大鼠发育过程中视网膜低氧诱导因子1α的变化★

背景: 研究发现，低氧诱导因子1α不仅与缺氧的生理反应有关，而且还参与了正常的胚胎发育过程。 目的：观察大鼠发育过程中视网膜低氧诱导因子1α的变化。 设计、时间及地点：随机对照动物实验，于2007-01/09在青岛大学医学院山东省分子病毒重点实验室完成。 材料：成年未经产清洁型Wistar大鼠，体质量200~250 g。 方法：雌鼠和雄鼠1∶1合笼，制成孕鼠。分别于孕12，16，20 d 时剖腹取胎，获得各阶段的鼠胚。出生后大鼠按日龄分别于1，5，10 d和12个月龄麻醉处死后摘除眼球，分离视网膜及制作石蜡切片。 主要观察指标：免疫组织化学方法、半定量反转录-聚合酶链反应检测大鼠视网膜在胚胎发育过程中各时间段低氧诱导因子1α蛋白及低氧诱导因子1α mRNA的表达。 结果：胚胎期视网膜神经上皮层及色素上皮层均有低氧诱导因子1α阳性表达，生后发育早期视网膜神经上皮层及色素上皮层也可见低氧诱导因子1α阳性表达，以神经节细胞、内网层更明显，随着发育进展，其阳性表达主要位于视网膜节细胞层。大鼠视网膜低氧诱导因子1α蛋白及mRNA的表达为胚胎期最高、生后发育期逐渐下降、成年期最低，3期之间相比，差异有显著性意义（P < 0.01）。 结论：大鼠发育过程中视网膜低氧诱导因子1α随着发育的进展逐渐降低，并逐渐集中表达于视网膜节细胞层。     

同种肾组织移植改善慢性肾功能衰竭贫血：红细胞质量和数量验证

背景：既往通常采用的反复输血和重组人类促红细胞生成素纠正慢性肾功能衰竭后贫血，但由于多种副作用使其临床应用受到很大限制。 目的：通过动物实验，以现代医学公认的治疗慢性肾功能衰竭后贫血的药物重组人类促红细胞生成素作为阳性对照，从红细胞数量、质量方面验证同种肾组织移植的治疗效果。 设计、时间及地点：混合模型重复测量资料的方差分析，随机分组动物实验于2004-06/2005-03在山西医科大学生理实验室完成。 材料：选用成年健康雄性Wistar大白鼠80只作为受体，成年受体大鼠尾静脉每天一次注射盐酸阿霉素6.5 mg/kg，每周3次，共6周。然后切除右肾建立慢性肾功能衰竭模型。供肾组织移植用Wistar新生鼠20只,出生三四天，雌雄不拘。实验用主要试剂重组人类促红细胞生成素：2×106 U/L,由山东阿华医药公司提供（批号99435）。 方法：取20只大鼠为正常对照组，无特殊干预；其余60只大鼠制备慢性肾功能衰竭模型后，随机分为3组，每组20只：肾组织移植组，将取处新生鼠的肾组织块多点植入受体肾包膜下；促红细胞生成素治疗组，每次按30 U/kg剂量腹腔注射重组人促红细胞生成素，每周3次，连续6周；模型组，不给予其他干预。 主要观察指标：以SABC法检测促红细胞生成素在肾组织和移植物的表达及分布。取大鼠内眦静脉血，以ELISA法直接测定血清促红细胞生成素水平，常规方法测定血红蛋白水平，以相应的试剂盒测定红细胞膜Na+-K+ATP酶、超氧化物歧化酶活力，以及丙二醛水平。 结果：①促红细胞生成素抗原阳性反应在正常对照组内表达呈强阳性。而在模型组呈弱阳性或不表达，在移植组中呈强阳性，模型组与其他两组比较，差异有显著性意义（P < 0.01）。②实验30，45，60 d时促红细胞生成素治疗组、肾组织移植组血清促红细胞生成素水平和血红蛋白和红细胞计数比模型组显著升高(P < 0.05~0.01)，实验60 d时促红细胞生成素治疗组血清促红细胞生成素水平高于肾组织移植组(P < 0.05)。③实验30，45，60 d时促红细胞生成素治疗组、肾组织移植组红细胞膜丙二醛含量低于模型组 (P < 0.05), 促红细胞生成素治疗组与肾组织移植组比较，差异无显著性意义 (P > 0.05)。红细胞膜超氧化物歧化酶和Na+-K+ATP酶活力组间差异与丙二醛相反。 结论：肾组织移植可提高慢性肾功能衰竭贫血大鼠红细胞数量和质量，作用与重组人类促红细胞生成素基本相当。     

博来霉素气管灌注构建肺纤维化模型大鼠肺组织低氧诱导因子1α的动态表达

背景：低氧诱导因子1α是介导低氧反应的核转录因子,其对肺纤维化的作用尚不明确。 目的：观察低氧诱导因子1α在肺纤维化发病中的作用。 方法：采用博来霉素(5 mg/kg)一次性气管内灌注建立SD大鼠肺纤维化模型。造模后7,14,28 d观察大鼠肺组织的病理学改变及肺组织中低氧诱导因子1α蛋白及mRNA的动态表达。 结果与结论：博来霉素灌注后,大鼠肺组织炎症反应明显,并逐渐出现纤维化及胶原纤维沉积。免疫组织化学及RT-PCR结果显示,在大鼠肺纤维化发病过程中,低氧诱导因子1α蛋白及mRNA的表达趋势相同,即随造模时间的延长表达逐渐增多,并于造模后第14天达高峰。提示低氧诱导因子1α在大鼠肺纤维化发病过程中起重要作用,其过度表达可能参与了肺纤维化的发生与发展。     

促红细胞生成素诱导骨髓内皮祖细胞功能活化与JAK2依赖ERK信号途径的作用

背景：促红细胞生成素能够促进内皮细胞增殖、迁延,形成新生血管,因此促红细胞生成素可能诱导内皮祖细胞功能活化。除了经典的造血功能以外,是否内皮祖细胞也是促红细胞生成素促血管生成效应的一个靶点。 目的：观察促红细胞生成素对大鼠骨髓内皮祖细胞功能活性的影响,并分析其信号途径。 方法：用密度梯度离心法分离大鼠骨髓内皮祖细胞。首先将细胞分为无血清DMEM培养液对照组、重组人促红细胞生成素500,1 000,2 000 U/L组、促红细胞生成素(2 000 U/L)与ERK抑制剂FR180204(50 µmol/L)共同作用组,分别用MTT比色法、Transwell小室、Matrigel、Western blot法检测内皮祖细胞的增殖活性、迁移、管腔形成能力及Bcl-2表达。然后将细胞分为无血清DMEM培养液对照组、重组人促红细胞生成素组2 000 U/L组,促红细胞生成素(2 000 U/L)与JAK2抑制剂SD1029(10 µmol/L)共同作用组,用Western blot法检测P-ERK的表达。 结果与结论：与对照组相比,随着浓度的增加,促红细胞生成素可明显增强内皮祖细胞的增殖活性,增加迁移的细胞数及形成的管腔数,上调Bcl-2蛋白的表达,在一定范围内呈剂量依赖效应。当加入ERK抑制剂FR180204后,与促红细胞生成素2 000 U/L组相比,这些效应明显减弱。此外,促红细胞生成素上调p-ERK1/2的表达,当加入JAK2抑制剂SD1029后,p-ERK1/2的表达明显下调。提示促红细胞生成素能够促进内皮祖细胞功能活化,这种效应可能是通过依赖JAK2的ERK信号途径调节的。     

促红细胞生成素干预缺氧缺血性脑损伤新生鼠神经干细胞巢蛋白的表达☆

背景: 巢蛋白是一种存在于神经干细胞的特异性抗原,在神经系统发生病变或损伤引起再生时广泛表达,因此巢蛋白表达常用作判定神经系统发生病变或损伤后能否促进神经再生的一种手段。 目的：从神经再生和神经干细胞激活的角度,探讨外源性促红细胞生成素对新生鼠缺氧缺血性脑损伤后神经干细胞巢蛋白表达的影响。 方法：结扎大鼠右侧颈总动脉和8%低氧暴露2 h制备新生大鼠缺氧缺血性脑损伤模型。对照组仅游离右侧颈总动脉,不予结扎和缺氧处理。干预组大鼠缺氧缺血后立即腹腔注射重组人促红细胞生成素5 000 IU/kg,1次/d,连用3 d。缺氧缺血性脑损伤组大鼠缺氧缺血后连续腹腔注射等量生理盐水溶液3 d。每组随机取8只分别于术后4,7,14 d处死。应用免疫组化方法和计算机图像分析技术检测不同时点海马齿状回巢蛋白标记阳性细胞的变化。 结果与结论：各时点缺氧缺血性脑损伤组巢蛋白阳性细胞数较对照组增加(P < 0.05);各时点干预组巢蛋白阳性细胞较对照组和缺氧缺血性脑损伤组均增加(P < 0.05)。3组大鼠海马齿状回区巢蛋白阳性细胞数均于术后 7 d 达高峰。结果提示早期给予重组人促红细胞生成素可促使新生鼠缺氧缺血性脑损伤后海马齿状回区巢蛋白表达增加,促进神经干细胞的增殖再生,在缺氧缺血性脑损伤后神经再生、修复中发挥一定的保护作用。     

光损伤诱导视网膜上皮细胞半胱天冬酶－3表达与促红细胞生成素的干预效应*☆

背景：有实验表明，促红细胞生成素对视网膜的光化学损伤有保护作用，该作用与光化学损伤视网膜色素上皮细胞中半胱天冬酶-3表达的变化有关？ 目的：采用光刺激诱导人视网膜色素上皮细胞凋亡，观察不同剂量促红细胞生成素对细胞半胱天冬酶-3表达的影响。 设计：观察对比实验。 单位：青岛大学医学院。 材料：成人视网膜色素上皮-19细胞株购自美国细胞培养收集公司。DMEM/F12混合培养基、新生牛血清、胰蛋白酶购自GIBCO生物技术公司。重组人促红细胞生成素购自Sigma生物技术公司。人半胱天冬酶-3定量EIA试剂盒购自上海西唐生物科技有限公司。半胱天冬酶-3单克隆抗体购自美国Santa Cruz 公司；PV6001免疫组织化学试剂盒和DAB显色试剂盒购自北京中山生物技术公司。 方法：实验于2006-05/2007-01在青岛大学医学院病理生理教研室完成。取成人视网膜色素上皮-19细胞株传代培养的2~5代细胞建立光损伤模型，传代细胞随机分为7组，每组4孔，①正常对照组：不加光照，不加促红细胞生成素药物干预。②光损伤模型组：光照12 h，不加促红细胞生成素药物干预。③光损伤＋10 000U/L 促红细胞生成素组、光损伤＋20 000 U/L 促红细胞生成素组及光损伤＋40000 U/L 促红细胞生成素组：光照12 h，分别加10 000、20 000及40 000 U/L促红细胞生成素。④光损伤＋40 000 U/L促红细胞生成素组＋AG490组：光照12 h，加促红细胞生成素 40 000 U/L及Jak2激酶抑制剂 50 000 U/L。⑤光损伤＋40 000 U/L促红细胞生成素组＋蛋白激酶B特异性抑制剂组：光照12 h，加促红细胞生成素 40 000 U/L及蛋白激酶B特异性抑制剂100 μmol/L。 主要观察指标：采用酶联免疫吸附实验和免疫组织化学法定量检测不同含量促红细胞生成素干预治疗前后视网膜色素上皮细胞半胱天冬酶-3表达的变化。 结果：正常对照组半胱天冬酶-3无明显表达；光损伤模型组半胱天冬酶-3表达于视网膜色素上皮细胞核上，呈大量特异性黄色着色；光损伤不同剂量促红细胞生成素组半胱天冬酶-3表达的特异性黄色着色随促红细胞生成素含量增加而减弱，以光损伤＋40 000 U/L 促红细胞生成素组最弱光损伤＋40 000 U/L促红细胞生成素组＋AG490组半胱天冬酶-3呈强阳性表达，光损伤＋40 000 U/L促红细胞生成素组＋蛋白激酶B特异性抑制剂组半胱天冬酶-3表达仍呈阳性，但较光损伤模型组稍弱。 结论：重组人促红细胞生成素可减少视网膜色素上皮细胞的光损伤后半胱天冬酶-3的表达。重组人促红细胞生成素抗光损伤诱导的视网膜色素上皮细胞凋亡作用机制之一可能是抑制半胱天冬酶-3的表达。     

高原低氧大鼠肺组织超微结构及其低氧诱导因子1α的表达*

背景：低氧诱导因子1α可介导哺乳动物细胞适应低氧环境。 目的：观察高原低氧对大鼠肺组织超微结构的影响及其低氧诱导因子1α表达变化。 方法：将SD大鼠分别为进行高原低氧干预1,2,3和30 d,并设置对照组。4个高原低氧组由海拔5 m的西安地区途中耗时1 d带到海拔2 700 m的青海格尔木地区、途中耗时2 d带到海拔5 000 m的唐古拉地区,途中耗时3,30 d分别带到海拔4 500 m的西藏那曲地区。 结果与结论：光镜及电镜观察显示,急性高原低氧2 d组肺组织出现明显的高原肺水肿,急性高原低氧30 d组低氧诱导因子1α mRNA的表达明显增高(P < 0.01),高原肺水肿现象则明显减轻。结果证实,低氧习服后肺组织低氧诱导因子1α mRNA表达的提高有利于减轻高原肺水肿。     

急性低氧条件下复氧后大鼠脑HIF—1α蛋白的表达与人参皂甙Rd干预研究

摘要：目的观察大鼠脑缺氧状态下缺氧诱导因子1α（HIF-1α）蛋白的表达及低氧状态下人参皂甙Rd干预对其影响。方法将成年Wistar大鼠90只随机分为急性低氧对照组、低氧预处理干预组、人参皂甙Rd预处理干预组,每组按缺氧后不同时间点（复氧后0h、4h、9h）再分为3亚组,每组10只大鼠。采用免疫组化法检测HIF-1α蛋白的表达。结果在缺氧后复氧即刻,HIF-1α蛋白少量表达,主要存在于海马细胞;随着时间的推移,在复氧后4h,HIF-1α表达逐渐达高峰,至9h时HIF-1α表达又明显减少。低氧预处理干预组及人参皂甙Rd干预组的实验结果发现HIF-1α表达较急性低氧对照组减少,与急性低氧对照组各时间点相比,差异均有显著性（P〈0．05）。两个干预组之间比较无统计学差异。结论急性低氧可以促使HIF-1α在大鼠海马神经细胞的表达,具有时间依赖性,低氧预处理干预及人参皂甙Rd干预均可促使大鼠脑组织HIF-1α表达减少。     

核因子κB在低氧诱导因子1α基因修饰神经干细胞上调血管内皮生长因子表达中的桥接作用**

背景：很多研究发现,在脑缺氧损伤区域核因子κB与血管内皮生长因子表达呈正相关。因此,作者大胆假设,核因子κB是否处于低氧诱导因子1α上调血管内皮生长因子作用通路上并起桥接作用。 目的：以低氧诱导因子1α修饰的神经干细胞为载体,观察核因子κB 在低氧诱导因子1α上调血管内皮生长因子表达通路中的作用。 设计、时间及地点：细胞学体外观察,于2008-03/12在佳木斯大学神经科学研究所完成。 材料：新生24 h内的Wistar大鼠,雌雄不拘。 方法：扩增腺病毒载体低氧诱导因子1α-绿色荧光蛋白后转染神经干细胞,荧光检测神经干细胞中低氧诱导因子1α-绿色荧光蛋白及空载体Ad-绿色荧光蛋白表达,分别提取基因转染后神经干细胞、空载体转染神经干细胞、正常神经干细胞蛋白。然后低氧诱导因子1α基因修饰的神经干细胞中按50,150,300 μmol/L浓度梯度加入核因子κB特异性抑制剂二硫氨基甲酸酞吡咯烷,Western Blot法检测其中血管内皮生长因子的表达变化。 主要观察指标：各组神经干细胞中低氧诱导因子1α、血管内皮生长因子和核因子κB 的表达;给予梯浓度核因子κB 特异性抑制剂后神经干细胞中血管内皮生长因子的表达。 结果：腺病毒低氧诱导因子1α-绿色荧光蛋白转染神经干细胞后基因表达强弱与MOI及转染时间有关;转染低氧诱导因子1α-绿色荧光蛋白后的神经干细胞中低氧诱导因子1α、血管内皮生长因子和核因子κB的表达呈正相关;给予梯浓度核因子κB 特异性抑制剂后腺病毒低氧诱导因子1α-绿色荧光蛋白修饰的神经干细胞中血管内皮生长因子的表达呈抑制剂浓度依赖性下调,各浓度组之间血管内皮生长因子表达差异有显著性意义(P < 0.05~0.01)。 结论：核因子κB位于低氧诱导因子1α上调血管内皮生长因子表达的信号通路上并起桥接作用。     

促红细胞生成素对β淀粉样蛋白诱导大鼠海马CA1区细胞凋亡的保护作用及机制

目的 探讨促红细胞生成素(Erythropoietin,EPO)对阿尔茨海默病(Alzheimer disease,AD)大鼠脑损伤的保护机制.方法 采用大鼠海马内注射B淀粉样蛋白制作AD模型.将SD大鼠随机分为假手术对照组、生理盐水对照组及EPO处理组.大鼠海马内注射Aβ1-40加造模,然后在生理盐水对照组大鼠行脑室立体定向注射生理盐水,EPO处理组则行脑室立体定向注射重组人促红细胞生成素(rHu-EPO).观察手术后24h大鼠海马CA1区抗凋亡蛋白Bcl-xl表达变化,以及术后7d海马CA1区细胞凋亡变化.结果 EPO处理组和生理盐水组海马CA1区大鼠Bcl-xl蛋白表达较假手术对照组减少,但是EPO处理组Bcl-xl蛋白表达高于生理盐水(P<0.05).生理盐水组海马CA1区凋亡细胞明显多于EPO组(P<0.05).结论 EPO可以抑制β淀粉样蛋白诱导海马CA1区细胞凋亡,与其抑制Bcl-xl蛋白表达下降有关.     

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.     

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.