体内和体外两种方法猪小体积肝移植模型建立的比较

背景：猪肝结构与人类较为相似,结构相对简单,是研究活体肝移植较好的模型之一。供肝体积过小是临床成人活体肝移植面临的主要问题之一,探索稳定高效的动物模型对于推动小肝综合征的相关研究具有重要意义。 目的：对体内和体外2种小体积肝移植物获取方法进行对比分析,以提供一个理想的成功率高的猪小体积肝移植模型建立方法。 设计、时间及地点：随机对照动物实验,于2007-01/03在上海市泰科公司医疗培训部完成。 材料：选用健康成年实验用广西巴马小型猪42 只,制备21例次猪小体积肝移植模型。 方法：选取体质量相近的广西巴马小型猪作为供受体,将动物按随机数字表法分为2组,体内切除减体积组共10对动物,体外切除减体积组共11对动物。应用全频超声乳化吸引刀+滴水双极电凝镊分别通过体内和体外2种途径,切除部分肝叶以获取小体积供肝植入受体。 主要观察指标：小体积肝移植的无肝期时间、总手术时间、冷缺血时间、受体移植术中出血量和移植后肝断面胆漏例数。 结果：两组在无肝期时间、总手术时间和冷缺血时间差异无显著性意义（P > 0.05）。在移植术中出血量上,体外切除减体积组明显多于体内切除减体积组（P < 0.05）。体外切除减体积组移植后肝断面胆漏发生率亦较体内切除减体积组高（50%,20%,P < 0.05）。 结论：选取体质量相近的供受体,应用超声刀行体内切除减体积是猪小体积肝移植模型建立可行有效的方法。     

改良大鼠减体积肝移植模型的效果分析

目的 探讨大鼠减体积肝移植术后肝脏再生实验研究中改良后的大鼠减体积肝移植模型的效果;方法 实验大鼠均为健康的SD大鼠,体重260g-280g,供体为雌性,受体为雄性,供、受体体重相差10g左右,一般为供体体重比受体体重轻;供体采用单人裸眼操作,在取肝的过程中即进行减体积操作;修肝时将套管柄置于门静脉和肝下下腔静脉的正前方,将幽门静脉结扎点外翻于套管外并置于套管柄的左侧,即肝脏的左侧;将右肾静脉结扎点外翻于套管外并置于套管柄的右侧,即肝脏的右侧;供肝套管完成后用灌注液对门静脉和肝下下腔静脉进行冲洗;然后以左膈静脉为标识点进行7-0无损伤血管缝线吊线;受体采用双人裸眼配合操作,肝上下腔静脉吻合时,左右固定位点采用“8”字形外翻缝合,后壁和前壁分别采用连续吻合,门静脉和肝下下腔静脉采用改良的双袖套法,胆管支撑管法建立大鼠减体积的稳定模型。 结果 供体手术时间为32±1.5min,修肝时间为6±1.6min,受体手术时间为40±2.5min,无肝期时间为14±2.3min;手术的成功率为92﹪,术后3天的存活率为90﹪,术后1周存活率为88.7﹪,术后2周存活率为88﹪;术后并发症较改良前明显较少,供肝的冷保存时间减少,差异有统计学意义。结论 改良后的大鼠减体积肝移植模型比较稳定和可靠,而且手术的成功率较高,术后的并发症较低,为更好的研究减体积肝移植术后肝脏再生的提供了有效的改良手段。     

冷保存方法构建的大鼠肝移植模型

背景：肝移植是终末期肝病最为有效的治疗手段，移植后胆病是制约肝移植发展的主要障碍之一。 目的：建立稳定的大鼠冷保存肝移植模型，探讨冷保存对肝移植后肝脏胆管的影响。 方法：120只雄性SD大鼠随机分为4组，按照组内随机配对的原则，体质量相对较轻的大鼠做为供体，供肝置于4 ℃ UW液中分别保存2，8，16 h后行原位肝移植。在“两套袖法”基础上，以“支架法”建立动脉化大鼠原位肝移植模型，供受体肝总动脉采用改良“支架法”进行端端吻合，重建肝动脉血供。记录移植手术时间及移植成功率，并分别于移植后3，7 d检测血清转氨酶、总胆红素、碱性磷酸酶水平，同时观察组织病理学改变。 结果与结论：实验共完成55例次大鼠原位肝移植手术，手术成功率为93%。冷保存2，8，16 h组术后7 d存活率分别为100%(9/9)，83%(10/12)，73%(8/11)。随着冷保存时间的延长，肝功能及肝内胆管损伤加重，胆管组织病理学评分显示各组间差异有显著性意义(P < 0.05)。其中供肝冷保存16 h大鼠肝移植模型既有较高的手术存活率又有严重的胆管损伤，是研究冷保存对肝移植胆管病影响的较好模型。 主要观察指标：移植手术时间，移植成功率。分别于移植后3，7d检测血清转氨酶、总胆红素、碱性磷酸酶及组织病理分析。 结果：冷保存时间延长导致胆道功能严重损伤，胆管组织病理学评分显示各组间差异有显著性。 结论：供肝冷保存16 h大鼠肝移植模型是研究冷保存对肝移植胆管病影响的较好模型。     

E不同冷保存时间热缺血供肝在肝移植中的应用**☆

背景：目前国内临床肝移植供肝的主要来源仍然是无心跳供体供肝,国外近年来也越来越多地使用无心跳供体供肝,但无心跳供体供肝这类经历了热缺血的供肝能够耐受冷保存的安全时限尚没有统一标准,也鲜有这方面的临床报道。 目的：评价不同冷保存时间的热缺血供肝在临床肝移植中的应用安全性及疗效。 设计、时间及地点：随机对照观察,于2006-01/2007-12在中山大学附属第一医院器官移植中心完成。 对象：无心跳供体供肝热缺血时间在10 min内的肝移植病例154例。 方法：根据冷保存时间不同分为3组,8 h内组58例,8~12 h组62例,13~16 h组34例。供肝按供体分配原则按随机数字表法分配给3组患者,移植后采用相同的免疫抑制方案。 主要观察指标：比较3组患者肝移植后谷丙转氨酶峰值、原发性移植肝无功能、急性排斥反应、胆道并发症、血管并发症、感染,以及移植肝存活和受体存活情况的差异。 结果：随访8~32个月,3组患者移植后均未发生原发性移植肝无功能。8~12 h组患者移植后仅谷丙转氨酶峰值高于8 h内组(P < 0.05),其余治疗两组比较差异均无显著性意义(P > 0.05)。与8 h内组患者比较,13~16 h组患者的移植后谷丙转氨酶峰值、感染发生率和胆道并发症发生率显著升高(P < 0.05),移植肝存活率和受体存活率显著降低(P < 0.05)。 结论：热缺血时间在10 min内的无心跳供体供肝能够耐受12 h的冷保存损伤,超过此时限,移植后胆道并发症和感染的发生率明显升高,移植肝存活率和受体存活率明显降低。     

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。     

诱导血红素加氧酶1高表达对减体积肝移植大鼠生存的影响

背景：血红素加氧酶1在防止和减轻缺血再灌注损伤方面扮演着重要角色，成为目前肝移植领域的研究热点。 目的：构建重组腺病毒Ad5-血红素加氧酶1，对肝移植供体进行预处理来诱导供肝血红素加氧酶1高表达，进一步观察其对减体积肝移植大鼠生存时间及肝功能的影响。 设计、时间及地点：随机对照动物实验，于2003-09/2005-03在重庆医科大学附属儿童医院儿科研究所完成。 材料：选用SD大鼠74只，制备原位减体积肝移植模型。 方法：利用分子生物学方法构建携带有血红素加氧酶1基因的重组腺病毒Ad5-血红素加氧酶1，对供体进行预处理。将74只大鼠按不同处理方案分组如下：生理盐水组（n=12）、诱导剂原卟啉钴组（n=13）、Ad5-血红素加氧酶1组（n=13）、Ad5-绿色荧光蛋白组（n=12）、Ad5-血红素加氧酶1+抑制剂原卟啉锌组（n=12）分别于取肝前注射生理盐水、诱导剂原卟啉钴、Ad5-血红素加氧酶1、Ad5-绿色荧光蛋白及Ad5-血红素加氧酶1+抑制剂原卟啉锌，取肝后HTK液4 ℃保存24 h后植入。对照组（n=12）取肝前48 h静脉注射生理盐水，取肝后马上植入。 主要观察指标：各组肝移植大鼠的存活率，肝功能指标测定，彩色多普勒超声监测移植后2 h门静脉血流变化，应用常规苏木精-伊红染色法观察移植肝组织病理学变化，肝组织血红素加氧酶1活性测定，应用免疫组织化学染色法检测血红素加氧酶1、肿瘤坏死因子α，bcl-2，bax在移植肝组织中的表达，从分子水平检测血红素加氧酶1、肿瘤坏死因子α，bcl-2，bax mRNA的表达变化。 结果：Ad5-血红素加氧酶1组大鼠肝移植后1，7，21 d的生存率显著高于生理盐水组 （P < 0.05）。与生理盐水组、Ad5-绿色荧光蛋白组及Ad5-血红素加氧酶1+抑制剂原卟啉锌组比较，Ad5-血红素加氧酶1组移植肝的谷丙转氨酶活性显著降低（P < 0.05），移植后2 h内门静脉血流量明显增加（P < 0.05），血红素加氧酶1活性显著升高（P < 0.05），反转录-聚合酶链反应和免疫组化检测中血红素加氧酶1、Bcl-2表达水平增高 （P < 0.05），Bax、肿瘤坏死因子α表达水平降低（P < 0.05）。 结论：构建重组腺病毒Ad5-血红素加氧酶1可以诱导供肝血红素加氧酶1高表达，显著增加大鼠减体积肝移植后2 h内门静脉血流，促进移植肝功能的恢复，从而延长肝移植后的生存时间。     

受体血预先经门静脉输入供体诱导移植肝浸润细胞凋亡

背景：肝移植后排斥反应发生时,肝细胞被浸润的T淋巴细胞破坏,肝细胞减少,肝功能进行性恶化。诱导肝移植免疫耐受仍然是目前面临的重大课题。 目的： 观察受体血预先经门静脉输入供体对大鼠移植肝内浸润淋巴细胞凋亡的影响。 设计、时间及地点：随机对照动物实验,于2002-05/2004-05在中国医科大学器官移植实验室完成。 材料：选用纯系大鼠制作大鼠原位肝移植模型。24只供体为雄性ACI大鼠(RT1a),24只受体为雄性LEW大鼠(RT1l)。 方法： 大鼠肝移植采用改良的两袖套法进行原位移植。受体大鼠按随机数字表法分为4组,每组6只。对照组未作处理;受体血经阴茎静脉输入组于移植前7 d将受体血1 mL经阴茎静脉输入供体;非受体血经门静脉输入组于移植前7 d将非受体大鼠（BN大鼠）血1 mL经门静脉输入供体;受体血经门静脉输入组于移植前7 d将受体血1 mL经门静脉输入供体。 主要观察指标：肝移植后观察大鼠生存时间;移植后检测各组大鼠血清γ-干扰素质量浓度;移植后观察移植肝组织学变化;移植后7 d检测移植肝内树突状细胞数量;移植后3,5,7,14 d检测移植肝内浸润淋巴细胞的凋亡情况。 结果： 受体血经门静脉输入组大鼠的生存时间显著长于对照组(P < 0.01)。肝移植后3,5 d,受体血经门静脉输入组大鼠的血清γ-干扰素质量浓度显著高于对照组(P < 0.05),受体血经阴茎静脉输入组、非受体血经门静脉输入组大鼠的生存时间及血清γ-干扰素质量浓度与对照组无显著差异(P > 0.05)。受体血经门静脉输入组大鼠移植肝汇管区内的淋巴细胞浸润显著减少,移植肝内检测到大量供体来源的树突状细胞。移植后受体血经门静脉输入组大鼠肝组织切片每平方毫米的凋亡细胞数显著多于对照组(P < 0.01)。 结论： 受体血预先经门静脉输入供体,可以延长异系肝移植受体大鼠生存时间,促进移植肝内浸润淋巴细胞的凋亡。     

大黄素对大鼠肝移植后急性排斥反应中肝细胞凋亡的影响

背景：抑制急性排斥反应的高效免疫抑制剂为器官移植所必需,较多的中药成分具有免疫调节作用。课题组在前期实验成功建立全血供大鼠肝移植模型基础上,初步发现大黄素对大鼠肝移植后急性排斥反应具有抑制作用,而且这种抑制作用可以通过多途径达到。 目的：观察大黄素对同种异体大鼠肝移植后早期急性排斥反应过程中肝细胞凋亡的影响。 设计、时间及地点：随机对照动物实验,于2005-04/09在西安交通大学第一附属医院肝胆外科实验室完成。 材料：供体选用SD大鼠80只,雌雄不限;受体选用雄性Wistar大鼠80只,制备SD→Wistar大鼠全血供肝移植模型。 方法：将制备的80只大鼠模型按随机数字表法分为4组,每组20只。于移植后第1天开始按分组设计行腹腔内药物注射,模型对照组仅给予生理盐水,大黄素组给予大黄素1.5 mg/（kg?d）,环孢素A组给予环孢素A 3 mg/（kg?d）,环孢素A+大黄素组给予环孢素A 3 mg/（kg?d）+大黄素1.5 mg/（kg?d）。 主要观察指标：移植后第7天各组处死10只大鼠,取肝脏标本,观察移植肝组织急性排斥反应强度、肝细胞凋亡指数、Bcl-2蛋白的表达。余受体继续应用药物干预直至死亡,记录其生存时间。 结果：与模型对照组相比,大黄素组、环孢素A组、环孢素A+大黄素组大鼠移植后存活时间明显延长（P < 0.05）,以环孢素A+大黄素组存活时间最长。移植后第7天,与模型对照组相比,大黄素组、环孢素A组、环孢素A+大黄素组大鼠移植肝排斥反应强度、肝细胞凋亡指数显著降低（P < 0.05）,Bcl-2蛋白表达水平显著升高（P < 0.05）;大黄素+环孢素A组大鼠的移植肝排斥反应强度、肝细胞凋亡指数显著低于其他3组（P < 0.05）,Bcl-2蛋白表达水平显著高于其他3组 （P < 0.05）。 结论：大黄素具有抑制同种异体大鼠肝移植急性排斥过程中肝细胞凋亡程度,改善肝功能的作用,与环孢素A具有一定的协同作用,同时又能减轻环孢素A引起的肝功能损害。     

缺血预处理大鼠自体肝移植后剩余肝细胞的凋亡和增殖☆

背景：肝脏缺血再灌注损伤后肝细胞受到增殖和凋亡的双重调控。肝大部切除后,余肝经历缺血再灌注损伤,其肝再生受到明显抑制,缺血预处理可减轻此损伤,促进肝再生,其机制是否也与这有关,目前未见相关报道。 目的：探讨缺血预处理对大鼠自体肝移植后余肝肝细胞凋亡和增殖的影响。 设计、时间及地点：随机对照动物实验,于2006-09/2007-07在中南大学湘雅医学院实验动物中心完成。 材料：雄性SD大鼠144只,随机分为3组：单纯肝叶切除组、自体肝移植组、缺血预处理组,48只/组。 方法：单纯肝叶切除组大鼠只行肝左、中叶切除,不阻断肝右、尾叶血流。自体肝移植组大鼠结扎切断肝后与食管腹段之间的静脉交通支,游离liberate尾状叶,游离第一肝门、肝上及肝下下腔静脉后,阻断并经门静脉持续低温灌注保存液,同时进行无血肝切除(切除肝左、中叶),肝脏在体持续低温灌洗15 min。解除肝门阻断,完全恢复肝脏血流。快速复温肝脏表面,并冲洗腹腔,缝合关腹。缺血预处理组大鼠在门静脉灌注前先阻断肝右、尾叶血流10 min,然后开放血流10 min,余步骤同自体肝移植组。各组大鼠分别于肝叶切除后0,1,3,6,12,24,48,72 h时取材。 主要观察指标：生化分析仪测定血清丙氨酸氨基转移酶及天冬氨酸氨基转移酶的水平,流式细胞仪检测肝细胞凋亡指数,通过Ki-67抗原的表达检测肝细胞增殖情况。 结果：与自体肝移植组比较,除肝叶切除后0 h 外,其余各时间点单纯肝叶切除组、缺血预处理组血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平均明显降低(P < 0.05)。各组在肝叶切除后0 h(即正常肝组织)基本不存在凋亡细胞;单纯肝叶切除组肝大部切除后余肝肝细胞凋亡指数稍有升高;自体肝移植组复灌注后肝细胞凋亡指数急剧升高,约在12 h达到高峰,而后逐渐下降;与自体肝移植组比较,缺血预处理组肝细胞凋亡指数明显降低(P < 0.05)。各组Ki-67表达率在肝叶切除后均明显升高,约在24 h达高峰,而后逐渐下降。与单纯肝叶切除组比较,自体肝移植组Ki-67表达率明显降低(P < 0.05);与自体肝移植组比较,缺血预处理组Ki-67表达率明显增高(P < 0.05)。 结论：缺血预处理可减轻自体肝移植后肝缺血再灌注损伤所致肝细胞凋亡,促进肝细胞增殖,这可能是其促进肝再生的机制之一。     

DA至Lewis大鼠肝移植急性排斥反应模型的建立：技术改良分析*☆

背景：国际上研究肝移植免疫耐受的基础动物模型是大鼠肝移植急性排斥反应模型,国际上公认的肝移植急性排斥反应模型鼠种配对方式为DA至Lewis大鼠、DA至BN大鼠及BN至Lewis大鼠,但由于鼠种缺乏和操作技术有待成熟的原因,国内较少引用以上鼠种配对方式进行该模型的建立。 目的：课题组在大量SD大鼠肝移植模型建立训练的基础上,采用DA大鼠为供体,Lewis大鼠为受体,摸索DA至Lewis大鼠肝移植急排模型建立技巧和经验。 方法：通过改良二袖套法,以雄性DA大鼠为供体,雄性Lewis大鼠为受体,建立原位肝移植动物模型60只,受体大鼠术前1 d和术后1周内饲喂治疗剂量的他克莫司,1周后半量递减并停药,记录移植手术时间,观察受体大鼠的术后生存状况、手术成功率及生存期,分别于术后7,14,21,28 d处死受体大鼠,获取肝组织标本,苏木精-伊红染色,观察肝脏大体和镜下的病理学变化,进行急性排斥反应评分。 结果与结论：供肝冷缺血时间30~60 min,供体手术时间(18.5±4.0) min,供肝修整时间(7±3) min,受体手术时间(35.0± 7.3) min,无肝期为(13.0±3.0) min,手术成功率为98%,1周存活率为91.6%。术后2周随着他克莫司撤药,受体大鼠迅速发生急性排斥反应,于术后14~28 d死亡,平均生存时间为(20.85±0.71) d,中位生存时间为21 d。实验建立DA至Lewis大鼠肝移植急性排斥反应动物模型需要以大量SD大鼠肝移植训练为基础进行,通过对二袖套法技术的改良和围手术期短期应用他克莫司有助于该模型的稳定建立。     

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.