Notch信号通路与关节软骨发育及骨关节炎

背景：骨性关节炎时往往伴随软骨细胞间信号转导的异常，提示细胞间信号转导在骨性关节炎发生、发展过程中可能发挥重要作用。 目的：综合分析Notch信号通路的最新进展，探讨Notch在调控骨髓间充质干细胞软骨相分化机制、调控软骨发育及软骨发生中的作用，分析Notch信号通路失调与骨关节炎的关系。 方法：以Notch signaling pathway, osteoarthritis, chondrocytes, chondrogenesis, bone marrow stem cells为检索词，检索Pubmed数据库(1919-03/2009-02)；以Notch信号通路，骨关节炎，软骨细胞，骨髓间充质干细胞为检索词，检索CNKI数据库(2004-02/2008-09)。文献检索语种限制为英文和中文。纳入与Notch信号通路有关的研究、Notch信号通路调控骨髓间充质干细胞软骨相分化机制的研究，以及Notch信号通路失调与骨关节炎的研究。排除重复性研究。以关节软骨的发育调控和软骨细胞的增殖胃评价指标。 结果与结论：计算机初检得到632篇文献，根据纳入排除标准，对其中30篇文献进行分析。Notch信号通路是一个在进化过程中高度保守的信号通路，它通过Notch 受体与配体的结合、Notch受体的酶切活化、可溶性Notch胞内区转移至细胞核并与CSL DNA 结合蛋白相互作用，最终调控靶基因的表达，从而在细胞增殖、分化、凋亡及器官发育中发挥重要的调控作用。目前已证实，Notch信号参与并调控关节软骨的发育、软骨细胞增殖、分化，而Notch信号的失调在骨关节炎的发生、发展中扮演着十分重要的角色。提示深入研究Notch信号在骨性关节炎发病机制中的确切作用将有助于骨性关节炎的靶向治疗，从而为骨性关节炎的治疗开辟更加广阔的前景。     

胰腺β细胞分化的信号通路调控

细胞替代治疗给糖尿病的根治带来了新希望。文章综述了近年来干细胞向胰岛细胞定向分化的分子研究进展,综合分析细胞信号通路在β细胞分化发育过程中所发挥的作用。其中Wnts信号是通过阻止β-Catenin分解从而激活Tcf/Lef介导的转录,促进干细胞向内胚层分化;Notch及其配体Delta或Jagged也对干细胞分化有重要影响,当Notch活性被抑制时,干细胞进入分化程序,发育为功能细胞;Hedgehog信号转导对许多发育过程是必须的,其主要以浓度依赖方式控制细胞的增殖、分化和组织的形成,这些信号通路按一定的顺序上调或下调,以启动PDX1等β细胞分化相关的转录因子的表达,从而调控着β细胞的分化发育。因此深入分析并通过调控这些信号通路为以后进行相关细胞定向分化,获取发育成熟、功能完整的β细胞,进行细胞治疗糖尿病奠定基础。     

Hedgehog信号通道与相关干细胞增殖与分化的研究进展

背景：Hedgehog蛋白为成形素蛋白，其相关信号通道参与胚胎发育和成体组织再生。 目的：对Hedgehog信号通道相关干细胞的增殖及分化研究近况进行综述。 方法：应用计算机检索CNKI和PubMed数据库中2000-01/2010-12关于Hedgehog信号通路的文章，在标题和摘要中以“hedgehog信号通道，细胞增殖，细胞分化，信号调控”或“Hedgehog signaling pathway，cell proliferation，cell differentiation，signal pathway controlling”为检索词进行检索，选择关于Hedgehog信号通道对各种干细胞及成体器官作用内容的文章，初检到169篇，根据纳入标准选择27篇进行综述。 结果与结论：具有多种分化潜能的干细胞发育成具有特定生物学功能的组织细胞是受到干细胞自身或外在的、近程或远程的信号调控的，其中细胞之间的相互信息传递在细胞发育分化过程中扮演着重要角色。Hedgehog 信号通路起到维持细胞增殖、分化、凋亡之间的平衡，其能够调节相邻细胞之间的分子差异，对细胞分化命运起决定性作用。     

Notch信号通路在神经干细胞分化与再生的研究进展

Notch信号通路是旁抑制效应调控神经干细胞分化及再生的重要信号通路之一,Notch信号通路维持神经干细胞静态,抑制神经干细胞的分化,对调节神经再生具有重要作用。     

Wnt信号与神经干细胞分化

背景：研究表明，移植入宿主体内的神经干细胞可分化为神经元或神经胶质细胞。Wnt信号通路与神经干细胞的分化密切相关。通过调节Wnt信号通路可控制神经干细胞的定向分化。 目的：对神经干细胞分化及其与Wnt信号通路的关系进行综述. 方法：应用计算机检索2002-02/2010-03 Medline数据库、Ovid数据库、CNKI、EBSCO数据库与神经干细胞相关文献。检索词为“神经干细胞，神经再生，Wnt信号，神经元，分化”。纳入与神经干细胞分化及Wnt信号系统相关文献，排除重复性研究，保留30篇文献进行综述。 结果与结论：神经干细胞是一类具有自我更新和多向分化潜能的细胞，能分化形成机体中枢神经系统几乎所有类型的细胞。Wnt信号通路在神经干细胞的分化中起重要作用。文章从神经干细胞、Wnt信号通路、Wnt信号通路与神经干细胞的分化等方面分别进行了叙述。然而，Wnt信号通路控制神经干细胞分化的具体机制还不是很清楚。     

造血干细胞自我更新的相关信号分子：作用及途径

背景：造血干细胞数目少,且在体外容易分化,这对其应用于移植存在很大的困难。 目的：文章集中阐述了Wnt、Notch、Bmi_1、Shh、HOXB4信号分子在维持造血干细胞自我更新调控中的作用及其途径。 方法：以HSC、Wnt、Notch、Bmi_1、Shh、HOXB4为检索词,检索PubMed数据库(2002-01/2008-12)。文献检索语种限制为英文。纳入与造血干细胞自我更新相关信号分子密切相关的文献。排除重复性研究和Meta分析。 结果与结论：计算机初步检索到216篇文献,对其中30篇文献进行研究。造血干细胞是具有自我更新、较强分化发育和再生能力、可以产生各种类型血细胞的始祖细胞,被广泛应用于治疗血液系统疾病,但是造血干细胞在体外容易分化,这对其应用于移植存在很大的困难。如何使造血干细胞在体外扩增和处理的同时保持造血干细胞的自我更新特性成为关键问题。近年来通过不同信号通路增强造血干细胞自我更新能力的信号分子成为研究热点。文章集中阐述了Wnt、Notch、Bmi_1、Shh、HOXB4在维持造血干细胞自我更新调控中的作用及其途径,发现上述5种信号分子均具有增强造血干细胞自我更新的功能。此外还有一些因素在维持造血干细胞自我更新的过程中起重要作用,如作为内源性因素的一系列转录因子Oct-4、Ehox、Nanog、SCL、Runx1等,探讨它们相互作用形成的调控网络如何调控造血干细胞的自我更新,将成为造血干细胞自我更新领域研究的一个重点。     

MicroRNA在干细胞增殖与分化过程中的调控作用

背景：研究表明MicroRNA(miRNA)可通过抑制干细胞特定mRNA序列的翻译来调控干细胞的自我更新和分化。 目的：探讨miRNAs在干细胞增殖和分化过程中的作用。 方法：由第一作者检索2000/2010 PubMed数据库、Elsevier数据库及Nature数据库。英文检索词为“stem cell,embryonic stem cell(ESC), induced pluripotent stem cells(iPS cell), microRNA(miRNA)”。排除重复性研究。共保留其中的39篇进行归纳总结。 结果与结论：胚胎干细胞有特异性的miRNAs表达,miRNAs对胚胎干细胞增殖与分化起重要的调控作用;miRNAs对造血干细胞分化的多个阶段和方向有调控作用;miRNAs还参与了神经干细胞、间充质干细胞和皮肤干细胞等成体干细胞分化的调控。干细胞特异性的miRNAs可提高体细胞重编程的效率。     

干细胞应力学效应机制的研究与进展

背景：近年来多种细胞信号转导的分子基础与相关功能调控机制的研究已取得重要进展，但干细胞的生物学行为相对复杂，其增殖分化的相关信号转导途径和机制尚未明确。 目的：复习相关文献，就干细胞力学影响下相关信号通路的研究现状与应用前景进行综述。 方法：应用计算机检索CNKI和PubMed数据库中2005/2010关于“干细胞应力学效应机制”的文章，以“干细胞，信号转导”或“干细胞，应力”为检索词进行检索。选择文章内容与干细胞信号转导通路相关，同一领域文献则选择近期发表或发表在权威杂志文章。初检得到中英文共179篇文献，根据纳入标准选择33篇文章进行综述。 结果与结论：调节干细胞应力下增殖与分化的多条信号通路，包括F-actin、Ca2+、MAPK、Wnt、Notch等，在干细胞的增殖分化中发挥着重要调控作用。应力作用下细胞内力学信号转导和基因表达调控的确切机制将是今后干细胞研究领域的重要内容。     

干细胞中的骨形态发生蛋白信号转导机制★

学术背景：骨形态发生蛋白属于TGF-β超家族的一类多功能分泌型信号分子，通过信号级联传导调节胚胎形态特征、组织器官的发育以及生殖细胞的分化；还能促进干细胞沿不同的方向分化与凋亡。骨形态发生蛋白在不同类型的干细胞中，其信号转导途径呈多样化；目前原因还不十分明确，但研究表明可能与受体或其细胞中多重信号的整合作用有关。 目的：综述骨形态发生蛋白信号转导途径在几种类型干细胞中所发挥的作用及其转导机制。 检索策略：由该论文的研究人员应用计算机检索Pubmed数据库 2007-04/07的相关文献，检索词“bone morphogenetic protein，the differentiation and proliferation of stem cell”，并限定文章语言种类为English。共检索到45篇文献，对资料进行初审，纳入标准：①文章所述内容应与骨形态发生蛋白信号转导途径相关。②同一领域选择近期发表或在权威杂志上发表的文章。排除标准：①重复性研究。②Meta分析。 文献评价：文献的来源主要是通过对骨形态发生蛋白信号转导途径方面内容进行汇总分析。所选用的31篇文献中，2篇为综述，其余均为临床或基础实验研究。 资料综合：①骨形态发生蛋白信号属于激酶转导系统，可通过Smads或p38 MAPK通路传递信号，在转导过程中受多种细胞内外因素的调节。②骨形态发生蛋白信号强弱、时间以及下游信号通路均对早期胚胎干细胞的增殖和分化产生重要影响，可能与Wnts信号通路等多重级联交互作用有关。③骨形态发生蛋白信号可促进神经干细胞向神经元和神经胶质细胞分化，抑制胰脏祖细胞的分化。骨形态发生蛋白4通过抑制分化作用和阻止其前体细胞的增殖这两方面来调节毛细胞数量，还能促进眼胚胎细胞的增殖与凋亡。骨形态发生蛋白和Nodal信号能通过与膜受体竞争性结合调节中胚层祖细胞的发育、增殖与分化。 结论：骨形态发生蛋白信号通路受细胞内外多种因素调控，能调控各种来源干细胞的分化与增殖，调节靶基因的转录。但其只是干细胞特性的调节因子，不是干细胞增殖与分化的标记物。目前，骨形态发生蛋白信号转导与整合作用的细胞学机制、信号转导作用的时间与空间位置等问题还有待进一步研究。     

miRNA与干细胞的生物学行为

背景：以往对干细胞的研究主要集中在基因方面，但目前越来越多的证据表明，miRNA在干细胞的自我更新和分化过程中发挥着重要的调控作用。 目的：介绍miRNA的形成及其对干细胞自我更新和多向分化的影响。 方法：以“microRNA，stem cell”为检索词，应用计算机检索Elsevier数据库2000-01/2010-05文章；以“miRNA，干细胞”为检索词检索中国期刊全文数据库2000-01/2010-05文章。 结果与结论：不同组织不同细胞存在自身特异的miRNA表达谱及序列特征，这可以作为某些组织或细胞的特异性分子标志。在细胞的不同发育阶段，miRNA组成不同，决定细胞的分化方向以及分化时相，是细胞“定时”、“定向”分化的“开关”。在各种干细胞中均存在特异性的miRNA，并且在干细胞的不同分化阶段亦有特异性miRNA表达，它们是保持干细胞自我更新和多向分化特性的关键分子之一。miRNA作为一种新的调控基因表达的小分子RNA，为干细胞的研究提供了一种新的途径。     

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.