体外诱导人骨髓间充质干细胞向肝样细胞分化：肝细胞生长因子和表皮细胞生长因子的作用*

背景：研究证实人骨髓间充质干细胞能够诱导分化为肝样细胞,但其具体生物学特性及分化机制尚不清楚,且诱导分化培养体系尚不成熟。 目的：探讨肝细胞生长因子和表皮细胞生长因子体外诱导人骨髓间充质干细胞向肝样细胞分化的可行性。 方法：取食管癌手术患者肋骨,采用密度梯度离心联合贴壁筛选法获取人骨髓间充质干细胞,流式细胞仪检测细胞表面分子的表达。取第3代人骨髓间充质干细胞,分为4组,肝细胞生长因子组加入20 μg/L肝细胞生长因子,表皮细胞生长因子组加入20 μg/L表皮细胞生长因子,联合组同时加入上述两种生长因子,空白对照组不加任何生长因子。倒置显微镜下观察细胞形态的变化,诱导7,14 d RT-PCR检测甲胎蛋白与白蛋白mRNA的表达。 结果与结论：人骨髓间质干细胞不表达造血细胞标志CD34,CD45,强表达β1-整合素CD29和基质受体CD44。肝细胞生长因子组、表皮细胞生长因子组、联合组诱导后,细胞形态由长梭形变为类圆形或多角形,诱导第7,14天甲胎蛋白、白蛋白 mRNA均呈阳性表达;空白对照组未见多角形细胞,甲胎蛋白、白蛋白 mRNA均呈阴性表达。证明肝细胞生长因子、表皮细胞生长因子以及二者联合均具有诱导人骨髓间充质干细胞向肝样细胞分化的能力,至于二者联合是否能增强其分化能力尚待进一步免疫细胞化学染色定量分析予以验证。     

不同浓度肝细胞生长因子及表皮细胞生长因子体外联合诱导兔骨髓间充质干细胞向肝细胞分化******

背景：研究证实在多种微环境下可以将骨髓间充质干细胞诱导分化为成熟肝细胞,但诱导条件及诱导分化率尚无定论,选择合适的诱导剂及诱导剂浓度尤为重要。 目的：观察肝细胞生长因子和表皮细胞生长因子体外联合诱导兔骨髓间充质干细胞向肝细胞分化的最适浓度。 方法：不同浓度肝细胞生长因子、表皮细胞生长因子联合诱导培养原代兔骨髓间充质干细胞,观察细胞形态学变化,并检测肝细胞表面标志物甲胎蛋白、白蛋白表达及肝细胞合成功能。 结果与结论：随诱导时间延长,可观察到多极性的肝细胞样细胞。7 d时甲胎蛋白表达阳性,14 d达最大值后即开始下降(P < 0.05),此后各浓度组间表达无差别(P > 0.05)。14 d时白蛋白表达阳性,随时间延长,阳性细胞数递增(P < 0.05),且细胞生长因子浓度越高,阳性细胞数越高(P < 0.05)。诱导早期(9~15 d) 白蛋白上清液中白蛋白水平与诱导剂浓度成正比(P < 0.05)。18 d或21 d达高峰后下降,此时各浓度组间含量无差别(P > 0.05)。结果显示高浓度的肝细胞生长因子及表皮细胞生长因子可提高骨髓间充质干细胞向肝细胞的分化率,诱导剂最适浓度为肝细胞生长因子60 μg/L、表皮细胞生长因子4.5 mg/L。     

急性肝衰竭大鼠血清诱导骨髓间充质干细胞表达甲胎蛋白和白蛋白

背景：研究发现肝细胞生长因子、成纤维细胞生长因子4和表皮细胞生长因子等可诱导骨髓间充质干细胞向肝细胞分化,关于肝衰竭大鼠血清对骨髓间充质干细胞的诱导分化作用尚未见报道。 目的：观察急性肝衰竭大鼠血清对骨髓间充质干细胞的诱导分化作用。 方法：采用密度梯度离心法从SD大乳鼠股骨、胫骨分离培养骨髓间充质干细胞,体外扩增培养。采用急性肝衰竭大鼠血清诱导培养骨髓间充质干细胞,以常规培养液诱导为对照,观察细胞形态的变化,诱导培养14 d采用免疫细胞化学方法检测甲胎蛋白、白蛋白的表达。 结果与结论：急性肝衰竭大鼠血清诱导培养14 d, 可见骨髓间充质干细胞发生明显的形态学改变,镜下观察细胞变得稍大而扁平,呈类上皮样细胞,甲胎蛋白和白蛋白表达阳性率分别为(54.8±7.64)%和(45.9±9.68)%;对照组细胞未发生形态学改变,无甲胎蛋白和白蛋白的表达。证明了急性肝衰竭大鼠血清对骨髓间充质干细胞的诱导分化作用,可诱导骨髓间充质干细胞表达甲胎蛋白和白蛋白。     

酒精性肝硬化患者血清诱导人骨髓间充质干细胞定向分化为肝细胞样细胞

背景：肝脏损伤后机体能够分泌一系列细胞因子和化学增活素,重型肝病患者血清中肝细胞生长因子、成纤维细胞生长因子等具有诱导骨髓间充质干细胞向肝细胞分化的作用。 目的：探讨在酒精性肝硬化患者血清诱导条件下,人骨髓间充质干细胞向肝细胞样细胞的定向分化情况。 设计、时间及地点：细胞学体外观察,于2006-07/2007-07在吉林省肝胆病医院科研室完成。 材料：创伤患者术后废弃肋骨,由吉林省人民医院胸外科提供。实验血清来源于吉林省肝胆病医院住院的1例40岁男性酒精性肝硬化患者。 方法：冲洗骨髓腔,采用密度梯度离心、贴壁培养法体外分离培养人骨髓间充质干细胞,接近融合时按1:4传代扩增。取第3代人骨髓间充质干细胞,按1×107 L-1密度接种,设立2组：诱导组加入含体积分数为0.2酒精性肝硬化患者血清的L-DMEM培养基,对照组仅加入常规L-DMEM培养基。 主要观察指标：相差显微镜下观察细胞形态变化,免疫组化法检测甲胎蛋白和白蛋白的表达。 结果：诱导组骨髓间充质干细胞在含体积分数为0.2酒精性肝硬化患者血清的L-DMEM培养基中生长状态良好,呈类上皮样细胞形态;对照组细胞未发生形态学改变,呈成纤维细胞样。培养7 d时,诱导组大部分细胞呈甲胎蛋白阳性,随培养时间延长甲胎蛋白表达减弱,而白蛋白阳性表达情况完全相反,呈逐渐增强趋势;整个培养过程对照组细胞始终未出现甲胎蛋白及白蛋白表达。 结论：密度梯度离心和贴壁培养法相结合可在体外分离获得纯度较高的人骨髓间充质干细胞,酒精性肝硬化患者血清能够诱导人骨髓间充质干细胞表达甲胎蛋白及白蛋白,向肝细胞样细胞分化。     

三种因子联合诱导大鼠骨髓间充质干细胞向肝细胞的分化**

背景：间充质干细胞的生物学特性及影响分化调控因子的研究认为,体外原代培养的间充质干细胞自然分化为肝细胞的比例较低,选择一种合适的诱导剂提高其分化为肝细胞的比例尤为必要。 目的：以肝细胞生长因子、表皮生长因子及成纤维生长因子体外联合,验证其诱导大鼠骨髓间充质干细胞向肝细胞分化的可行性。 设计、时间及地点：细胞学体外观察,于2007-08在潍坊医学院实验中心完成。 材料：Sprague-Dawley大鼠40只,由潍坊医学院实验动物中心提供。 方法：采用贴壁法分离培养大鼠骨髓间充质干细胞,取传至第3代细胞,设立2组：空白对照组加入含体积分数为10%胎牛血清的L-DMEM培养基;联合诱导组在此基础上,另加入10 µg/L成纤维生长因子、8 µg/L肝细胞生长因子、8 µg/L表皮生长因子。 主要观察指标：倒置显微镜观察诱导后细胞形态变化,免疫荧光染色观察甲胎蛋白及白蛋白的表达,PAS检测糖原的表达,靛青绿摄入情况,酶学检测谷丙转氨酶、谷草转氨酶、碱性磷酸酶的水平。 结果：联合诱导组细胞呈多角形、卵圆形或圆形细胞的特征性改变,空白对照组骨髓间充质干细胞仍保持梭形或纺锤形。联合诱导组培养14 d可见白蛋白和甲胎蛋白免疫反应阳性细胞;诱导7 d时偶见PAS阳性细胞与靛青绿阳性细胞,随诱导时间延长,阳性细胞逐渐增多;诱导14 d时开始检测到谷丙转氨酶、谷草转氨酶、碱性磷酸酶的合成,21 d达高峰,之后下降。上述各指标空白对照组细胞均呈阴性。 结论：成纤维生长因子、肝细胞生长因子与表皮生长因子体外联合应用,能够成功诱导大鼠骨髓间充质干细胞向肝样细胞的分化。     

大鼠骨髓间充质干细胞体外诱导为肝细胞样细胞***

背景：目前体外诱导骨髓间充质干细胞分化为肝细胞样细胞的研究主要集中在不同诱导因子的诱导作用,而微环境的诱导作用研究较少。 目的：观察肝细胞生长因子、胎肝细胞对骨髓间充质干细胞体外诱导分化为肝细胞样细胞的影响。 方法：采用密度梯度离心法分离大鼠骨髓间充质干细胞,反复贴壁法纯化扩增骨髓间充质干细胞;采用Ⅰ型胶原酶消化法分离孕3周大鼠胚胎肝脏细胞,差速贴壁法纯化肝脏细胞;阴性对照组骨髓间充质干细胞只加入含体积分数为10%胎牛血清的L-DMEM培养基。诱导组在阴性对照组基础上加入一定浓度肝细胞生长因子或者与胎肝细胞共培养进行诱导分化。 结果与结论：诱导组白蛋白、甲胎蛋白水平均高于非诱导组(P < 0.01),诱导组糖原染色阳性,免疫细胞化学染色CK-18阳性,而非诱导组糖原染色、CK-18均阴性。结果显示肝细胞生长因子和胎肝细胞均可在体外诱导大鼠骨髓间充质干细胞分化为具有肝细胞样细胞表型和功能的类肝细胞。     

大鼠骨髓间充质干细胞向肝细胞的分化

背景：提供肝细胞生长因子的微环境可体外诱导骨髓间充质干细胞分化为肝细胞。 目的：实验拟验证并简化成年大鼠骨髓间充质干细胞体外向肝细胞的诱导分化。 设计、时间及地点：观察实验，于2006-10/2008-05在北华大学完成。 材料：实验动物为成年SD大鼠，雌雄不限，体质量180~230 g。 方法：采用Percoll梯度离心方法获取骨髓间充质干细胞，调整细胞密度为1×108 L-1,加入含有20 μg/L肝细胞生长因子培养液培养，定期更换培养液。 主要观察指标：流式细胞仪检测细胞表面标志和碱性磷酸酶染色鉴定细胞类型。倒置显微镜连续观察细胞分化过程的形态学变化。培养的1，3，7， 14， 21， 28 d以细胞免疫组织化学检测细胞甲胎蛋白、细胞角蛋白18和清蛋白的表达。 结果：接种后，细胞体积增大，形态多样贴壁细胞分化为体积较大的多角形和部分梭形，胞浆丰富，可见多核，接种早期细胞生长比接种晚期生长较快。分离纯化的SD大鼠骨髓间充质干细胞的表面标志为CD29+，CD44+，CD34-，CD45-和CD90+，细胞的碱性磷酸酶染色阴性，细胞纯度达98%以上。骨髓间充质干细胞的甲胎蛋白细胞免疫组织化学染色培养第7天即出现阳性，第14天清蛋白和细胞角蛋白18免疫组织化学染色阳性。 结论：成年大鼠骨髓间充质干细胞在20 μg/L肝细胞生长因子的诱导下，可分化为肝细胞。     

体外诱导人脐带间充质干细胞向肝样细胞的分化

背景：多项研究表明间充质干细胞具有向肝细胞分化的潜能,这将为肝细胞移植、生物人工肝、肝组织工程提供大量种子细胞,也有望在急性肝衰竭、终末期肝病和遗传代谢性肝脏疾病治疗方面带来较大突破。 目的：拟在体外诱导人脐带间充质干细胞向肝样细胞分化,观察其形态及功能变化。 方法：取体外培养第3代处于对数生长期的人脐带间充质干细胞,以1×109 L-1的细胞浓度种植在培养瓶中,加入含体积分数为10%胎牛血清的DMEM/F12培养基,设立3组：实验1组加入20 μg/L肝细胞生长因子+10 μg/L碱性成纤维细胞生长因子,实验2组在其基础上另加入20 μg/L制瘤素,空白对照组不加入任何生长因子。根据细胞生长情况,每周换液两三次。分别于培养7,14,18 d在倒置显微镜下观察细胞形态,采用免疫细胞化学检测甲胎蛋白、白蛋白及细胞角蛋白18的表达,运用PAS法检测糖原的表达。 结果与结论：人脐带间充质干细胞可在含20 μg/L肝细胞生长因子、10 μg/L碱性成纤维细胞生长因子、20 μg/L制瘤素、体积分数为10%胎牛血清的DMEM/F12培养体系中诱导分化为具有肝细胞表型和功能的细胞,且肝细胞生长因子、碱性成纤维细胞生长因子、制瘤素联合应用的诱导效果优于单纯应用前两者。     

肝细胞生长因子与成纤维生长因子联合诱导人脐带间充质干细胞向肝样细胞的分化

背景：成纤维生长因子可促进间充质干细胞增殖、贴壁生长,但对其诱导间充质干细胞向肝细胞分化的实验报道为数不多。当肝细胞生长因子质量浓度达1 μg/L时,可促进肝细胞有丝分裂,它是正常肝细胞最强的促有丝分裂剂。 目的：体外分离培养人脐带间充质干细胞,拟揭示其生物学特性及在细胞因子联合诱导下向肝样细胞分化的能力。 设计、时间及地点：细胞学体外观察,于2008-08/2009-04在暨南大学血研所完成。 材料：脐带取自健康足月胎儿,产妇对实验知情同意,由广州华侨医院提供。肝细胞生长因子、成纤维生长因子为美国Peprotech产品。 方法：Ⅳ型胶原酶消化+差速贴壁法分离培养人脐带间充质干细胞,取传至第3代细胞,进行细胞表面抗原分析、细胞周期测定,检测其成脂、成骨能力。取第5代细胞,调整细胞密度为5×109 L-1,分为2组：对照组用含体积分数为5%胎牛血清的DMEM/F12培养液培养;诱导组在其基础上,添加20 μg/L肝细胞生长因子、10 μg/L成纤维生长因子联合诱导其向肝样细胞分化。 主要观察指标：人脐带间充质干细胞的生物学特性,人脐带间充质干细胞体外向肝样细胞的分化情况。 结果：成功从人脐带中分离并纯化得到间充质干细胞,第3代细胞92.2%处在G0/G1期;表达CD29,CD44,CD105,不表达造血细胞标志CD34,CD45;油红O染色后胞浆中呈现红色颗粒,碱性磷酸酶染色后细胞质呈黑色,具有成脂、成骨能力。经肝细胞生长因子、成纤维生长因子联合诱导10 d后,RT-PCR及Western blot检测结果显示细胞表达肝细胞特异性抗原甲胎蛋白、白蛋白,对照组均呈阴性表达。 结论：人脐带中含有丰富的间充质干细胞,其具有较强的多向分化潜能,经肝细胞生长因子与成纤维生长因子联合诱导后,易向肝样细胞分化。     

体外诱导大鼠骨髓干细胞向肝干细胞分化的特征**★

目的：骨髓干细胞分化为肝干细胞的发现具有重要的临床应用价值,可用其作为生物人工肝或肝细胞移植的供体细胞,以解决供体缺乏，同时自体细胞还可免除异基因或异种细胞所致的许多问题。为此，实验模拟肝脏发育的微环境，观察体外诱导分化大鼠骨髓干细胞为肝干细胞的可行性及特征。 方法：实验于2006-10/2007-08在解放军第一二三医院南京军区肝病中心实验室完成。①实验动物: SPF级SD大鼠，2月龄，体质量（200±20） g,雌雄不拘，购于上海斯莱克实验动物公司。实验过程中对动物处置符合动物伦理学标准。②实验方法：采用密度梯度分离法分离培养大鼠骨髓干细胞，并设诱导组和非诱导组，应用25 μg/L肝细胞生长因子、10 μg/L成纤维生长因子-4、10 μg/L干细胞生长因子共同诱导。③实验评估：于诱导第0，7，14，21，28天，观察细胞形态变化，采用放射免疫法检测培养上清液中甲胎蛋白浓度，免疫组织化学染色检测甲胎蛋白、细胞角蛋白19、白蛋白的表达，应用流式细胞仪检测甲胎蛋白、细胞角蛋白19表达阳性细胞比例。 结果：①诱导培养的骨髓干细胞呈卵圆形或圆形的肝干细胞样改变。②放射免疫法检测到诱导组细胞甲胎蛋白浓度逐渐升高，第14天达高峰，随后呈下降趋势，与非诱导组相比，除第0，7天无差异，其余各时间点差异均显著（P < 0.05）。③免疫细胞化学法检测到诱导组细胞特异性表达甲胎蛋白、细胞角蛋白19及白蛋白，非诱导组不表达3种蛋白。④流式细胞分析诱导组甲胎蛋白阳性细胞比例为66.20%、细胞角蛋白19阳性细胞的比例为44.96%。 结论：在实验建立的诱导培养体系中，骨髓干细胞在体外能分化为肝干细胞样细胞，诱导细胞有分泌甲胎蛋白、细胞角蛋白19、白蛋白的特征性功能。     

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.     

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.     

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.