成骨生长肽对骨髓基质细胞增殖和向成骨方向分化的影响

背景: 成骨生长肽是新近发现的一种具有促进成骨作用的生长因子,其对骨髓基质细胞增殖分化作用受到越来越多的关注。 目的：验证成骨生长肽在体外对骨髓基质细胞增殖和成骨向分化的影响。 设计、时间及地点：随机对照实验,于2006-02/06在教育部口腔生物医学工程重点实验室完成。 材料：6周龄雄性SD大鼠用于骨髓基质细胞提取;成骨生长肽为Sigma公司产品。 方法：体外培养骨髓基质细胞,加入含不同浓度(10-11,10-10,10-9,10-8,10-7 mol/L)成骨生长肽及小牛血清的α-MEM培养基培养,以单纯含小牛血清的α-MEM培养基培养作对照。 主要观察指标：①骨髓基质细胞的鉴定。②用四甲基偶氮唑盐法检测细胞增殖情况。③酶联免疫法检测细胞内碱性磷酸酶的表达。④反转录-聚合酶链反应法检测细胞内核心结合因子1mRNA的表达。 结果：成骨生长肽对骨髓基质细胞增殖有促进作用(P < 0.05),最大效应浓度为 10-9 mol/L;能增加细胞内碱性磷酸酶活性(P < 0.05),最大效应浓度为10-8 mol/L;可诱导核心结合因子1mRNA的表达(P < 0.05)。 结论：成骨生长肽可促进骨髓基质细胞的增殖,并通过诱导其内核心结合因子1mRNA的表达促进其成骨向的分化。     

土鳖虫干预激素诱导骨髓间充质干细胞Ⅰ型胶原mRNA的表达

研究表明激素性股骨头缺血性坏死的早期病理变化可能与激素诱导下骨髓间充质干细胞的成脂分化有关。 目的：观察土鳖虫含药血清对骨髓间充质干细胞成骨的促进作用。 方法：第3代骨髓间充质干细胞随机分为中药低剂量组、中药中剂量组、中药高剂量组、对照组和空白组。中药低、中、高剂量组分别加入用不同剂量含药血清配制的培养液(1 L培养基中含100 g含药血清),同时加地塞米松至终浓度10-6 mol/L;对照组加入含生理盐水血清的培养液,同时加地塞米松至终浓度10-6 mol/L;空白组加入含生理盐水血清的培养液,不加地塞米松。检测干预6 d后各组细胞内成骨标志物Ⅰ型胶原mRNA及碱性磷酸酶的表达。 结果与结论：干预6 d后,细胞内碱性磷酸酶活性及Ⅰ型胶原 mRNA表达对照组较空白组明显降低,而中药各组较对照组均有不同程度的增高,且差异均具有显著性意义(P < 0.01)。说明土鳖虫防治激素性股骨头缺血坏死的机制不仅是改善股骨头的微循环,还与其抑制激素诱导下的骨髓间充质干细胞成骨分化减少有关。     

三七总皂苷对酒精诱导骨髓基质干细胞分化影响的实验研究*

目的：三七总皂苷能阻断受体操纵性钙通道，增强一氧化氮的扩张血管作用，改善微循环，具有抗缺血再灌注损伤的作用，关于三七总皂苷对酒精性骨坏死防治作用的研究尚少。实验拟观察三七总皂苷对酒精诱导兔骨髓基质干细胞成脂分化的抑制作用。 方法：实验于2006-11/2007-08在广西医科大学完成。①实验材料：三七总皂苷由江苏康宝制药有限公司提供（国药准字Z32020670）。4周龄大白兔由广西医科大学实验动物中心提供，清洁级，实验过程中对动物处置符合动物伦理学标准。②实验方法：采用密度梯度离心法与贴壁法相结合体外分离、培养兔骨髓基质干细胞。取第3代细胞,并随机分为3组：空白组：细胞在含10%胎牛血清DMEM培养基中培养,不加酒精和三七总皂苷；模型组:每次更换培养液时加酒精0.09 mol/L；50 mg/L三七总皂苷组:每次更换培养液时, 加0.09 mol/L酒精与三七总皂苷50 mg/L；100 mg/L三七总皂苷组:每次更换培养液时, 加酒精0.09 mol/L与三七总皂苷100 mg/L。③实验评估：检测细胞内三酰甘油含量与碱性磷酸酶活性。 结果：①干预14 d时,模型组细胞内碱性磷酸酶活性降低,明显低于三七总皂苷干预组和空白组（P < 0.05）。三七总皂苷干预两组细胞内碱性磷酸酶活性,与空白组比较差异无统计学意义（P > 0.05）。②干预21 d时,模型组脂滴最多,三七总皂苷干预两组较模型组明显减少(P < 0.05),空白组未见明显脂滴出现。③三七总皂苷干预组和空白组三酰甘油含量差异无统计学意义 (P > 0.05) ,三七总皂苷干预组和空白组细胞内三酰甘油含量低于模型组细胞内三酰甘油含量(P < 0.05)。 结论：三七总皂苷能抑制酒精诱导的兔骨髓基质干细胞成脂分化,而促进成骨分化,可能有治疗酒精性骨股头缺血性坏死的作用。     

DNA去甲基化对大鼠骨髓间充质干细胞端粒酶反转录酶的调节

背景：DNA去甲基化是一种重要的表观遗传修饰,对肿瘤细胞的端粒酶具有重要调节作用,而对骨髓间充质干细胞端粒酶活性有何影响尚不清楚。 目的：观察DNA去甲基化对骨髓间充质干细胞增殖及端粒酶反转录酶蛋白表达的影响。 方法：全骨髓贴壁培养法分离培养大鼠骨髓间充质干细胞;按照下列分组加入5-杂氮胞苷,使各组5-杂氮胞苷终浓度分别为0,3,6,12,24 μmol/L。加入5-杂氮胞苷后第1,2,3,5,7天进行指标检测。 结果与结论：与对照组相比,5-杂氮胞苷干预24 h,各浓度组均显著促进细胞增殖活性(P < 0.05);干预48 h,6,12,24 μmol/L组显著促进细胞增殖活性(P < 0.05);干预72 h,12,24 μmol/L组显著抑制细胞增殖活性(P < 0.05);干预120,168 h,对照组与各浓度组间差异均无显著性意义(P > 0.05)。5-杂氮胞苷干预48 h,6,12,24 μmol/L组端粒酶反转录酶蛋白IA值较对照组显著增加(P < 0.05)。提示在一定浓度范围及一定作用时间内,5-杂氮胞苷可以促进骨髓间充质干细胞增殖与端粒酶反转录酶蛋白的表达。     

pcDNA3.1-成骨生长肽真核表达载体在骨髓基质干细胞中的表达**

背景：成骨生长肽具有明显的促进成骨细胞增殖、分化、成熟的作用。 目的：观察成骨生长肽基因转染兔骨髓基质干细胞后的表达及表达产物对骨髓基质干细胞向成骨细胞分化的影响。 方法：构建重组真核表达载体pcDNA3.1-成骨生长肽,并在脂质体介导下,将其导入兔骨髓基质干细胞。通过G418筛选获得阳性克隆。RT-PCR方法检测成骨生长肽基因在骨髓基质干细胞内的表达,并观察转染pcDNA3.1-成骨生长肽后骨髓基质干细胞向成骨细胞分化的情况。 结果与结论：实验成功构建了真核表达载体pcDNA3.1-成骨生长肽,转染pcDNA3.1-成骨生长肽的骨髓基质干细胞可见成骨生长肽mRNA的表达,同时羟脯氨酸的分泌水平增加,碱性磷酸酶活性增高。证实经pcDNA3.1-成骨生长肽转染的兔骨髓基质干细胞不仅可以表达成骨生长肽,而且具有向成骨细胞分化的特性。     

富血小板血浆诱导兔骨髓基质干细胞向成骨细胞的分化

背景：对于骨髓基质干细胞向成骨细胞的定向诱导分化,目前大多存在诱导物价格昂贵、制备困难或细胞培养周期长、成骨能力低等缺点,近年研究发现浓缩血小板中存在的生长因子有诱导骨再生的作用。 目的：观察富血小板血浆对体外培养兔骨髓基质干细胞的增殖和成骨细胞分化作用。 方法：从8只兔双侧股骨大转子抽取骨髓,体外分离培养兔骨髓基质干细胞,传至第3代分为两组,实验组用含1%富血小板血浆的DMEM进行干预,对照组加入普通DMEM条件培养液。 结果与结论：倒置显微镜下,原代培养细胞24~36 h后开始贴壁,10~12 d细胞融合成单层。实验组细胞培养第2天已贴壁,第6天细胞大部分融合;对照组细胞形态学变化较实验组晚出现1~3 d。培养第2,6,10,14天,碱性磷酸酶活性测定和茜素红钙结节染色结果显示,体外培养的兔成骨细胞生长良好,生化指标稳定,表现出与典型的成骨细胞相似的形态特征和生物学特性,证实富血小板血浆能促进体外培养的兔骨髓基质干细胞增殖,并能促使其向成骨细胞分化。     

骨髓基质干细胞成骨分化过程中Wnt、骨形态发生蛋白2信号通路相关因子与辛伐他汀的作用*

背景：辛伐他汀可促进体外培养的人或鼠骨髓基质干细胞向成骨细胞分化,但作用机制尚不清楚。 目的：观察辛伐他汀对大鼠骨髓基质干细胞向成骨细胞分化过程中Wnt与骨形态发生蛋白2信号途径中相关因子表达的影响。 方法：取6周龄雌性SD大鼠双侧股骨、胫骨全骨髓进行体外成骨细胞诱导培养。实验分为对照组及SIM组。SIM组加入浓度为10-7 mol/L辛伐他汀,对照组加入等量无水乙醇和PBS。培养14 d,行碱性磷酸酶染色,28 d时,行von Kossa染色观察细胞外基质矿化情况;培养14,21 d,免疫荧光细胞化学染色观察成骨细胞中β-catenin,Smad1/5,Cbfa1的表达及分布。 结果与结论：大鼠骨髓基质干细胞经体外诱导后可分化为具有碱性磷酸酶活性和矿化细胞外基质能力的成熟成骨细胞。辛伐他汀可显著上调骨髓基质干细胞成骨分化过程中碱性磷酸酶的表达。同时,与对照组比较,SIM组β-catenin,Smad1/5,Cbfa1表达明显增多(P < 0.05),且呈现明显的核内聚集趋势。说明辛伐他汀促进骨髓基质干细胞向成骨细胞分化的作用可能与调控Wnt与骨形态发生蛋白2信号通路中相关因子的表达及细胞内分布有关。     

地塞米松诱导联合骨形成蛋白２基因修饰兔骨髓间质干细胞的成骨转化★

背景：骨髓间质干细胞在地塞米松等骨诱导剂的作用下能够向成骨细胞分化；同时骨形成蛋白2在骨修复过程中促进细胞增殖分化和基质分泌，在体内外均可诱导骨形成，以上二者联合应用可能会产生一定的协同效应。 目的：分析体外经地塞米松诱导是否能增强骨形成蛋白2基因修饰的骨髓间质干细胞的成骨转化能力。 设计：随机化配对设计。 单位：解放军第四军医大学西京医院。 材料：实验于2004-02/2004-08在解放军第四军医大学全军骨肿瘤研究所完成。选用2月龄新西兰白兔20只，由解放军第四军医大学实验动物中心提供（许可证号：军动管字第2005C00117号）。室温、常湿，正常喂食。双侧取材，左侧肢体来源骨髓间质干细胞为地塞米松诱导组，右侧为对照组（未经诱导）。 方法：将地塞米松诱导组和对照组兔骨髓间质干细胞分别转导含有人骨形成蛋白2基因的复制缺陷重组腺病毒Ad-BMP-2后，以反转录-聚合酶链反应和免疫组化方法检测细胞中骨形成蛋白2的表达情况。观察骨髓间质干细胞的生长情况，并应用碱性磷酸酶检测试剂盒及骨钙素放免试剂盒测定Ad-BMP-2转导5 d后两组骨髓间质干细胞的碱性磷酸酶活性和骨钙素含量。 主要观察指标：①骨髓间质干细胞中骨形成蛋白2的表达情况。②骨髓间质干细胞的形态学变化。③骨髓间质干细胞中碱性磷酸酶活性和骨钙素含量。 结果：①转导后骨形成蛋白2基因在地塞米松诱导组和对照组兔骨髓间质干细胞中均有表达。②骨髓间质干细胞经地塞米松成骨诱导后形态较不规则，呈三角形、多角形改变，较基础培养基培养细胞生长缓慢。基因转导后细胞形态无明显改变。③转基因5 d后，地塞米松诱导组骨髓间质干细胞培养上清中碱性磷酸酶活性高于对照组[(134.36±8.84，104.02±7.83) nkat/L(t =3.350 6，P < 0.01，n =20)]；地塞米松诱导组骨髓间质干细胞骨钙素分泌量高于对照组[(14.68±0.73，6.52±1.21) μg/L(t =3.568 2，P < 0.01，n =20)]。 结论：转基因前的地塞米松诱导能够促进骨形成蛋白2基因修饰的骨髓间质干细胞增殖和成骨转化。     

杜仲诱导大鼠间充质干细胞成骨分化中成骨与成脂相关转录因子的表达

背景：杜仲对骨质疏松具有明显的干预和治疗作用,前期研究发现杜仲能够显著诱导骨髓间充质干细胞成骨分化和抑制成脂分化,而对于学术界广泛认同的成骨和成脂相关转录因子的表达变化还未见报道。 目的：观察杜仲诱导大鼠骨髓间充质干细胞成骨分化过程中成骨和成脂相关转录因子表达的变化。 方法：制备杜仲水/醇提取物,诱导培养至第3代的SD大鼠间充质干细胞,提取物按生药2 g,定容至15 mL体积为原液,诱导时按10-3、10-4倍稀释度稀释。诱导实验分为6组：阴性对照组(加入与诱导物等量的PBS);阳性对照组(诱导物为地塞米松0.01 mmol/L,β-甘油磷酸钠10 mmol/L,L-抗坏血酸钠50 mg/L);杜仲水提取物10-4稀释度诱导组;杜仲水提取物10-3稀释度诱导组;杜仲醇提取物10-4稀释度诱导组;杜仲醇提取物10-3稀释度诱导组,各组于诱导之后的第15天终止培养。RT-PCR和荧光定量PCR方法检测成骨分化转录因子基因Runx2、Osterix和成脂分化转录因子基因过氧化物酶体增殖物激活受体γ、脂肪酸结合蛋白的表达。 结果与结论：Runx2除在10-3稀释度水提取物组表达下调,在10-4稀释度醇提取物组上调外,其他各组无显著变化;Osx在各诱导组的表达均明显下调;过氧化物酶体增殖物激活受体γ在各组中无显著变化;脂肪酸结合蛋白在各组均下调。提示杜仲诱导间充质干细胞成骨分化与成脂相关转录因子脂肪酸结合蛋白的表达抑制相关。     

合成成骨生长肽对人骨髓间充质干细胞成骨转化的促进

背景：成骨生长肽在体内外细胞培养中具有明显的促成骨活性,这种促成骨作用的分子机制还不清楚,现已通过人工方法成功制备了合成成骨生长肽。 目的：探讨合成成骨生长肽对体外培养的人骨髓间充质干细胞向成骨方向分化的作用。 设计、时间及地点：基因和蛋白水平的细胞学体外观察,于2006-07/2007-12在福建省医学科学研究所基因工程实验室及复旦大学附属中山医院中心实验室完成。 材料：骨髓标本来源于福建省立医院骨一科收治的男性髂骨植骨患者,合成成骨生长肽由中国科学院上海生命科学研究院生物化学与细胞生物学研究所崔大敷教授惠赠,ERK1/2抑制剂U0126为美国CST公司产品。 方法：密度梯度离心法体外分离培养人骨髓间充质干细胞,单纯矿化液组加入由10 mmol/Lβ-甘油磷酸钠、50 mg/L L-抗坏血酸组成的矿化液;10-7,10-9,10-11 mol/L合成成骨生长肽组分别加入对应浓度的合成成骨生长肽,再加入矿化液;常规培养组加入含体积分数为0.1胎牛血清的低糖DMEM。 主要观察指标：倒置显微镜观察细胞形态变化,RT-PCR法和免疫组织化学染色检测成骨标志物的表达,Western-blot法分析合成成骨生长肽对ERK1/2信号通路的影响,观察U0126对合成成骨生长肽作用的干预。 结果：加入合成成骨生长肽后,骨髓间充质干细胞体积增大,突起增多,呈多角形,胞浆含有较多颗粒状物质,出现致密细胞结节。合成成骨生长肽在mRNA和蛋白水平均能促进成骨标志物碱性磷酸酶、Ⅰ型胶原、骨钙素的表达,定量分析结果显示10-9 mol/L合成成骨生长肽促成骨作用最强。加入合成成骨生长肽后能够引起ERK1/2信号通路的持续性激活,经U0126预处理后几乎完全阻断了合成成骨生长肽对骨髓间充质干细胞的促成骨作用。 结论：合成成骨生长肽可明显促进人骨髓间充质干细胞向成骨方向的转化,在10-9 mol/L浓度下促成骨能力最强,其促成骨作用可能是通过激活MAPK家族ERK1/2途径实现的。     

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.