体内环境培养的小口径组织工程血管

背景：人造血管是临床组织修复领域广泛应用的重要器官,但小口径人造血管易于栓塞、难以长期保持通畅,而组织工程血管虽有永久替代作用,培养时间长,不符合血管修复的临床实际。寻找既能及时修复血管、恢复血运,又能在体内形成生物性血管保持长期通畅,是最理想的血管修复重建方法。 目的：观察以改性猪小肠黏膜下层组织为支架,在体内血流条件下培养小口径组织工程血管的可行性。 方法：自犬隐动脉分离出血管内皮细胞、平滑肌细胞,与胶原蛋白凝胶均匀混合,分别种植于小肠黏膜下层膜表面,包绕 3 mm聚乙烯管制成30个3层管状支架,植入犬股动脉缺损处进行桥接吻合为实验组;植入犬皮下组织为对照组。术后进行彩超、组织学检测评价血管的形成过程和免疫组化鉴定。 结果与结论：术后12周,实验组14个血管支架保持通畅,有明显的血管生物结构形成,种子细胞生长增殖良好,管腔有完整内皮细胞覆盖,平滑肌细胞形态、分布良好;对照组管腔结构不完整,种子细胞增殖弱,腔面无内皮细胞覆盖。结果表明通过体内组织工程技术可在血流条件下培养形成小口径组织工程血管。     

低温等离子体肝素化改性后小肠黏膜下层的血液相容性及其构建小口径血管的可行性*★

背景：栓塞是小口径血管植入后失败的主要原因，目前常常对血管支架材料进行抗凝改性，以期提高其血液相容性，从而提高血管的有效通畅性。 目的：观察低温等离子体肝素化改性后的内植物修复材料小肠黏膜下层的血液相容性，并探讨其体内构建小口径血管的可行性。 设计：单一样本实验。 单位：上海交通大学附属第六人民医院骨科、上海市四肢显微外科研究所。 材料：实验于2006-01/10在上海市四肢显微外科研究所实验室进行。小肠黏膜下层来自农场猪。 方法：①改性：将猪小肠黏膜下层用氩等离子体处理器照射处理，氩气流量20 mL/min，照射时间分别为0, 2, 4, 6, 8, 10, 12, 14 s，接着浸入肝素钠溶液24 h。②体内抗凝血实验：将20条狗分为2组，分别植入经过改性或未改性的小肠黏膜下层缝合成的3 mm口径血管支架，与股动脉直接吻合，观察6周。 主要观察指标：①血液相容性检测：通过扫描电镜观测表面形态，并通过液滴接触角、凝血时间及血小板黏附实验检测小肠黏膜下层改性前后的抗凝性。②体内抗凝血：通过彩色多普勒和组织学检测，评价血管支架直接在体内循环血流下的长期通畅性和形成血管的可行性。 结果：①改性小肠黏膜下层膜表面呈现出均匀的微结构改变，随着等离子体照射时间增加，表面液滴接触角降低；改性后凝血酶原时间、活化部分凝血活酶时间和凝血酶时间延长；血小板黏附减少。②植入体内后未改性小肠黏膜下层血管支架3 d内栓塞，改性组在6周内仍保持通畅，管腔内表面有完整内皮细胞覆盖。 结论：经低温等离子体肝素化改性后小肠黏膜下层的亲水性、抗凝性有明显提高。     

小肠黏膜下层覆膜支架促进经颈静脉肝内门腔静脉分流道内皮化的有效性

背景：达到支架内腔内皮化是血管支架置入,也是颈静脉肝内门腔静脉内支架分流防治再狭窄的目标,有学者已提议将促使内皮细胞功能及完整性的恢复作为预防术后再狭窄的新策略。 目的：探讨小肠黏膜下层覆膜支架促进经颈静脉肝内门腔静脉分流后分流道内皮化的有效性。 方法：建立猪经颈静脉肝内门腔静脉分流模型,以数字表法随机分成2组,实验组将外覆小肠黏膜下层膜单丝编织网络型镍钛记忆合金支架置入肝内分流道,对照组植入单丝编织网络型镍钛记忆合金支架。术后2,4周于直接门脉造影复查后,获取支架内及周围肝组织,行大体、病理组织形态学及扫描电子显微镜检查。 结果与结论：术后2周造影复查示对照组、实验组分流道分别闭塞3,1只,术后4周分别闭塞4,6只,其余均不同程度狭窄,对照组血管再狭窄率高于实验组(P < 0.05)。病理及显微镜检查结果显示,实验组内皮化程度较对照组高,且实验组内皮细胞形态、大小均匀,排列接近血流方向。结果证实小肠黏膜下层是一种可行的加快颈静脉肝内门腔静脉分流后分流道内皮化的生物材料,但小肠黏膜下层覆膜支架未能明显提高颈静脉肝内门腔静脉分流道的通畅率。     

几丁糖对大鼠股动脉吻合口通畅率的影响

背景：几丁糖在预防术后组织粘连方面疗效确切,但在断指再植术后能否应用,其对血管吻合口的愈合是否有影响,国内外文献较少提及。 目的：观察医用几丁糖对成年大鼠股动脉吻合口通畅率的影响。 方法：离断SD大鼠双侧股动脉,左侧为实验组,右侧为对照组,显微镜下吻合双侧股动脉,所有吻合动脉即时通畅率达100%,且为同一人操作,吻合后,实验组吻合口周围均匀涂布医用几丁糖1滴,对照组不涂。分别观察术后7,14,21,28 d大鼠吻合口的通畅情况,吻合口口径、吻合口周围有无感染、周围粘连情况及病理切片观察吻合口内皮细胞覆盖情况。 结果与结论：术前、术后吻合口管径无明显变化,实验组和对照组吻合口周围均无明显感染,实验组吻合口周围粘连较对照组轻,吻合口总体通畅率实验组为96%,对照组为89%,差异无显著性意义。术后各个时间段实验组、对照组内皮细胞覆盖情况差异无显著性意义。提示医用几丁糖的放置不影响大鼠股动脉吻合口的总体通畅率。     

小肠黏膜下层无细胞基质作为阴道平滑肌细胞载体的可行性

摘要 背景：目前国内外用于阴道组织工程研究的主要支架材料聚乙醇酸存在降解过快等缺陷。天然脱细胞支架材料尤其是小肠黏膜下层逐渐成为组织工程研究的重点。 目的：探索用猪小肠黏膜下层基质作为组织工程学阴道细胞载体的可行性。 方法：取新西兰雌兔,分离出阴道平滑肌组织块,组织块+酶消化法原代培养阴道平滑肌细胞。体外培养传代后作为种子细胞接种于自制猪小肠黏膜下层基质体外联合培养,倒置显微镜动态观察细胞形态及生长增殖情况,分别于1,2,3,4周时取标本,行组织学检查。 结果与结论：①体外成功培养出阴道平滑肌细胞,倒置显微镜下,见培养的阴道平滑肌细胞呈现长梭状,细胞集结于培养皿上形成典型的“峰和谷”样构型。②黏膜下层无细胞基质外观呈白色,半透明,有一定韧性。苏木精-伊红染色未见细胞成分存在。③阴道平滑肌细胞-肠黏膜下层标本切片苏木精-伊红染色后,光镜下可见细胞成分逐渐增多,由表浅向深层部位生长。④阴道平滑肌细胞-肠黏膜下层标本切片采用抗兔平滑肌α-肌动蛋白单克隆抗体免疫组化染色后,均可见抗兔α-Actin的阳性细胞。结果初步证明了猪小肠黏膜下层基质可作为一种平滑肌细胞载体。 关键词：阴道平滑肌细胞;组织工程;猪小肠黏膜下层;细胞载体;支架材料 doi:10.3969/j.issn.1673-8225.2010.47.001     

小口径生物型人工血管移植后的血管壁重构☆

背景：人工血管相对人体血管最大的优势就是来源丰富,经过生物化改造的人工血管,其特性更接近人体血管,移植后自体化程度也较高。 目的：观察新型小口径生物型人造血管移植后1.5年内不同时期实验犬的生存、生活状况,移植材料的组织相容性、移植血管壁重构的组织病理学变化。 方法：以猪血管为基材,经交联固定,多方位去抗原,共价结合肝素,以及偶联可黏附、富集生长因子的特定多肽等系列生化处理而制成的一种高抗凝的人造血管,管径3.5~4.5 mm。建立犬颈总动脉-人造血管端端连续缝合的动物模型,1.5年内不同时期切取标本,做病理组织学检查。 结果与结论：切取标本发现,移植血管与周围组织粘连少、疏松。病理组织学检查：移植后8周,镜下开始发现宿主组织通过人造血管孔隙长入血管腔内参与移植血管新内膜的形成,移植后12周,镜下于吻合口处,可见新内膜表面有不连续的内皮细胞生长,移植后6个月,通畅的人造血管整段管腔内面均可见内皮细胞生长。移植后12个月,移植血管管壁VG染色尚可见支架层内有大量胶原纤维和毛细血管生长,原先的支架结构已部分被宿主血管壁组织取代。移植后18个月,原先的支架结构已大部分被宿主血管壁组织取代。说明新型小口径生物型人造血管新内膜形成早且完整,自然内皮化相对满意,血管壁重构和血管支架的再生能力强,生物相容和稳定性好。     

复合许旺细胞的猪肠黏膜下层桥接修复周围神经缺损

背景：小肠黏膜下层作为一种天然的生物材料，能提供适合神经生长的三维支架，而许旺细胞又在神经再生过程中发挥重要作用。如果能将许旺细胞种植在小肠黏膜下层，用来桥接周围神经缺损，理论上更有利于神经的长入，极有可能获得良好的实验效果。 目的：应用复合有许旺细胞的小肠黏膜下层桥接周围神经缺损，观察桥接后神经生长情况。 设计、时间及地点：对比观察实验，于2008-01在深圳市松岗人民医院完成。 材料：取健康成年猪的新鲜近段空肠制备小肠黏膜下层。 方法：SD大鼠20只随机分成2组，即复合有许旺细胞的小肠黏膜下层桥接组、自体神经移植组。每组10只。首先在距坐骨神经出口1 cm处用双面刀片切取1 cm长度的坐骨神经，造成神经缺损模型。然后分别用复合有许旺细胞的小肠黏膜下层桥接、自体神经移植桥接。 主要观察指标：于术后6，12周自近端缝合口的近端至远端缝合口的远端切取大鼠的坐骨神经，用于病理组织学观察并进行图像分析。同时用生理示波器测定大鼠两侧坐骨神经的潜伏期和诱发电位的波幅。 结果：复合有许旺细胞的小肠黏膜下层桥接神经组可见有再生神经组织长过缺损，呈条索状连续，且神经纤维多集中在小肠黏膜下层形成的桥接管周缘区域，而中心区域可见胶原组织且孔隙较多。复合有许旺细胞的小肠黏膜下层桥接神经组潜伏期的延迟率均高于自体神经移植组（P < 0.05），而诱发电位的波幅恢复率均低于自体神经对照组（P < 0.05）。复合有许旺细胞的小肠黏膜下层桥接神经组轴突的平均直径、单位面积的轴突数量和神经组织所占的百分比均低于自体神经移植组（P < 0.05）。 结论：复合有许旺细胞的小肠黏膜下层具有促进周围神经轴突再生的作用，但较自体神经移植略差。     

脱细胞猪小肠黏膜下层支架复合软骨细胞构建组织工程软骨*☆

背景：关节软骨损伤后无论是否施加干预,都难以达到满意的修复效果。 目的：观察以猪自体软骨细胞为种子细胞复合脱细胞猪小肠黏膜下层构建组织工程软骨的可行性。 方法：将培养至第3代的猪膝关节软骨细胞接种于小肠黏膜下层膜上,复合培养48 h,构建细胞-载体复合物,光学显微镜、扫描电镜观察软骨细胞在小肠黏膜下层膜上的生长情况。 结果与结论：苏木精-伊红染色见细胞在小肠黏膜下层基质层表面呈单层或复层生长;免疫组织化学染色结果显示软骨细胞与小肠黏膜下层表面之间形成一条连续阳性表达条带;扫描电镜见软骨细胞在支架孔隙内贴壁良好生长。     

组织工程小血管支架移植于异种动物的实验

背景：脱细胞的异种小血管支架已被初步去除引起排斥反应的异种抗原。 目的：将脱细胞的Wistar大鼠尾动脉支架移植于日本大耳白兔耳血管间，长时间观察术后血流和管壁变化，探讨异种脱细胞小血管支架的实验移植应用。 设计、时间及地点：观察对比实验，于2003-03/2004-12在中国医科大学解剖学教研室完成。 材料：供体用Wistar大鼠15只，受体为日本大耳白兔15只。从15只Wistar大鼠每只取2条长2.50cm的尾动脉干共30条作为异种小血管，其中的15条作为供体尾动脉干（尾动脉移植组），另15条经1%Triton X-100脱细胞处理作供体组织工程小血管支架（小血管支架移植组）。受体为15只日本大耳白兔左右耳背面中央动脉。 方法：在外科显微镜下，用11-0线将实验兔中央动脉近侧断端套入供体血管近侧腔内，作全层套叠吻合；远侧断端按常规端端吻合。采用勒通试验法和常规血管管腔血液、管壁染色法连续观察血管内血流状况。 主要观察指标：血管吻合术后，外科显微镜下不同时间血流通畅和光镜、电镜下血管腔血液与管壁结构变化。 结果：血管移植术后的即刻通畅率达100%。 异种小血管支架移植术后最长通畅时间为46小时47分，而尾动脉干为14小时。两组远侧的端端吻合区首先出现血流不畅；套叠区小血管支架与中央动脉外膜间由蒂状结缔组织相连。第10天，小血管支架可见内膜纤维组织仍然呈梳头状整齐排列，未见细胞附着；在术后第100天，仍保留着血管支架的完整性。 结论：①异种小血管支架可以作为血管移植物吻合于异种动物宿主体内，到100天时仍保留着较完整结构。②异种小血管支架血液通畅最长时间为46小时47分，长于异种小血管移植。③异种小血管支架移植的套叠式吻合法优于经典的端端吻合法。     

脱细胞羊膜修复兔尿道组织缺损的可行性

背景：脱细胞羊膜的抗原性低,组织相容性好,在眼科眼表疾病及大面积烧伤中有较多的研究和临床应用,但在泌尿系统中的组织缺损修复较少报道。 目的：通过脱细胞羊膜修复兔尿道组织的缺损实验,探讨去细胞人羊膜是否能作为修复尿道组织缺损的一种有效安全的支架材料。 设计、时间及单位：随机对照动物实验,实验于2007-04/06在广西医科大学动物实验中心完成。 材料：新西兰兔32只由广西医科大学动物实验中心提供。新鲜人羊膜取自广西医科大学一附院产科。 方法：脱细胞羊膜的制备：新鲜羊膜先使用1%甲醛-0.2%戊二醛交联保护,再使用0.125%胰酶-0.05 mol/L EDTA消化,最后使用0.5%曲拉通洗涤。32只新西兰雄兔分为3组,实验组12只,对照组12只,假手术组8只。前2组制备尿道缺损模型,实验组以脱细胞羊膜修复兔尿道组织缺损,对照组直接吻合尿道,假手术组仅游离尿道组织,不行尿道手术。 主要观察指标：术后10,21,42 d行修复尿道病理组织学检查观察上皮细胞血管及平滑肌细胞生长情况,炎症细胞浸润情况。术后42 d行尿道造影﹑尿动力学检查观察尿道压力变化及膀胱容量和称膀胱质量。 结果：①制备好的脱细胞羊膜白色半透明,无细胞及碎片残留。②脱细胞羊膜修复兔尿道组织缺损实验组一病理切片检查：10 d脱细胞羊膜周边已有尿道上皮细胞生长,未见急性排斥反应。21 d脱细胞羊膜处尿道表面已被尿道上皮细胞覆盖,小血管生长,炎症细胞浸润减轻。42 d实验组一少量平滑肌长入,血管生长良好,少量炎症细胞。3组尿动力学结果,尿道最高压,尿道最低压比较均无统计学意义(P > 0.05)。称膀胱质量,假手术组和对照组膀胱质量差异有统计学意义(P < 0.05)。 结论：脱细胞羊膜修复兔的尿道组织缺损,上皮细胞和平滑肌细胞生长良好,未出现排斥反应和毒性表现,尿道通畅无狭窄,证实脱细胞羊膜是一种前景良好的尿道组织修复材料。     

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.