From self-induced to perceived errors – A generalized over-monitoring activity in obsessive–compulsive disorder

Well-functioning error monitoring of the inner and outer environments is essential for adaptively altering behavior, while malfunction characterizes conditions such as obsessive–compulsive disorder (OCD). The underlying brain processing is manifested as Error-Related Negativity (ERN) signal elicited following error comission, and Perceived Error Related Theta Activity (PERTA) signal elicited following detection of discrepancy in the environment. Yet, while enhanced ERN was repeatedly demonstrated in OCD patients and was found to be potentiated among their unaffected first degree relatives, no comparable observations were reported with regard to PERTA. We recorded EEG activity while OCD patients, OCD patients’ siblings (Family), and healthy controls (HC) performed computerized tasks. For the examination of ERN we used the Stroop task and for the examination of PERTA we presented correct and incorrect mathematical equations. Increased ERN (0–120 ms post response) was observed in both the OCD and Family groups, but only the OCD patients’ signal significantly differed from that of HC's. Similarly, modified PERTA activity was observed in both the OCD and Family groups in the N1 peak (65–125 ms post perceived error), but only for the OCD group this activity significantly differed from that of HC. Both ERN and PERTA's N1 are fast occurring peaks, which suggests that OCD is associate with a constantly over-activated detection system that monitors the inner and outer environment and reacts promptly following detection of a mistake. Furthermore, the modified but non-significantly different activity of the Family group suggests that the pathological condition evolves in vulnerable individuals with neuronal predisposition.     

DNA methylation of the ELOVL2, FHL2, KLF14, C1orf132/MIR29B2C,and TRIM59 genes for age prediction from blood,saliva, and buccal swab samples

Many studies have reported age-associated DNA methylation changes and age-predictive models in various tissues and body fluids. Although age-associated DNA methylation changes can be tissue-specific, a multi-tissue age predictor that is applicable to various tissues and body fluids with considerable prediction accuracy might be valuable. In this study, DNA methylation at 5 CpG sites from the ELOVL2, FHL2, KLF14, C1orf132/MIR29B2C, and TRIM59 genes were investigated in 448 samples from blood, saliva, and buccal swabs. A multiplex methylation SNaPshot assay was developed to measure DNA methylation simultaneously at the 5 CpG sites. Among the 5 CpG sites, 3 CpG sites in the ELOVL2, KLF14 and TRIM59 genes demonstrated strong correlation between DNA methylation and age in all 3 sample types. Age prediction models built separately for each sample type using the DNA methylation values at the 5 CpG sites showed high prediction accuracy with a Mean Absolute Deviation from the chronological age (MAD) of 3.478 years in blood, 3.552 years in saliva and 4.293 years in buccal swab samples. A tissue-combined model constructed with 300 training samples including 100 samples from each blood, saliva and buccal swab samples demonstrated a very strong correlation between predicted and chronological ages (r = 0.937) and a high prediction accuracy with a MAD of 3.844 years in the 148 independent test set samples of 50 blood, 50 saliva and 48 buccal swab samples. Although more validation might be needed, the tissue-combined model’s prediction accuracies in each sample type were very much similar to those obtained from each tissue-specific model. The multiplex methylation SNaPshot assay and the age prediction models in our study would be useful in forensic analysis, which frequently involves DNA from blood, saliva, and buccal swab samples.     

抗NMDA受体脑炎的脑电图特点及其临床评估价值

  目的  总结分析抗N-甲基-D-天冬氨酸受体脑炎（抗NMDA受体脑炎）患者的脑电图特点,并探索脑电背景慢化分级、δ刷对临床评估的价值。  方法  纳入52例抗NMDA受体脑炎患者临床资料,包括年龄、性别、起病形式、合并肿瘤情况、辅助检查（脑脊液抗NMDA受体抗体滴度、MRI报告和脑电图结果）、治疗情况和出院随访情况。分析不同临床特征患者的脑电背景异常程度(EEG)、δ刷情况。  结果  52例患者中7例脑电图正常（14%）,45例脑电图异常（87%）,包括:轻度异常25例（48%）,中度异常 11例（21%）,重度异常9例（17%）。6例出现δ刷（12%）。脑电图检查时病情轻组有32例（62%）,病情重组有20例（38%）。随访1年后,预后良好组有45例（86%）,预后不佳组有7例（14%）。脑电背景异常程度越重、出现δ刷提示病情重、需要ICU治疗、预后不佳的比例增高（P<0.01）。脑电背景异常程度越重,CSF抗体滴度>1∶10的比例越高（P=0.035）,脑电背景异常程度越重,启动二线免疫治疗比例越高（P=0.008）。合并肿瘤的患者出现δ刷的比例更高（P=0.012）。首发病例较复发病例出现δ刷的概率更高（P=0.023）。  结论  脑电慢化程度和δ刷在评估病情、预测预后结果上一致,EEG越慢病情越重、预后越差,出现δ刷提示病情重、预后差。EEG慢化与抗MNDA受体脑炎的免疫状态相关,EEG越慢,免疫异常越重,临床上可动态检测患者的EEG以评估免疫治疗效果,若EEG慢化未改善应及早考虑加强免疫治疗。合并肿瘤的患者出现δ刷的比例更高,因此当出现δ刷时应积极排查肿瘤。     

Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder

PurposeRPH3A encodes a protein involved in the stabilization of GluN2A subunit of N-methyl-D-aspartate (NMDA)-type glutamate receptors at the cell surface, forming a complex essential for synaptic plasticity and cognition. We investigated the effect of variants in RPH3A in patients with neurodevelopmental disorders.MethodsBy using trio-based exome sequencing, GeneMatcher, and screening of 100,000 Genomes Project data, we identified 6 heterozygous variants in RPH3A. In silico and in vitro models, including rat hippocampal neuronal cultures, have been used to characterize the effect of the variants.ResultsFour cases had a neurodevelopmental disorder with untreatable epileptic seizures [p.(Gln73His)dn; p.(Arg209Lys); p.(Thr450Ser)dn; p.(Gln508His)], and 2 cases [p.(Arg235Ser); p.(Asn618Ser)dn] showed high-functioning autism spectrum disorder. Using neuronal cultures, we demonstrated that p.(Thr450Ser) and p.(Asn618Ser) reduce the synaptic localization of GluN2A; p.(Thr450Ser) also increased the surface levels of GluN2A. Electrophysiological recordings showed increased GluN2A-dependent NMDA ionotropic glutamate receptor currents for both variants and alteration of postsynaptic calcium levels. Finally, expression of the Rph3A^Thr450Ser variant in neurons affected dendritic spine morphology.ConclusionOverall, we provide evidence that missense gain-of-function variants in RPH3A increase GluN2A-containing NMDA ionotropic glutamate receptors at extrasynaptic sites, altering synaptic function and leading to a clinically variable neurodevelopmental presentation ranging from untreatable epilepsy to autism spectrum disorder.     

中药汤剂治疗奥氮平药物副反应的临床经验

目的:分析总结中药汤剂治疗奥氮平药物副反应的临床经验。方法:调查服用奥氮平1月以上的精神病患者,统计服用药物后较常出现的中医证候及舌脉象,类推奥氮平的中医“药毒”特性;将60例受试者随机分为2组,其中奥氮平合并服用中药汤剂的为治疗组,中药汤剂根据辨证论治选用温胆汤、玉女煎、补中益气汤、补脾胃泻阴火升阳汤加减治疗,对照组服用奥氮平合并安慰剂,观察治疗前、治疗1月、2月后中医证候评分及糖脂代谢指标的前后变化及组间差异,对疗效进行评估。结果:服用奥氮平1月前后比较,受试者便秘、纳多、肥胖、口干、脉数、精神疲倦、苔厚腻、肢体乏力、舌红、舌淡、脉滑、舌边齿痕、舌胖大、苔白的中医证候评分较前显著升高,具有统计学差异(P<0.05或P<0.01)。中医辨证分型为痰湿内阻证、胃热伤津证、脾气亏虚证和兼有脾虚、痰湿、胃热证。运用传统中医分析中药药性及功效的方法,类推奥氮平的“药毒”性热,入脾胃经,具有胃热伤津、伤脾生湿的作用。经过2月中药汤剂治疗后,试验组中医证候总分较前显著降低,差异具有统计学意义(P<0.01);试验组与对照组比较治疗后中医证候总分差异有显著性(P<0.01)。治疗后试验组与对照组的空腹血糖、餐后2h血糖、血清胰岛素、总胆固醇、甘油三酯、高密度脂蛋白、低密度脂蛋白、体重、腰围、腰臀比及BMI值差异有显著性(P<0.05)。结论:临床上依据奥氮平“药毒”特性来辨证论治,运用中药汤剂治疗可以显著减少奥氮平所致的药物副反应。     

Thromboprophylaxis in the oldest old with atrial fibrillation: Between Scylla and Charybdis

Within a few decades half of the patients with non-valvular atrial fibrillation (AF) will be older than 80 years. These patients are at particularly high risk of thromboembolism (Scylla) but also of the hemorrhagic complications of thromboprophylaxis (Charybdis). A frequent compromise is to use as antithrombotic agents instead of vitamin-K antagonists aspirin or other antiplatelet drugs, which are ineffective for thromboprophylaxis in the oldest old and definitely not free from a high risk of severe bleeding. All the new direct anticoagulants currently licensed (dabigatran, rivaroxaban, apixaban) are at least as effective as warfarin for thromboprophylaxis in AF, but the risk of the intracranial bleeding, the most feared complication of anticoagulant therapy, is at least halved. In the oldest patients of 80 years of age or more preliminary data, available so far only for dabigatran, indicate that the favorable outcomes of direct anticoagulants are also present in this subgroup, often left untreated for fear of intracranial bleeding. The choice between the different direct anticoagulants is driven by the presence or not of renal insufficiency, the presence and degree of multimorbidity and polypharmacy and by the likelihood or not of poor treatment adherence in patients who are often frail and with some degree of cognitive impairment.     

Cassane-type diterpenes from Caesalpinia minax induce apoptosis in pituitary adenoma: structure–activity relationship,ER stress and Wnt/β-catenin pathways

Plant-derived natural products have been the highly significant sources of novel antitumor agents. The cassane-type diterpenes of genus Caesalpinia have been reported to bear antiproliferative activities toward different types of cancer cells. In this study, we evaluated the antineoplasmic activities of 16 natural origin cassane-type diterpenes isolated from the CHCl₃ extract of the seeds of C. minax in pituitary adenomas cells and identified caesalpin G (CAG) showed the strongest cytotoxicity. Moreover, we further investigated the structure–activity relationship and molecular mechanism of these derivatives systematically. The results confirmed the unsaturated lactone-type ring, hydroxyl at C-7, and alkenyl at C-11 or C-14 functionality as critical for anticancer activity in this family of natural products. In addition, the mechanism experiments also demonstrated unfolded protein response and ER stress and Wnt/β-catenin pathway were involved in the CAG-induced apoptosis.