质和（或）细胞核，具有明显的异质性；肿瘤浸润边缘部的肿瘤细胞表达明显增强；而阴性对照标本和10例对照脑组织标本则无表达。胶质瘤组织中低氧诱导因子-1α阳性表达率为71．67％（43／60），其中Ⅰ级为27．27％（3／11），Ⅱ级70．00％（14／20），Ⅲ级85．71％（18／21），Ⅳ级100％（8／8）。高级别胶质瘤者低氧诱导因子-1α阳性表达率明显高于低级别者，不同级别间差异有高度统计学意义（X^2=15．907，P〈0．01）；表达强度与病理级别间呈高度正相关（rn=0．480，P〈0．01）。（2）低氧诱导因子-1α表达与患者年龄、性别及原发肿瘤体积的大小等均无相关性（均P〉0．05）。结论脑胶质瘤低氧诱导因子-1α的表达强弱与肿瘤病理分级相关。     

Moesin在人脑星形细胞瘤的表达及意义

目的探讨膜结构伸展刺突蛋白（Moesin）在人脑星形细胞瘤中的表达及意义。方法应用免疫组织化学链霉菌抗生物素蛋白-过氧化物酶连结法（SP法）,检测56例人脑星形细胞瘤和10例正常脑组织中Moesin和磷酸化Moesin的表达,并结合临床随访资料分析表达水平与星形细胞瘤临床预后的相关性。结果Moesin的阳性表达率在人脑星形细胞瘤组96．4％（54／56）和正常脑组织对照组0％（0／10）之间有统计学差异（P〈0．01）。Ⅲ～Ⅳ级星形细胞瘤Moesin的强阳性表达高于Ⅰ～Ⅱ级,两者相比有统计学差异（χ^3=27．50,P〈0．01）,磷酸化Moesin的表达结果与Moesin的结果基本一致。Moesin强阳性表达组患者比弱阳性＋阴性表达组患者的术后无瘤生存时间短,其差异有统计学意义（χ^2=29．85,P=0．000）。结论Moesin的表达水平与人脑星形细胞瘤的恶性程度密切相关,Moesin的过度表达对星形细胞瘤发展和预后起重要作用,提示Moesin可以作为反映星形细胞瘤预后的一种有价值的分子标志物。     

PTEN／MMAC1基因表达与星形细胞瘤细胞增殖的相关性研究

目的研究人脑星形细胞瘤中PTEN/MMAC1基因编码蛋白的表达和星形细胞瘤增殖的关系,探讨PTEN/MMAC1基因突变在人脑星形细胞瘤增殖中的作用。方法应用PCR-SSCP、SP免疫组织化学法检测了52例星形细胞瘤中PTEN/MMAC1基因突变及表达情况,和肿瘤细胞核增殖抗原(PCNA)增殖程度;并用SPSS10.0统计软件分析PTEN/MMAC1基因表达与PCNA的关系。结果52例人脑星形细胞瘤中,PTEN/MMAC1蛋白表达缺失率约40.4%(21/52)。PTEN/MMAC1表达与肿瘤病理分级有显著关系,其中Ⅰ-Ⅱ级阳性率约80.0%,Ⅲ级约55.0%、Ⅳ级为33.3%,各级别组PTEN/MMAC1表达的差异有显著性(P<0.01);PTEN/MMAC1表达程度与星形细胞瘤的增殖呈显著负相关(r=-0.846,P<0.01)。结论PTEN/MMAC1表达与星形细胞瘤的恶性程度有关系,恶性程度越高,病人预后越差,该蛋白水平越低,肿瘤细胞的恶性增殖越明显。     

Olig-2在人脑胶质细胞瘤中的表达及临床意义

目的研究少突胶质细胞转录因子-2（Olig-2）在人脑胶质细胞瘤组织中的表达,并探讨其临床意义。方法采用免疫组化sP法和蛋门印迹技术（Westernblot）,检测96例脑胶质细胞瘤患者的手术标本,WHO分类：Ⅰ级26例,Ⅱ级28例,Ⅲ级20例,Ⅳ级22例;组织学分类：巨细胞星形胶质细胞瘤26例,少突胶质细胞瘤28例,间变性星形胶质细胞瘤20例,多形胶质母细胞瘤10例,髓母细胞瘤12例和10例颅脑损伤内减压脑组织标本中Olig-2蛋白的表达水平：结果免疫组化结果表明：巨细胞星形胶质细胞瘤阳性表达牢为23．08％（6／26）,少突胶质细胞瘤阳性表达率为82．14％（23／28）,间变性星形胶质细胞瘤阳性表达率为40．00％（8／20）,多形胶质母细胞瘤阳性表达率为30．00％（3／10）,髓母细胞瘤阳性表达率为75．00％（9／12）和正常脑组织阳性表达率为60．00％（6／10）;Olig-2阳性率在良性（Ⅰ＋Ⅱ）和恶性（Ⅲ＋Ⅳ）中分别为53．70％（29／54）和47．62％（20／42）,统计学处理无明显差异（P〉0．05）;少突胶质细胞瘤Olig-2阳性率82．14％（23／28）和其它病理类型肿瘤阳性率38．24％（26／68）比较有明显差异（P〈0．05）;Westernblot结果显示少突胶质细胞瘤中Olig-2蛋白的表达明显高于其它类型胶质细胞瘤及正常脑组织（P〈0．05）。结论Olig-2在少突胶质细胞瘤中明显高表达,但表达水平与脑胶质细胞瘤恶性程度无明显相关,Olig-2可以作为人脑少突胶质细胞瘤与其它类型胶质细胞瘤鉴别诊断的重要标记物.     

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.     

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.     

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.     

Treatment Considerations in Anticonvulsant Monotherapy

Summary: The long-standing practice of polypharmacy in treating epilepsy is giving way to use of monotherapy. Monotherapy can improve seizure control as well as reduce the risk of serious idiosyncratic reactions, dose-related side effects, and complex drug interactions. Monotherapy also offers improved compliance and cost-effectiveness. The basis of monotherapy is accurate diagnosis and assessment of the patient's seizure type(s), followed by selection of a single appropriate anticonvulsant drug. Many patients currently treated with multiple anticonvulsants can be successfully converted to monotherapy with a carefully monitored program in which troublesome and redundant drugs are gradually withdrawn from the therapeutic regimen.     

Anticonvulsant Drugs and Cognitive Function: A Review of the Literature

Summary: Alterations of cognitive function are separate from disturbances of behavior seen in association with epilepsy. The nature of the cognitive disability may to a certain extent depend on the seizure type. Partial seizures, mainly derived from a temporal lobe focus, impair memory tasks, while generalized seizures seem to have more effect on attentional abilities. A number of studies, reviewed in this paper, suggest that anticonvulsant drugs further impair cognitive function. Maximal impairments are seen in patients receiving polytherapy: rationalization of polytherapy improves cognitive abilities. Studies in children and adults have allowed differentiation of the effects of various commonly used antiepileptic agents. Maximal cognitive deficits are seen with. phenytoin, while phenobarbital and sodium valproate induce moderate disturbances, and carbamazepine seems relatively free from such toxicity. Further research is needed on the interrelationship between types of seizure disorders, types of anticonvulsant medications, and cognitive function.     

Dextromethorphan: Cellular Effects Reducing Neuronal Hyperactivity

Summary: Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and an-tiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N -methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.     

Effects of NMD A- and AMPA-Receptor Antagonists on Different Forms of Epileptiform Activity in Rat Temporal Cortex Slices

Summary: Lowering extracellular magnesium induces different patterns of epileptiform activity in rat hippocampus and entorhinal cortex. Short recurrent epileptiform discharges in the hippocampus are stable over time, whereas seizurelike events (SLEs) in the entorhinal cortex, the subiculum, and the neighboring neocortex develop into late recurrent discharges which are not blocked by clinically employed antiepileptic drugs. We tested the sensitivity of the different epileptiform discharge patterns to. /V-methyl-D-aspartate (NMDA)- and non-NMDA-receptor antagonists. As NMDA-receptor antagonist we used dextrorphan, ket-amine, and 2-aminophosphonovalerate (2APV); as α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-receptor antagonist we employed the quinoxaline derivative glutamate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The findings show that the different patterns of epileptiform activity, including the late recurrent discharges, are sensitive to all NMDA-receptor antagonists. However, when dextrorphan was employed to suppress seizure-like events, later recurrent discharges did not develop during the remaining time course of the experiment. CNQX reversibly suppressed recurrent discharges in the hippocampus and SLEs in the entorhinal cortex. However, late recurrent discharges become insensitive to CNQX, even at a high concentration of 60 μM m. This finding suggests a prominent role for NMDA receptors in the generation of late recurrent discharges.