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。     

脑胶质瘤端粒酶活性的表达及端粒长度的分析

目的　研究分析在不同级别脑胶质瘤细胞端粒酶活性的表达及端粒长度的变化。方法　采集 40例脑胶质瘤手术切除标本、 4例正常脑组织 ,通过半定量端粒重复序列扩增 (telomererepeatamplificationprotocol,TRAP) 银染方法检测端粒酶活性水平 ,应用人的端粒序列特异性探针32 P (CCC TAA) 3 进行Southern杂交检测脑胶质瘤细胞的端粒长度。结果　在 40例胶质瘤标本中的 33例(82 5 % )中均检出端粒酶活性 ,而在正常脑组织中无端粒酶活性的表达 ,不同级别胶质瘤之间端粒酶活性水平有明显差异 ;恶性胶质瘤细胞中端粒的长度明显比正常胶质细胞缩短 ,端粒的长度与端粒酶活性的水平有着显著的的负相关。结论　端粒酶活性可以作为脑胶质瘤的恶性标记之一 ,端粒的缩短可能是脑胶质瘤进展的重要因素 ,端粒的修复机制对于维持端粒的稳定性和肿瘤细胞的增殖潜能具有十分重要的意义     

脑胶质瘤端粒酶的活性研究

目的 探讨各类脑胶质瘤端粒酶的活性和端粒酶在胶质瘤的恶性程度评估、预后预测等方面的意义。方法 利用TRAP－ELISA方法检测27例胶质瘤中端粒酶的活性，结合肿瘤的病理分类资料进行对照分析。结果 27例胶质瘤中，低级别胶质瘤（星形细胞瘤Ⅰ－Ⅱ级、少胶质细胞瘤和室管膜瘤）14例，端粒酶阳性2例(16．7%)；高级别胶质瘤（呈形细胞瘤Ⅲ－Ⅳ级和间变性室管膜瘤）13例，端粒酶阳性10例（76．9％）。两组之间端粒酶阳性率有显著差异（P＜0．01）。另外，两组之间端粒酶活性定量水平也有显著差异（P＜0．05）。端粒酶阳性组和端粒酶阴性组胶质瘤患者在性别、年龄方面无显著差异（P＞0．05）。10例正常脑组织中未检测到端粒酶活性。结论 端粒酶活性的激活在胶质瘤中是常见的现象。不同恶性程度的胶质瘤，端粒酶活性的阳性率和端粒酶活性水平定量差异显著。端粒酶作为肿瘤标志物，在胶质瘤的恶性程度评估1预后预测等方面具有重要的意义。     

人脑胶质瘤中PCNA的表达及临床意义

目的探讨增殖细胞核抗原(PCNA)在人脑胶质瘤中的表达与肿瘤生长、侵润、转移、复发的关系及在胶质瘤发生发展中的作用,拟为手术治疗及疗效提供客观依据。方法采用免疫组织化学染色方法检测正常脑组织及胶质瘤细胞中增殖细胞核抗原PCNA阳性表达率。结果对照脑组织增殖细胞核抗原表达阴性;不同级别胶质瘤细胞增殖细胞核抗原阳性表达率依次为WHOⅣ级100%(6/6)、WHOⅢ级94.44%(17/18)、WHOⅡ级62.50%(10/16)和WHOⅠ级42.86%(3/7);增殖细胞核抗原表达率与胶质瘤组织病理学分级呈正相关(rs=0.589,P=0.000);WHOⅢ-Ⅵ级与WHO I-Ⅱ级之间差异具有统计学意义(H=13.239,P=0.000)。结论胶质瘤组织中增殖细胞核抗原表达水平和肿瘤组织病理学分级呈正相关。提示,增殖细胞核抗原与胶质瘤恶性进展密切相关。     

胶质瘤Polo样激酶1的表达与肿瘤细胞增殖活性及预后的关系

目的探讨Polo样激酶1(PLK1)在人脑胶质瘤组织上的表达及其与胶质瘤细胞增殖活性、临床病理和预后的关系。方法应用免疫组化法检测47例胶质瘤和8例正常脑组织中的PLK1和增殖细胞核抗原(PCNA)的表达,并随访病人。结果正常脑组织未见PLK1明显表达。Ⅰ～Ⅱ级、Ⅲ级和Ⅳ级脑胶质瘤中PLK1表达阳性率分别为64.3%、93.8%和100%,Ⅲ和Ⅳ级分别与Ⅰ～Ⅱ级比较差异有显著性意义(P<0.05)。PLK1表达与胶质瘤病理级别和PCNA表达均呈正相关(r=0.424,P<0.05;r=0.745,P<0.01)。PLK1高表达组和低表达组患者两年生存率分别为41.4%(12/29)和72.2%(13/18),差异显著(P<0.05)。结论PLK1在胶质瘤的发生发展和增殖中起重要作用,与肿瘤分化程度和患者预后密切相关。     

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。     

人脑胶质瘤中Fas系统与其患者外周血中MDSC表达的相关性

目的探讨Fas、Fas配体(FasL)在人脑胶质瘤中和髓系衍生抑制细胞(MDSC)在胶质瘤患者外周血中的表达及它们与脑胶质瘤恶性程度的关系。方法采用免疫组织化学方法检测22例人脑胶质瘤组织和6例正常脑组织中Fas和FasL的表达,采用流式细胞分析术检测上述22例胶质瘤患者手术前和6例正常成人外周血中MDSC的表达。结果①高级别(Ⅲ、Ⅳ级)胶质瘤中Fas和FasL的表达水平明显高于低级别(Ⅰ、Ⅱ级)胶质瘤中的表达(P<0.05);而在后者中的表达水平又明显高于正常脑组织中的表达(P<0.05)。②高级别胶质瘤患者外周血中MDSC表达较正常人和低级别胶质瘤患者明显增加(P<0.05)。③Fas、FasL的表达与MDSC的表达呈正相关(P<0.05)。结论脑胶质瘤中Fas、FasL的表达及其患者外周血MDSC表达均与胶质瘤恶性程度正相关。     

结缔组织生长因子在脑胶质瘤组织中的表达和肿瘤级别的关系

目的通过检测人脑胶质瘤患者肿瘤组织中结缔组织生长因子的表达水平,探讨其和肿瘤级别的关系及作用机制。方法采用荧光实时定量聚合酶链式反应(RT-PCR)法检测结缔组织生长因子(CTGF)mRNA在47例脑胶质瘤组织和25例正常脑组织中的表达水平,统计分析表达水平和肿瘤级别之间的关系。结果CTGF在胶质瘤Ⅰ-Ⅱ级(高分化组)及胶质瘤Ⅲ~Ⅳ级(低分化组)中的表达均明显高于正常脑组织(P<0.01),而且在Ⅲ~Ⅳ级胶质瘤中的表达量显著高于胶质瘤Ⅰ~Ⅱ级(P<0.01),说明随着肿瘤级别的升高CTGF表达也增强。结论CTGF在胶质瘤组织中高表达,而且表达水平和恶性程度有密切联系。CTGF的检测可作为胶质瘤恶性程度判断的参考,为从基因水平上探讨胶质瘤的生物学行为、预后及治疗提供新的思路。     

ILK及CD151在人脑胶质瘤中的表达及其意义

目的探讨整合素连接激酶(ILK)及CD151在人脑胶质瘤中的表达及意义。方法采用免疫组化SP法检测ILK及CD151在74例人脑胶质瘤及15例正常脑组织中的表达。按2007年WHO中枢神经系统肿瘤分类:低级别(Ⅰ、Ⅱ级)胶质瘤31例,高级别(Ⅲ、Ⅳ级)43例。结果高级别胶质瘤、低级别胶质瘤及正常脑组织ILK的阳性表达分别为83.72%、61.29%、20.00%,CD151阳性表达率分别为81.40%、54.84%、13.33%。ILK和CD151在胶质瘤中阳性表达明显高于正常脑组织(P0.05),在高级别胶质瘤中影响表达率显著高于低级别胶质瘤(P0.05);而且二者在胶质瘤组中的表达呈正相关(r=0.294,P0.05)。结论 ILK及CD151在人脑胶质瘤中的表达随胶质瘤恶性程度的增高而增高,二者可能共同促进胶质瘤的生长和浸润。     

胶质瘤c-myc基因表达水平与其细胞增殖和凋亡关系的研究

目的探讨胶质瘤细胞c-myc基因表达水平与肿瘤恶性程度、细胞增殖活性以及凋亡程度的关系。方法选择67例脑胶质瘤患者,其中Ⅰ～Ⅱ级者24例,Ⅲ级22例,Ⅳ级21例。应用原位杂交、原位细胞凋亡检测(TUNEL法)和免疫组织化学染色方法对其标本进行观察。结果67例患者中57例(85.1%)表达c-mycmRNA,56例(83.6%)表达c-Myc蛋白,两者表达水平呈正相关(rs=0.999,P<0.01),并均显示表达水平Ⅰ～Ⅱ级<Ⅲ级<Ⅳ级者(P<0.05或P<0.01);肿瘤细胞增殖活性和凋亡程度之间呈负相关(r=?0.775,P<0.01)。肿瘤细胞增殖活性随着肿瘤细胞c-Myc蛋白表达水平的升高而相应增强,而肿瘤细胞的凋亡则相应减少,c-Myc蛋白表达强阳性组与阳性组间,以及此两组与弱阳性组及阴性组之间比较,肿瘤细胞增殖活性和凋亡程度的差异均有显著性意义(均P<0.01)。结论c-myc基因表达水平对评价脑胶质瘤生物学行为具有临床参考价值。胶质瘤细胞c-myc基因表达异常增加可能会促进其细胞增殖和抑制其凋亡,并在胶质瘤的发生及恶性进展过程中起重要作用。     

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.     

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.     

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.     

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.     

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.     

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.