物质成瘾的表观遗传机制

<正>表观遗传(epigenetic)是指在基因DNA序列没有发生改变的情况下,基因表达发生可遗传的改变,并最终导致可遗传的表型变化,而且这种改变在个体发育和细胞增殖过程中能稳定遗传并具有可逆潜能。表观遗传包括DNA甲基化、组蛋白修饰、非编码RNA调控等。表观遗传参与大脑分化与发育,越来越多证据表明,表观遗传机制参与精神分裂症、双相情感障碍、物质成瘾、孤独症等精神障碍     

脯氨酰羟化酶RNA干扰慢病毒载体的构建与鉴定

背景：慢病毒载体可稳定介导基因沉默且具有较高的转染效率。 目的：构建并鉴定脯氨酰羟化酶 RNA干扰慢病毒载体。 方法：针对脯氨酰羟化酶2基因序列设计RNA干扰靶序列,合成靶序列的寡聚DNA,退火形成双链DNA,与经Age Ⅰ和EcoR Ⅰ酶切的pGCSIL-GFP连接、转化大肠杆菌感受态细胞,产生重组RNA干扰慢病毒表达载体,PCR筛选阳性克隆,测序鉴定。 结果与结论：PCR和DNA测序证实合成的含脯氨酰羟化酶短发卡RNA慢病毒载体寡核苷酸链正确插入pGCSIL-GFP载体。说明实验成功构建脯氨酰羟化酶基因RNA干扰慢病毒载体。     

铁死亡与神经变性疾病的研究进展

正铁是人体必需的一种金属微量元素,在体内参与DNA、RNA和蛋白质的生物合成,并作为多种关键酶或辅酶的重要因子,参与亚铁血红素和神经鞘磷脂的合成,对维持神经系统的正常结构和功能起重要作用。由于金属铁离子具有较强的氧化作用,各种原因所致的脑内铁的蓄积可产生过量的过氧化物和氧自由基,引起脂质过氧化反应、DNA链断裂以及蛋白质功能紊乱,并最终导致神经元变性、死亡。研究资料发现,铁代谢的异常与阿尔茨海默病(Alzheimer's     

氧化应激与老年性痴呆发病的相关性研究

氧化应激作为老年性痴呆的发病机制之一越来越受到学术界关注。活性氧可氧化DNA、RNA和蛋白质导致基因突变、转录错误、转录效率降低、翻译错误,以及影响蛋白质正常功能的发挥。该文就氧化应激对DNA、RNA和蛋白质的氧化损伤与老年性痴呆发病的相关性进行综述。     

长链非编码RNA在神经胶质瘤的研究进展

长链非编码RNA(long non-coding RNA,lncRNA)是一类转录本长度超过200 nt的RNA,其与mRNA不同,没有开放阅读框,不能编码蛋白.随着基因测序、基因芯片和基因组学的发展,已经发现越来越多lncRNA参与胶质瘤发生发展.本文就近期国内外lncRNA相关研究作一综述.     

circRNAs在儿童中枢神经系统肿瘤的研究进展

环状RNA(circRNAs)是一种在真核细胞中广泛表达的非编码RNA,是由一段基因中单个或多个外显子及少量内含子的3’端和5’端通过头到尾的反向剪接后环化形成,相对于线性RNA拥有较为稳定的性质。已有许多实验结果证实circRNAs参与神经、消化、内分泌、泌尿等多个系统恶性肿瘤的调控,且在这些肿瘤的发生发展过程中发挥重要作用。近年来,以circRNAs为代表的一系列非编码RNA(ncRNAs)参与儿童中枢神经系统（CNS）恶性肿瘤调控的相关机制成为研究热点,并有望成为儿童CNS肿瘤靶向治疗的新靶点,为早期诊断和改善患儿预后提供新的思路。[国际神经病学神经外科学杂志, 2022, 49(6):97-101]     

微小RNA及其在精神疾病研究中的应用

长期以来,人们认为RNA只是起到遗传信息"桥梁"的作用,从DNA获得遗传信息后转译成蛋白质(遗传中心法则).然而,近年来研究表明高级生物仅2%～3%转录产物编码蛋白质,大部分DNA转录产物为非蛋白编码RNA(nonprotein coding RNA, ncRNA),并不被翻译成蛋白质.     

miRNA在神经系统疾病的研究进展

miRNA是一类长度约为22个核苷酸的非编码调节RNA,参与RNA介导的基因沉默[1].miRNA的研究始于Lee等[2]在秀丽隐杆线虫中发现了第一个定时调控胚胎后期发育的基因lin-4.随后在人类、果蝇、植物等多种生物体内鉴别出数百个miRNA,并且发现它与多种重要生理功能有关.目前,已经鉴别出500多个人类miRNA.miRNA是重要的基因调节因子,参与细胞分化、增殖、凋亡、胰岛素分泌以及心脏、大脑和骨骼肌的发育过程[3-5].现对miRNA在神经系统功能和疾病中的研究进展进行简要综述.     

表观遗传学与神经发育性疾病

研究[1,2]认为,一些复杂性疾病与DNA甲基化、基因组印记、X染色体失活以及非编码RNA调控等表观遗传过程相关.现将表观遗传学的基本机制和与表观遗传学相关的神经发育性疾病论述如下.     

帕金森病表观遗传学研究进展

正近年来,作为遗传与环境之间纽带的表观遗传修饰与PD发病的关系越来越受到重视,表观遗传是指在没有DNA序列改变的情况下出现的基因表达或功能的改变~([1])。表观遗传修饰包括DNA甲基化、DNA羟甲基化、组蛋白修饰以及非编码RNA(non-coding RNA,ncRNA)介导的基因表达变化等。本文将着重从上述四个方面介绍PD相关的     

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.     

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.     

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.     

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.