嗅鞘细胞移植治疗免疫性脑脊髓炎：有免疫学排斥现象吗？

目的：研究嗅鞘细胞（OECs）的免疫原性及移植实验性免疫性脑脊髓炎（EAE）后颈淋巴系统的反应。方法：用新生ICR小鼠嗅球培养出OECs, 流式细胞术（FCM）检测其表面主要组织相容性抗原I、II类（MHC-I、MHC-II）表达情况。将经荧光染料CFSE标记OECs悬液或PBS注入EAE大鼠或正常大鼠的侧脑室,收集移植7天后颈部淋细胞,FCM检测CFSE+、抗原提呈细胞标志物CD83+及CFSE+CD83+的表达率,混合淋巴细胞培养检测淋巴细胞增殖率（PI）。结果：OECs高表达MHC-I (78.4±4.45%),中表达MHC-II(43.2±2.98%)。移植实验显示移植OECs的EAE大鼠颈部淋巴结中CD83+（3.83±0.03%）、CFSE+（2.47±0.05%）及CD83+CFSE+（1.98±0.04%）检出率及OECs诱导的PI值（1.32±0.06）均高于对照组或正常大鼠（P<0.05）。同时,PBS注射的EAE大鼠,较正常大鼠亦有较高的CD83+检出率（3.12±0.04%）及PI值（1.20±0.03）（P<0.05）。结论： OECs高表达的MHC分子提示OECs有免疫原性,移植后局部淋巴系统可出现针对OECs的抗原引流、提呈及T细胞的活化,进一步分析提示这种免疫反应的启动依赖于EAE的炎性环境,而OECs移植则加重这一过程。     

高氧液对大鼠胰腺移植的保护作用

背景：目前可供移植的器官日益短缺，但因灌注冷保存所至的原发性移植物无功能仍然有一定的发生率，减少灌注保存所至的器官损伤有较大的临床意义。 目的：探讨高氧液对大鼠胰腺移植的保护作用。 方法：40只SPF级Wistar 大鼠，随机分成2组(n=20)，高氧液组灌注高氧液，对照组灌注普通林格液，比较两组灌注后胰尾组织电镜结果、移植后第1天、3天血血糖浓度，以及两组移植后胰腺组织病理急性排斥评分。 结果与结论：移植前两组差异无显著性意义，灌注后高氧液组胰腺组织超微结构基本正常，细胞核形态完整，大量线粒体存在；对照组胰腺组织细胞大部分排列仍有序整齐，胞浆内线粒体水肿明显，部分线粒体空泡变性。移植后第1，3天血血糖高氧液组低于对照组(P < 0.05)；高氧液组评分低于对照组(P < 0.05)。可见高氧液可减轻缺血再灌注损伤，对大鼠胰腺移植有一定的保护作用。 关键词：高氧液；器官移植；胰腺移植；急性排斥反应；保护     

神经梅毒患者外周血T淋巴细胞亚群水平检测 及临床意义

目的 探讨外周血 T 淋巴细胞亚群 CD3+ 、CD4+ 、CD8+ 水平和 CD4+ /CD8+ 比值识别早期 神经梅毒的作用。方法 回顾性分析 2020 年 2 月至 2022 年 1 月杭州市西溪医院神经内科因梅毒就诊 的 100 例患者的临床资料,根据有无神经系统累及分为神经梅毒组和非神经梅毒组,每组 50 例。选取 同期我院的 50 名健康体检者作为对照组。比较患者和对照组受试者 CD3+ 、CD4+ 、CD8+ T淋巴细胞水 平和 CD4+ /CD8+ 比值。采用受试者工作特征（ROC）曲线分析外周血 T 淋巴细胞亚群识别早期神经梅毒 的价值。结果 神经梅毒组、非神经梅毒组和对照组的 CD4+ T 淋巴细胞水平分别为（30.48±4.08）%、 （32.16±4.08）%、（34.50±4.49）%,CD4+ /CD8+ 比值分别为（1.25±0.19）、（1.35±0.25）、（1.47±0.23）,3 组比 较差异有统计学意义（F=11.428、11.970;P＜ 0.01）;两两比较,差异均有统计学意义（均P＜ 0.05）。将神 经梅毒组患者分为早期组（n=30）、晚期组（n=20）并与对照组进行比较,结果显示 CD4+ T 淋巴细胞水平分 别为（31.23±4.28）%、（29.35±3.57）%、（34.50±4.49）%,CD4+ /CD8+ 比值分别为（1.29±0.21）、（1.18±0.13）、 （1.47±0.23）,3 组比较差异有统计学意义（F=12.289、15.350;P＜ 0.01）。晚期组的 CD4+ T淋巴细胞水 平、CD4+ /CD8+ 比值低于对照组,CD4+ /CD8+ 比值低于早期组,差异有统计学意义（P＜ 0.05）。CD4+ / CD8+ 比值预测神经梅毒的 ROC 曲线下面积为 0.725（95%CI：0.645～0.805）,高于 CD3+ 、CD4+ 和 CD8+ 。 结论 CD4+ T 淋巴细胞水平或 CD4+ /CD8+ 比值下降高度提示神经梅毒,CD4+ /CD8+ 比值更有助于早期识 别神经梅毒。     

丹参对大鼠移植肝血红素氧合酶1表达的影响*

背景：器官移植前使用丹参预处理能够保护组织缺血-再灌注损伤,改善移植器官存活率。 目的：观察含丹参的冷灌注液对同种异体大鼠移植肝脏中血红素氧合酶1表达的影响,以及对供体肝脏缺血-再灌注损伤的保护作用。 方法：将SD雄性大鼠随机分成UW液组(术中使用UW液灌注保存)、丹参+UW液组(术中使用丹参+UW液灌注保存)、ZnPP预处理组(移植前24 h腹腔内注射ZnPP,术中使用丹参+UW液灌注保存),建立稳定的大鼠同种异体肝移植模型。同时取10只正常大鼠作为正常对照。 结果与结论：丹参+UW液组和UW液组血清总胆红素、谷丙转氨酶、谷草转氨酶水平明显低于ZnPP预处理组(P < 0.01)。血红素氧合酶1mRNA及其蛋白在丹参+UW液组中较UW组表达更明显,在ZnPP预处理组中表达明显受到抑制(P < 0.05)。丹参+UW液组肝脏Suzuki标准评分明显低于ZnPP预处理组及UW液组(P < 0.05)。表明丹参能上调同种异体的大鼠移植肝脏中血红素氧合酶1 mRNA及其蛋白的表达,减轻供肝缺血-再灌注损伤,保护移植大鼠肝脏。     

C6细胞热休克蛋白抗原肽复合物的提纯及抑瘤作用的研究

目的 提纯大鼠脑胶质瘤C6细胞热休克蛋白抗原肽复合物(HAC),免疫SD大鼠,观察HAC的抑瘤作用。方法 采用免疫亲和层析方法提纯大鼠脑胶质瘤C6细胞HAC,免疫20只大鼠为实验组,以另20只大鼠作为对照组,于免疫后1周,采用立体定向脑内接种方法,以C6细胞攻击两组大鼠,于肿瘤细胞攻击后第二周,取两组动物外周静脉血,测定外周静脉血淋巴细胞计数,并应用流式细胞仪技术测定外周血中CD3+CD4+和CD3+CD8+T淋巴细胞的比例。观察饲养过程中实验动物出现的症状、体征和第四周实验动物存活率。于第四周处死存活动物,取脑组织进行HE染色病理组织学检查,并用免疫组化方法分析脑胶质瘤浸润区T淋巴细胞分布情况。结果 实验组大鼠外周血淋巴细胞计数显著高于对照组(P<0.01),CD3+CD4+和CD3+CD8+T淋巴细胞的比例实验组均显著高于对照组(P<0.01)。实验组动物症状出现时间显著晚于对照组动物(P<0.01),实验组动物第四周末存活率显著高于对照组(P<0.05)。实验组胶质瘤局部浸润的CD3+和CD4+细胞数均显著高于对照组(P<0.01),实验组胶质瘤局部浸润的CD8+细胞数与对照组比较无显著差异(P>0.05),实验组胶质瘤局部浸润T淋巴细胞CD4+/CD8+显著高于对照组(P<0.01)。结论 C6细胞中HAC可以诱导大鼠产生对C6细胞的细胞免疫,提高大鼠存活率。     

缺血预处理减轻大鼠减体积肝移植损伤并促进肝再生

背景：近年来,肝移植技术迅速发展,如何预防缺血再灌注损伤并有效保护肝再生成为研究的热点。缺血预处理是保护肝缺血损伤的有效方法,但其确切机制尚存争议。 目的：研究缺血预处理在大鼠减体积肝移植肝损伤和肝再生中的作用及机制。 方法：动物随机分为3组,肝移植组建立大鼠减体积肝移植模型。缺血预处理+肝移植组在供肝灌注前阻断第1肝门行缺血预处理10 min,再灌注15 min。假手术组在开腹后游离肝周韧带,然后关腹。分别于术后0.5,2,6,24 h取材。通过血清谷丙转氨酶水平和移植肝组织病理检查评估肝损伤。半定量免疫组织化学和western blot法测定氧化还原蛋白1表达水平,检测移植肝细胞增殖细胞核抗原评估肝再生情况。 结果与结论：与肝移植组相比,缺血预处 理+肝移植组术后6,24 h受体血清谷丙转氨酶明显降低(P < 0.05;P < 0.01)。病理学分析显示肝移植组术后24 h可见到门脉周围大量炎细胞浸润,肝窦扩张明显,肝组织损伤较重;而缺血预处理+肝移植组则损伤较轻。半定量免疫组织化学显示缺血预处 理+肝移植组移植肝中Ref-1蛋白表达明显增加,这一结果同样在westernblot检测中得到验证：缺血预处理+肝移植组移植肝术后24 h Ref-1蛋白表达较肝移植组明显增强 (P < 0.05)。同时,术后2,6和24 h 缺血预处理+肝移植组增殖细胞核抗原阳性细胞数较肝移植组明显增加(P < 0.05)。结果提示缺血预处理可减轻大鼠减体积肝移植术后早期移植物肝损伤并促进肝再生,这与Ref-1蛋白高表达密切相关。     

银杏内酯K通过PI3K/Akt/mTOR通路促进血管生成改善缺血性卒中

目的 探究银杏内酯 K（Ginkgolide K ，GK）通过磷脂酰肌醇 -3- 激酶（PI3K）/ 蛋白激酶 B （Akt）/ 哺乳动物雷帕霉素靶蛋白（mTOR）信号通路对缺血性卒中小鼠血管内皮生长因子（VEGF）表达 和脑血管生成的作用。方法 将 40 只 C57BL/6 小鼠随机分为对照组、大脑中动脉闭塞（MCAO）组、低 剂量 GK（GK-L）组（3.5 mg/kg）、中剂量 GK（GK-M）组（7 mg/kg）和高剂量（GK-H）组（14 mg/kg），每组各 8 只。建立 MCAO 模型和氧葡萄糖剥夺发（OGD）体外模型；采用改良后的神经系统严重程度评分（mNSS） 评估法检测小鼠神经功能缺损；2，3，5- 三苯基氯化四氮唑（TTC）染色检测小鼠脑缺血面积；免疫荧 光染色检测小鼠梗死灶周围皮质血管生成和星形胶质细胞覆盖。培养 hCMEC/D3 细胞，分为对照组， OGD 组、OGD+CK 组、OGD+LY 组（LY 为 PI3K 信号通路抑制剂）和 OGD+GK+LY 组，采用细胞计数试 剂盒 -8（CCK-8）检测内皮细胞活性；Western blot 检测内皮细胞缺氧诱导因子 1α（HIF-1α）、VEGF 和 PI3K/Akt/mTOR 通路相关基因蛋白表达；细胞划痕实验检测内皮细胞迁移能力；血管形成实验检测内 皮细胞管腔形成能力。结果 与 MCAO 组［（5.37±1.25）分、（11.99±1.72）%］比较，GK-M 组和 GK-H 组 小鼠 mNSS 评分［分别为（3.37±1.32）、（2.23±0.38）分］和脑缺血面积［（4.75±0.89）%、（2.42±0.42）%］ 均 显 著 降 低（P＜ 0.05）。 与 MCAO 组 EdU+ /CD31+ 细 胞 数、EdU+ /GFAP+ 细胞数和星形胶质细胞覆盖 率［分 别 为（3.33±0.58）个、（4.33±1.53）个、（69.20±5.60）%］比 较，GK 组 小 鼠 EdU+ /CD31+ 细胞数 ［（13.67±2.08）个，t=3.576］、EdU+ /GFAP+ 细 胞 数［（8.33±1.53）个，t=6.008］和 星 形 胶 质 细 胞 覆 盖 率 ［（82.26±7.77）%］显著升高（均P＜ 0.05）。与对照组细胞活力、HIF-1α、VEGF 蛋白表达、Akt 和 mTOR 磷酸化水平［分别为（100.31±3.01）%、（0.09±0.03）、（0.13±0.03）、（0.20±0.04）、（0.18±0.03）］比较，OGD 组细胞活力［（52.37±9.06）%］、HIF-1α（0.17±0.02）和 VEGF 蛋白表达（0.18±0.03）、Akt 和 mTOR 磷酸 化水平［（0.28±0.06），（0.38±0.05）］均显著升高（均P＜ 0.05）；与 OGD 组比较，OGD+GK 组细胞 HIF-1α （0.22±0.03）和 VEGF 蛋白表达（0.23±0.03）、Akt 和 mTOR 磷酸化水平［（0.48±0.09），（0.52±0.05）］、细胞 活力［（61.07±3.48）%］、迁移率［（85.26±11.03）%］和管状结构数量［（81.97±5.79）%］均显著升高（均 P＜0.05），OGD+LY组则表现出相反变化；PI3K信号通路抑制剂LY294002可逆转GK对OGD细胞的影响。 结论 GK 通过 PI3K/Akt/mTOR 信号通路上调 VEGF 表达促进脑血管生成，改善小鼠缺血性卒中。     

同种异体肢体移植中他克莫司的应用剂量*☆

背景：他克莫司应用于同种异体肝移植的免疫耐受已多见报道。 目的：探索他克莫司在异体肢体移植时的最佳应用剂量。 方法：建立同种异体肢体移植大鼠模型,移植造模后设立给予不同他克莫司剂量的0.5,1,2 mg/(kg•d)组及对照组,对大鼠进行大体观察、组织学、淋巴细胞亚群测定。 结果与结论：移植后出现排斥反应的时间分别是对照组(3.43±0.79) d、0.5 mg/(kg•d)组(5.68±0.97) d、1 mg/(kg•d)组(9.13±1.17) d、2 mg/(kg•d) 组(9.61±2.38) d,排斥反应的病理分级4组分别为(2.61±0.38),(1.57±0.43),(0.85±0.24),(0.71±0.19)级。移植后各给药组CD4+、CD8+检测值均明显下降,CD4/CD8比值轻度增加或在正常值范围内;对照组CD4+、CD8+无明显变化,CD4/CD8比值明显增加。提示,他克莫司的应用剂量在1 mg/(kg•d)时就能达到理想的抑制免疫排斥反应,提高用量后意义不大。     

丹参素干预体外低温保存大鼠肝脏血红素氧合酶1的表达

背景：研究发现丹参能够降低诱导型一氧化氮合酶mRNA 的表达，减少一氧化氮的产生，抑制肿瘤坏死因子、白细胞介素等炎性因子的分泌，具有抗氧化作用。丹参素作为丹参的重要单体成分，是否具有相同的作用? 目的：验证丹参素干预大鼠肝脏血红素氧合酶1的表达，以及对体外肝脏低温保存肝脏的保护。 方法：建立大鼠肝脏低温灌注保存模型。分为3组，对照组术前腹腔注射生理盐水，术中用乳酸林格液灌注；实验组术前腹腔注射生理盐水，术中用丹参素+乳酸林格液灌注；抑制剂组：术前腹腔注射锌原朴啉，术中用丹参素+乳酸林格液灌注。保存0，1，3，6 h，分别RT-PCR检测血红素氧合酶1mRNA及蛋白表达的情况，检测细胞线粒体钙离子含量及钙离子ATP酶活性，电镜观察各组肝细胞、线粒体形态改变，光镜观察肝细胞、肝小叶形态改变。 结果与结论：实验组肝血红素氧合酶1 mRNA及蛋白的表达水平明显比其他两组高(P < 0.05)。实验组的肝细胞线粒体钙离子含量明显较其他两组低，Ca2+-ATP酶活性较其他两组高。结果提示，丹参素灌注保存液可以诱导大鼠肝脏中血红素氧合酶1的过表达，延长肝脏低温保存时间。     

应用供体抗原特异性CD4+CD25+ Treg细胞延长大鼠移植肾的存活

背景：随着磁分选技术的完善,体外分选、扩增足量的对移植抗原具有特异性的细胞已成为可能,但就其在体内应用剂量及免疫耐受的效能问题目前鲜有报道。 目的：探索供体抗原特异性CD4+CD25+Treg细胞在体内应用诱导移植免疫耐受的量效关系。 方法：以SD大鼠为供体、Wistar大鼠为受体,建立同种异体肾移植动物模型;体外分选、富集Wistar大鼠脾脏CD4+CD25+Treg细胞,并诱导其对SD大鼠供体抗原的特异性表型;根据不同数量(2×105、5×105、1×106、2×106)供体抗原特异性CD4+CD25+Treg细胞在肾移植中单剂量尾静脉注射,并以未注射组为对照。术后15 d分析移植肾脏存活状况。术后4,9,15 d采血检测各组肌酐水平,同时进行移植肾脏病理检查,按照Banff Schema标准进行诊断,并根据Watanabe的方法进行半定量评分。 结果与结论：术后15 d内对照组死亡率最高83.3%,2×105组次之66.7%,2×106组为58.3%,5×105组为33.3%,1×106组则全部存活;各实验组术后4,9,15 d血肌酐水平均明显低于对照组(P < 0.05,P < 0.01);术后第9,15天,2×105组、5×105组血肌酐水平均明显高于1×106组、2×106组(P < 0.05);术后第4,9,15天移植肾脏病理检查的半定量评分结果显示,各时间段5×105组、2×105组与对照组间差异无显著性意义,各时间段1×106组与2×106组优于对照组 (P < 0.05)。结果初步证实供体抗原特异性CD4+CD25+Treg细胞受体内应用能够改善大鼠移植肾功能,延长移植肾存活时间,1×106为相对理想的单次应用剂量。     

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.