脑膜瘤中HIF-1α和COX-2的表达及与血管生成的关系

目的探讨缺氧诱导因子-1(HIF-1α)和环氧化酶-2(COX-2)在人脑膜瘤中表达的意义及与肿瘤血管形成的关系。方法应用免疫组织化学方法检测54例人脑膜瘤和10例正常脑组织中HIF-1α和COX-2的表达,用CD34抗体标记微血管并计数相应的微血管密度(MVD),对所得资料进行统计学分析。结果脑膜瘤组织中HIF-1α、COX-2表达均高于正常脑组织,差异有统计学意义(P<0.05);肿瘤组中MVD值(32.9±12.9)高于正常对照组(11.2±3.3),并且随病理分级的增高而增加(P<0.05);HIF-1α、COX-2表达与MVD存在显著相关性(rs=0.65、0.72,P均<0.01);HIF-1α与COX-2表达呈正相关(rs=0.35,P<0.01)。结论HIF-1α和COX-2的表达异常在脑膜瘤的发生发展中起重要作用,并且在促进肿瘤血管形成过程中两者可能起协同作用。     

脑膜瘤缺氧诱导因子-lα表达与瘤周血管生成及病理级别的关系及意义

目的探讨脑膜瘤缺氧诱导因子-lα(HIF-lα)表达与瘤中血管生成及病理级别之间的关系,探讨HIF-lα在脑膜瘤发生和发展中的作用,为治疗脑膜瘤提供理论依据。方法选取脑膜瘤标本45例,正常脑组织标本10例(均为重型颅脑损伤急症行内减压术)作为对照。采用免疫组化ElivisionTMplus两步法,检测缺氧诱导因子-lα在脑膜瘤标本和正常脑组织标本中的表达,以人原始造血细胞(CD34)标记肿瘤微血管,用微血管密度(MVD)作为血管生成指标测定肿瘤血管生成,比较缺氧诱导因子-lα表达与血管生长及病理级别关系。结果45例脑膜瘤组织切片中有23例表达HIF-1α,染色阳性率为51.1%,HIF-1α在正常脑组织及脑膜瘤Ⅰ级、Ⅱ级、Ⅲ级中的阳性表达率分别为0.00%、32.00%、66.67%和87.50%。在各个级别的脑膜瘤及正常脑组织中,HIF-1α的阳性表达率间差异有显著性(P<0.05)。正常脑组织组、I、II和III级脑膜瘤组中的MVD值分别为10.34±2.78,17.25±2.69,20.43±5.20和30.79±5.64,MVD值随着脑膜瘤级别的升高逐渐增加。HIF-lα表达程度与MVD呈正相关。结论缺氧诱导因子-lα表达强度与脑膜瘤血管生成可能有关,为治疗脑膜瘤提供了新的思路。     

缺氧诱导因子-1α、血管内皮生长因子与脑膜瘤血管生成、肿瘤恶性程度的关系

采用免疫组织化学二步法对48例脑膜瘤及9例瘤旁正常脑组织中的缺氧诱导因子-1α(HIF-1α)和血管内皮生长因子(VEGF)的表达进行研究，以探讨脑膜瘤组织血管生成及其与临床预后的关系。     

缺氧诱导因子-lα和血管内皮生长因子在人脑胶质瘤中的表达及意义

目的:探讨缺氧诱导因子-1α(HIF-1α)、血管内皮生长因子(VEGF)和微血管密度(MVD)在人脑胶质瘤中的表达情况,分析三者的关系及其意义。方法:应用免疫组化方法分析62例人脑胶质瘤中HIF-1α、VEGF、和MVD的表达情况。结果:本组HIF-1α的总阳性表达率是66.1%,它们在正常脑组织和Ⅰ-Ⅱ、Ⅲ、Ⅳ肿瘤组织的阳性率分别为0%、39.3%、81.8%、100%与正常对照组比较有显著性差异(P<0.01)。HIF-1α表达水平与胶质瘤恶性度存在相关性(P<0.01)。VEGF在HIF-1α阳性组中的阳性率(95.1%)明显高于HIF-1α阴性组中的VEGF的阳性率47.6%(P<0.01)。结论:HIF-1α和VEGF的表达与MVD存在正相关关系;VEGF与HIF-1α表达呈正相关性,二者与人脑胶质瘤的病理分级呈正相关,与脑胶质瘤新生血管生成有关。     

脑膜瘤内的血管分布和血管生成与HIF-1α、VEGF的关系

目的 探讨脑膜瘤内部的血管分布以及缺氧诱导因子-1α(HIF-1α)、血管内皮生长因子(VEGF)与脑膜瘤血管生成的关系. 方法 选取中山大学附属一院和中山市人民医院神经外科自2010年5月至2011年3月间手术切除并经病理证实的人脑膜瘤标本15例,收集每例标本硬膜鼠尾征处、基底中心、瘤中央、瘤缘4个不同部位的脑膜瘤组织,每个部位分别连续切片3张,应用免疫组化染色检测CD34、VEGF、HIF-1α的分布和表达. 结果 CD34主要表达在细胞膜和细胞浆,染色呈棕黄色颗粒,VEGF定位于肿瘤细胞胞浆内,而HIF-1α主要在细胞核,少量在胞浆.尾征和瘤缘部位MVD、VEGF、HIF-1α的表达高于基底中心和瘤中央,差异有统计学意义(P＜0.05).脑膜瘤MVD与VEGF、MVD与HIF-1α、VEGF与HIF-1α表达之间均呈正相关关系(r=0.960,P=0.040;r=0.964,P=0.036;=0.998,P=0.002). 结论 脑膜瘤外周部的血管生成比中央区丰富;HIF-1α、VEGF在诱导并促进脑膜瘤的血管生成方面发挥一定作用.     

缺氧诱导因子-1α、增殖细胞核抗原表达与脑胶质瘤预后相关性的研究

目的探讨缺氧诱导因子-1α(HIF-1α)、增殖细胞核抗原(PCNA)表达对人脑胶质瘤预后的影响。方法采用免疫组织化学方法检测63例脑胶质瘤HIF-1α、PCNA的表达状况,并将结果与随访结果进行综合分析。结果HIF-1α总阳性表达率为71.4%(45/63)。其强表达16例(25.4%),中度表达14例(22.2%),弱表达15例(25.4%),阴性表达18例(28.6%)。与正常对照组比较有显著性差异(P<0.01)。HIF-1α表达水平与胶质瘤恶性程度呈正相关(r=0.467,P<0.01)。HIF-1α主要表达于肿瘤边缘或与正常组织交界处的细胞及坏死的肿瘤组织中。不同组织学分级的脑胶质瘤标本肿瘤细胞均有PCNA表达,脑质瘤Ⅰ级、Ⅱ级和Ⅲ-Ⅳ级PCNALI分别为1.8±1.2、2.9±1.1、4.2±1.0,组间比较有显著性差异(P<0.01)。PCNA表达与HIF-1α表达水平呈正相关(r=0.847,P<0.01)。结合随访结果提示,HIF-1α阳性表达患者的生存时间明显短于阴性表达者。结论脑胶质瘤PCNA与HIF-1α表达有一定的相关性。HIF-1α与脑胶质瘤的恶性程度有关。HIF-1α、PCNA联合检测可能用于判断患者的预后。     

HIF-1α和COX-2在脑膜瘤中的表达与血管生成的相关性研究

目的探讨HIF—1α、COX-2两种血管生成因子在脑膜瘤中的表达及与临床病理分期和微血管密度的关系。方法采用免疫组化技术（S-P法）检测52例不同分化程度的脑膜瘤组织中HIF—1α、COX-2、CDl05的表达。结果52例脑膜瘤中HIF—1α、COX-2的阳性率分别为65．4％,69．2％,HIF-1α、COX-2阳性组的MVD均高于阴性组。HIF-1α、COX-2阳性率在不同WHO分期之间的差别有统计学意义。HIF-1α的表达与COX-2表达具有相关性。结论HIF—1α、COX-2在脑膜瘤中的表达与微血管密度呈正相关,通过抑制它们在脑膜瘤中表达可能成为抑制脑膜瘤血管生成的途径。在脑膜瘤中HIF—1α的表达与COX-2呈正相关。检测HIF-1α、COX-2在脑膜瘤中的表达对判断脑膜瘤的临床病理分期有价值。     

脑胶质瘤中缺氧诱导因子-1α的表达及与肿瘤分级的相关性

目的观察胶质瘤中缺氧诱导园子-1α(HIF-1α)蛋白及HIF-1αmRNA的表达情况,探讨HIF-1α在胶质瘤中的表达特点,与胶质瘤分级的关系及意义。方法用SABC免疫组化法和原位杂交检测41例胶质瘤和8例正常脑组织标本中HIF-1α蛋白和HIF-1αmRNA的表达,并将胶质瘤分级,比较各级之间阳性表达率的差异。结果41例胶质瘤标本中HIF-1α蛋白阳性表达率为56.1%(23/41例),而8例正常恼组织中HIF-1α蛋白阳性表达率为0,二者相比有显著性差异(P<0.05)。HIF-1α蛋白在胶质瘤各病理分级中的阳性表达率分别为Ⅰ+Ⅱ级42.3%(11/26例),Ⅲ+Ⅳ级80.0%(12/15例),二者之间有显著性差异(P<0.05)。HIF-1αmRNA在胶质瘤中与正常脑组织表达无显著性差异(P>0.05),在胶质瘤各病理分级中的表达亦无显著性差异(P>0.05)。结论HIF-1α在胶质瘤中的表达上调,且与胶质瘤病理分级相关,它有助于肿瘤细胞在缺氧状态下的存活,协助肿瘤的生长和侵袭。HIF-1α在胶质瘤中表达的调节是在转录后水平。     

缺氧诱导因子-1在缺氧幼鼠脑组织中的表达及意义

目的探讨缺氧窒息幼鼠脑组织中缺氧诱导因子-1α(hypoxia-inducible factor-1alpha,HIF-1α)表达水平的变化。方法取50只SD幼鼠,随机分为模型组(n=25)和对照组(n=25)2组,模型组做缺氧处理,对照组不作缺氧处理,于缺氧后48h测定幼鼠脑组织中HIF-1αmRNA表达的相对含量。结果 2组幼鼠脑组织中HIF-1αmRNA表达含量的差异有统计学意义(P<0.05)。HIF-1αmRNA表达的相对含量缺氧组[(1.00±0.02)ng/L]比正常组[(0.040.01)ng/L]显著增高(P<0.05),正常组HIF-1α表达含量相对极少。结论 HIF-1α是在缺氧条件下产生的一种转录因子,通过调控一系列与适应缺氧有关的基因表达来减缓细胞缺氧所带来的损伤。     

脑胶质瘤细胞中HIF-1α表达及其与细胞凋亡、增殖关系

目的探讨缺氧诱导因子-1α(HIF-1α)在人脑胶质瘤中的表达及其与肿瘤细胞增殖、细胞凋亡和肿瘤恶性程度的关系。方法采用免疫组化法检测60例脑胶质瘤HIF-1α、增殖细胞核抗原(PCNA)的表达,用TUNEL法检测肿瘤细胞凋亡情况,对结果进行综合分析。结果HIF-1α总阳性表达率为73.3%,其中强表达19例(31.7%),中度表达14例(23.3%),弱表达11例(18.3%),不表达16例(26.7%);胶质瘤Ⅰ~Ⅱ级、Ⅲ~Ⅳ级HIF-1α的阳性率分别为50.0%、86.8%,组间有统计学差异(P<0.01)。脑胶质瘤标本PCNA及细胞凋亡均阳性,胶质瘤Ⅰ~Ⅱ级、Ⅲ~Ⅳ级PCNA阳性细胞数分别为54.9±8.2、121.6±15.6,凋亡细胞阳性数分别为85.4±10.4、52.1±7.6,比较均有显著性差异(P<0.01)。HIF-1α表达与肿瘤细胞的PCNA阳性数呈正相关(P<0.01),与肿瘤细胞的凋亡数无明显关系(P>0.05)。结论脑胶质瘤细胞HIF-1α表达与肿瘤的恶性程度有一定相关性;HIF-1α表达水平与肿瘤细胞增殖呈正相关,而与肿瘤细胞的凋亡无关。     

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.