TRIM38基因非CpG岛DNA甲基化与胶质母细胞瘤临床预后的关系

目的 探讨免疫基因TRIM38非CpG岛DNA甲基化在胶质母细胞瘤（GBM）中改变模式和临床意义。方法 利用公共数据库,比较TRIM38甲基化在GBM与非肿瘤脑组织（NTB）中的差异程度,并通过统计分析探讨该基因甲基化水平与基因表达、病人预后、生物学背景的关系。结果 纳入3组GBM（共509例）和3组NTB（共37例）样本。TRIM38基因非CpG岛DNA甲基化位点在GBM中呈低甲基化改变（P<0.05）,而其基因表达呈现高表达改变（P<0.05）,并且甲基化与基因表达呈显著负相关（P<0.05）。TRIM38低甲基化病人生存时间明显短于高甲基化组（P<0.05）,甲基化水平是独立的预后影响因子（P<0.05）。TRIM38低甲基化GBM样本可能富集免疫调节及Toll样受体通路相关的基因簇。结论 TRIM38可能在GBM中通过非CpG岛低甲基化介导的基因异常表达上调,参与肿瘤发生、发展;TRIM38非CpG岛甲基化可能作为指导GBM预后评价的潜在生物标记物;TRIM38甲基化导致的预后差异很可能与Toll样受体通路及免疫调节的差异有关。     

着丝粒蛋白F在胶质瘤组织中的表达及预后分析

目的 探究着丝粒蛋白F（CENPF）在脑胶质瘤中的表达及预后分析。方法 通过对癌症基因组图谱（TCGA）和中国脑胶质瘤图谱（CGGA）数据库进行生物信息分析,比较CENPF在低级别胶质瘤（LGG）、胶质母细胞瘤（GBM）和癌旁组织中的表达差异以及与患者预后之间的关系,并在数据库中对CENPF mRNA与P53、Ki-67以及IDH-1分型进行相关性分析。采用实时荧光定量PCR（qRT-PCR）法检测CENPF mRNA表达水平,免疫组织化学法和Western blotting法检测癌旁组织和不同级别胶质瘤组织中CENPF表达水平。多因素COX分析CENPF与临床病理参数及患者预后的关系,并绘制Kaplan‐Meier生存曲线。利用TCGA数据库对CENPF进行KEGG富集分析,探索该基因在胶质瘤中发展中可能参与的信号通路。结果 CENPF表达水平与胶质瘤WHO分级呈正相关,且CENPF高表达的胶质瘤患者生存时间短于低表达患者。数据库相关性分析显示CENPF mRNA与P53、Ki-67以及IDH-1野生型呈正相关。qRT-PCR实验结果表明CENPF mRNA在胶质瘤组织中表达增高,免疫组织化学和Western blotting实验结果表明CENPF表达与WHO等级呈正相关。临床病理参数分析表明在胶质瘤组织中CENPF表达情况与胶质瘤WHO分级（P=0.002）、P53（P=0.016）、Ki-67（P<0.001）表达有关。多因素COX分析显示WHO分级（P<0.001）、CENPF表达（P=0.008）、P53（P=0.003）和Ki-67（P=0.006）表达为胶质瘤患者预后不良的危险因素。Kaplan‐Meier生存曲线表明CENPF高表达的胶质瘤患者生存时间短于低表达患者（P<0.0001）。KEGG富集分析显示CENPF在参与细胞周期、DNA复制、WNT/beta-catenin、mTORC1等通路中具有显著富集。结论 CENPF在胶质瘤组织中表达增高,其表达与WHO分级、Ki-67以及P53分型相关;CENPF可作为判断胶质瘤患者预后的生物标志物。     

胶质母细胞瘤FMOD基因非CpG岛DNA甲基化水平与病人预后的关系

目的 探讨纤调蛋白（FMOD）基因非CpG岛区域DNA甲基化在人脑胶质母细胞瘤（GBM）中的改变模式以及与基因表达、临床预后的关系。方法 检索国癌症基因组图谱计划数据库（TCGA）和国国立卫生院下属基因表达数据库（GEO）下载人脑GBM组织基因表达芯片GSE36278、GSE22891及GSE50923。分析FMOD基因的CpG探针[cg26987645和cg03764585,均来自人类全基因组DNA甲基化芯片（Infinium HumanMethylation 27 k和450 k BeadChips）,均位于非CpG岛区域（www.illumina.com）]β值（与甲基化水平呈正相关）。结果 与非肿瘤组织相比,GBM组织FMOD基因非CpG岛区域探针cg26987645和cg03764585的β值均显著下降,提示GBM组织FMOD基因发生特异性低甲基化。将CpG岛区域探针cg26987645和cg03764585的β值与mRNA数据进行关联分析发现,DNA甲基化水平与FMOD基因表达水平呈显著负相关（P<0.001）。Cox回归分析显示,随FMOD基因CpG岛区域探针cg26987645和cg03764585的β值增加,GBM病人生存期显著延长（P<0.05）。FMOD基因非CpG岛cg03764585和cg26987645探针分析显示,非G-CIMP亚型病人甲基化水平较G-CIMP亚型病人明显降低（P<0.05）,而FMOD基因表达水平明显增高（P<0.05）。结论 本文结果提示,GBM组织FMOD基因非CpG岛区域呈低甲基化表现,与FMOD基因表达和病人生存预后均呈明显负相关。     

细胞周期依赖激酶抑制基因2A/B纯合缺失在组织病理2或3级脑胶质瘤中的临床意义

目的 细胞周期蛋白依赖激酶抑制基因2A/B（CDKN2A/B） 纯合缺失在较低级别胶质瘤（2或3级）中罕见，新版WHO分类将其定为恶性度最高4级。该研究旨在系统报道CDKN2A/B纯合缺失在较低级别胶质瘤中的临床特点、预后及相关功能通路。方法 收集473例有CDKN2A/B纯合缺失、临床和预后信息的较低级别胶质瘤患者，对发生率、临床特点及预后统计分析；收集27例新鲜肿瘤标本（13例CDKN2A/B纯合缺失），通过Ki-67和CD31免疫组织化学分析细胞增殖和血管增生；在1 116例胶质瘤RNA测序数据中对CDKN2A/B纯合缺失的相关功能和通路进行分析。结果 CDKN2A/B纯合缺失在较低级别胶质瘤中发生率为7.2%（34/473），该缺失在年龄偏大、星形细胞瘤、3级、近全切及IDH野生型患者中发生率更高（均P<0.05）。在IDH突变型或野生型较低级别胶质瘤中，CDKN2A/B纯合缺失均与患者更短的总生存期和无进展生存期相关。缺失型标本Ki-67(P=0.045)和CD31(P=0.058)蛋白表达高于野生型。生物信息学显示CDKN2A/B纯合缺失激活DNA复制、修复和细胞周期等功能和通路。结论 CDKN2A/B纯合缺失与较低级别胶质瘤患者差的预后和恶性表型有关，该类患者临床应积极治疗。     

血小板相关参数对胶质瘤患者预后的影响

目的 探讨术前血小板相关参数对胶质瘤患者肿瘤复发的预测作用。方法 分析联勤保障部队第九〇九医院2015—2017年收治的93例胶质瘤患者临床病理资料,根据随访期间肿瘤是否复发分为无复发组（n=52）和复发组（n=41）,分析血小板相关参数与胶质瘤分级的相关性,采用ROC曲线分析血小板计数（PLT）、血小板体积分布宽度（PDW）、血小板压积(PCT)、平均血小板体积（MPV）、平均血小板体积/血小板计数（MPV/PLT）对肿瘤复发的预测作用,多因素Cox分析肿瘤复发的影响因素,采用Kaplan-Meier曲线分析这些因素对肿瘤复发的影响。结果 胶质瘤Ⅲ、Ⅳ级患者PLT、PCT、高于胶质瘤Ⅰ、Ⅱ级患者（t=-2.388、-2.335,均P<0.05）;胶质瘤Ⅲ、Ⅳ级患者中MPV、MPV/PLT低于胶质瘤Ⅰ、Ⅱ级患者（均P<0.05）;无复发组患者PLT和PCT低于复发组（均P<0.05）;无复发组患者MPV和MPV/PLT高于复发组（均P<0.05）;PLT的ROC曲线下面积（UAC）为0.630（95%CI=0.517~0.743,P=0.032）,阈值为216×10⁹/L;MPV的UAC为0.633（95%CI=0.518~0.747,P=0.029）,阈值为8.65 fL;MPV/PLT的UAC为0.731（95%CI=0.626~0.835,P<0.001）,阈值为0.040;多因素分析结果发现,肿瘤分级（Ⅲ、Ⅳ）、MPV≤8.65 fL、MPV/PLT≤0.040是术后肿瘤复发的危险因素（95%CI分别为1.778~3.530、1.730~4.450、1.811~6.067,均P<0.05）;肿瘤分级（Ⅲ、Ⅳ）预测术后肿瘤复发曲线下面积为0.679（95%CI=0.569~0.789,P=0.003）。Kaplan-Meier曲线分析显示,MPV≤8.65 fL患者术后3年复发率高于MPV>8.65 fL患者（Long Rank=10.990,P=0.001）;MPV/PLT≤0.040患者术后3年复发率高于MPV/PLT>0.040患者（Long Rank=6.289,P=0.012）。结论 胶质瘤患者术前MPV和MPV/PLT与术后肿瘤复发有关,可以用于肿瘤预后预测,具有一定临床意义。 [国际神经病学神经外科学杂志, 2023, 50(4): 29-33]     

微小RNA-346与IDH基因野生型胶质瘤TRIM38基因表达和患者预后的关系

目的 探讨微小RNA (miR)-346与异柠檬酸脱氢酶(IDH)基因野生型胶质瘤中三基序蛋白质38 (TRIM38)基因表达水平和患者总体生存期(OS)的关系。方法 利用中国胶质瘤基因组图谱计划(CGGA)数据库的多组学分子数据,比较miR-346在胶质瘤中的表达改变以及与TRIM38基因表达和患者OS的关系;采用细胞转染和双荧光素酶实验检测miR-346与TRIM38基因在胶质瘤细胞中的相互关系。结果 共纳入CGGA中各级别胶质瘤样本198例及对照脑组织样本5例进行比较,发现miR-346表达水平随肿瘤级别的增加而降低(P<0.05),且IDH基因野生型肿瘤表达水平低于IDH基因突变型肿瘤(P<0.05)。Pearson相关性分析发现IH基因野生型胶质瘤中,miR-346与TRIM38基因表达之间呈显著负向相关性(P<0.05)。生存分析显示miR-346低表达组患者的OS与miR-346高表达组患者相比显著缩短(P=0.05),其预后指示能力独立于患者年龄及治疗方案等因素(^均P<0.05),但不独立于肿瘤级别(P>0.05)。细...     

CUX-1和XRCC3在胶质瘤中的表达及其与预后的关系

目的 探讨同源框CUT样蛋白1（CUX-1）及X射线交错互补修复基因3（XRCC3）在组织中的表达水平，及与胶质瘤患者病理指标及预后的关系。方法 采用免疫组织化学染色及蛋白质印迹法检测66例胶质瘤组织以及10例正常脑组织CUX-1及XRCC3的表达水平，分析它们之间的关系及其与患者临床病理指标和预后的关系。结果 CUX-1和XRCC3表达水平随肿瘤WHO分级的升高而上调（P<0.01），且两者的表达与胶质瘤WHO分级及增殖指标Ki67、P53mut相关（P<0.01）。CUX-1与XRCC3之间的表达呈正相关（r_s=0.773，P=0.006）。Kaplan-Meier生存曲线表明CUX-1及XRCC3高表达患者生存时间缩短（P<0.05）。结论 CUX-1及XRCC3两者之间的表达呈正相关，并在胶质瘤中表达上调，且与不良预后相关。     

颅底脊索瘤中突变型p53相关的临床和细胞水平研究

目的 探讨突变型p53在颅底脊索瘤中的表达与患者预后及临床特点的关联,并在细胞层面验证突变型p53在颅底脊索瘤中的功能。方法 纳入2005年1月—2014年12月在首都医科大学附属北京天坛医院接受手术治疗的颅底脊索瘤患者49例,应用石蜡切片进行免疫组织化学染色,分析突变型p53表达与颅底脊索瘤患者预后及临床特点的关系。应用siRNA敲降脊索瘤细胞系UCH-1中的p53基因,分析敲降前后细胞功能的变化。结果 在蛋白水平,突变型p53表达水平是肿瘤术后进展的风险因素,随突变型p53表达水平升高,肿瘤进展风险增加（OR：1.040,95%CI：1.007~1.073,P=0.016）;另外,骨质浸润型肿瘤较非浸润型中突变型p53表达升高（t=3.319,P=0.002）,质地硬的较质地软的肿瘤突变型p53表达升高（t=-3.503,P=0.001）,血供丰富型较不丰富型肿瘤突变型p53表达升高（t=2.081,P=0.043）。细胞水平,与对照组相比,p53敲降组的细胞活力在不同时间点间有差异（F=305.715,P=0.000）;p53敲降组细胞凋亡率低于对照组（t=-3.961,P=0.017）;与对照组相比,p53敲降组在第6（t=-5.232,P=0.014）、12（t=4.778,P=0.017）及24（t=-9.303,P=0.003）小时穿透至下室的肿瘤细胞均增多。结论 颅底脊索瘤中突变型p53表达升高可导致术后肿瘤进展风险增加,其表达与肿瘤质地、侵袭性和血供情况相关;突变型p53表达受抑制后脊索瘤细胞增殖和侵袭能力提高,凋亡减少。     

SCARB2基因突变致动作性肌阵挛―肾衰综合征

背景 动作性肌阵挛―肾衰综合征(AMRF)是进行性肌阵挛性癫痫(PME)的一种类型，是一种常染色体隐性遗传性疾病，与SCARB2基因的突变相关。目的 报道SCARB2基因突变相关性AMRF家系的1个病例，并总结目前所有文献报道的AMRF患者的临床表型和遗传学特征，以提高对该病的认识。方法 回顾AMRF患者的临床资料，采用全外显子组基因靶向二代测序对AMRF家系的1个病例进行基因检测。结合文献报道，对28例（包含本例）AMRF病例资料进行总结分析。结果 AMRF患者主要临床特征为动作性肌阵挛、全身性强直阵挛性癫痫、共济失调、无认知功能障碍、伴或不伴肾功能障碍。先证者携带SCARB2基因纯合移码突变(c.350_351delAT, p.Y117Cfs*3, NM_005506.3)。先证者未患病的母亲及姐姐携带该位点的单杂合突变。国际上目前报道的28例（包括本例）SCARB2基因突变相关性AMRF中共发现22种不同的突变位点，均以常染色体隐性遗传方式发病。结论 该研究在与SCARB2基因突变相关的AMRF患者中发现了1个未见报道过的新的移码突变位点。结合文献复习，可推测当突变位点位于更靠近5端和更重要的功能域时，对蛋白产物功能的影响会更大。 [国际神经病学神经外科学杂志, 2022, 49(3): 51-58.]     

ADAMTS基因多态性与脑梗死体检患者颈动脉粥样硬化性斑块易损性及阿托伐他汀降脂疗效的相关性研究

目的 探讨Ⅰ型血小板结合蛋白基序的解聚蛋白样金属蛋白酶（a disintegrin and metalloproteinase with thrombospondin type 1 motifs，ADAMTS）基因多态性与脑梗死体检患者颈动脉粥样硬化性斑块易损性及阿托伐他汀降脂疗效的相关性。方法 收集2016年1月至2019年1月河北医科大学第一医院收治的684例脑梗死体检患者的临床资料，根据颈动脉超声检查结果分为稳定斑块组（338例）和易损斑块组（346例）。比较2组患者的一般资料、生化检测指标、ADAMTS rs402007（G/C）位点基因型及等位基因频率。采用Logistic回归分析探讨颈动脉粥样硬化性斑块易损性的危险因素和ADAMTS基因多态性与危险因素在颈动脉粥样硬化性斑块易损性中的交互作用。比较不同基因型患者阿托伐他汀降脂疗效，分析不同基因型与阿托伐他汀疗效的相关性。结果 稳定斑块组和易损斑块组糖尿病比例及低密度脂蛋白胆固醇（low-density lipoprotein cholesterol，LDL-C）、总胆固醇（total cholesterol，TC）、同型半胱氨酸（homocysteine，HCY）、纤维蛋白原（fibrinogen，FIB）水平的比较差异有统计学意义（P<0.05）。2组患者间GG基因型与GC+CC基因型分布的比较差异有统计学意义（P<0.05）。糖尿病、LDL-C、HCY、FIB是影响颈动脉粥样硬化性斑块易损性的危险因素（P<0.05）。LDL-C与ADAMTS基因rs402007位点存在交互作用（P<0.05）。GG、GC、CC基因型组阿托伐他汀降脂治疗有效率分别为144例（82.29%）、209例（84.27%）、233例（89.27%）。各基因型患者阿托伐他汀治疗前后血脂水平比较差异有统计学意义（P<0.05）。稳定斑块组和易损斑块组治疗前、治疗后LDL-C水平，以及治疗后高密度脂蛋白胆固醇、甘油三酯、TC水平比较差异有统计学意义（P<0.05）。以GG基因型为参考，GC基因型与阿托伐他汀治疗的疗效无相关性（P>0.05），CC基因型与疗效有相关性（P<0.05）。结论 ADAMTS基因多态性与颈动脉粥样硬化性斑块易损性存在相关性，与阿托伐他汀的降脂疗效存在相关。     

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.