Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

IntroductionLarge variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways.MethodsGenome Research at Fundacio ACE ([email protected]) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, [email protected] series were meta-analyzed with additional genome-wide association study data sets.ResultsWe classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444.DiscussionThe regulation of vasculature is a prominent causal component of probable AD. [email protected] meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.     

Brain gliomas,hydrocephalus and idiopathic aqueduct stenosis in children with neurofibromatosis type 1

PurposeTo evaluate the incidence and clinical importance of brain gliomas – optic pathway gliomas (OPGs) and especially gliomas outside the optic pathway (GOOP) for children with neurofibromatosis type 1 (NF1), additionally, to assess the causes of obstructive hydrocephalus in NF1 children with an emphasis on cases caused by idiopathic aqueduct stenosis.Subjects and methodsWe analysed data from 285 NF1 children followed up on our department from 1990 to 2010 by the same examination battery.ResultsWe have found OPGs in 77/285 (27%) children and GOOPs in 29/285 (10,2%) of NF1 children, of who 19 had OPG and GOOP together, so the total number of brain glioma was 87/285 (30,5%). GOOPs were significantly more often treated than OPGs (p > 0.01). OPGs contain clinically important subgroup of 14/285 (4.9%) spreading to hypothalamus. Spontaneous regression was documented in 4/285 (1.4%) gliomas and the same number of NF1 children died due to gliomas.Obstructive hydrocephalus was found in 22/285 (7.7%) patients and 14/22 cases were due to glioma. Idiopathic aqueduct stenosis caused hydrocephalus in 6/22 cases and was found in 2.1% of NF1 children. Two had other cause.ConclusionsThe total brain glioma number (OPGs and only GOOPs together) better reflected the overall brain tumour risk for NF1 children. However, GOOPs occur less frequently than OPGs, they are more clinically relevant. The obstructive hydrocephalus was severe and featuring frequent complication, especially those with GOOP. Idiopathic aqueduct stenosis shows an unpredictable cause of hydrocephalus in comparison with glioma and is another reason for careful neurologic follow up.     

Investigation of the mechanisms of Genkwa Flos hepatotoxicity by a cell metabolomics strategy combined with serum pharmacology in HL-7702 liver cells

1. To investigate Genkwa Flos hepatotoxicity, a cell metabolomics strategy combined with serum pharmacology was performed on human HL-7702 liver cells in this study.

2. Firstly, cell viability and biochemical indicators were determined and the cell morphology was observed to confirm the cell injury and develop a cell hepatotoxicity model. Then, with the help of cell metabolomics based on UPLC-MS, the Genkwa Flos group samples were completely separated from the blank group samples in the score plots and seven upregulated as well as two down-regulated putative biomarkers in the loading plot were identified and confirmed. Besides, two signal molecules and four enzymes involved in biosynthesis pathway of lysophosphatidylcholine and the sphingosine kinase/sphingosine-1-phosphate pathway were determined to investigate the relationship between Genkwa Flos hepatotoxicity and these two classic pathways. Finally, the metabolic pathways related to specific biomarkers and two classic metabolic pathways were analyzed to explain the possible mechanism of Genkwa Flos hepatotoxicity.

3. Based on the results, lipid peroxidation and oxidative stress, phospholipase A₂/lysophosphatidylcholine pathway, the disturbance of sphingosine-1-phosphate metabolic profile centered on sphingosine kinase/sphingosine-1-phosphate pathway and fatty acid metabolism might be critical participators in the progression of liver injury induced by Genkwa Flos.     

Inter-ictal assay of peripheral circulating inflammatory mediators in migraine patients under adjunctive cervical non-invasive vagus nerve stimulation (nVNS): A proof-of-concept study

Objective

To assay peripheral inter-ictal cytokine serum levels and possible relations with non-invasive vagus nerve stimulation (nVNS) responsiveness in migraineurs.

鞘磷脂类信号通路与动脉粥样硬化的研究进展

动脉粥样硬化是临床常见的冠心病和脑梗死等缺血性心脑血管疾病的主要病理基础,其病因复杂,发病机制尚未完全阐明。近年来,越来越多的研究显示鞘磷脂类信号通路可通过调节脂代谢、炎症和血管内皮功能等影响动脉粥样硬化的发生发展。文章综述了鞘磷脂类信号通路关键分子鞘磷脂、神经酰胺和1-磷酸鞘氨醇与动脉粥样硬化的关系,旨在为防治疾病提供新思路。     

足头向穿刺路径在膈肌下方肝肿瘤消融治疗中的CT模拟测量研究

【摘要】 目的 对足头向穿刺路径进行模拟测量并评价在膈肌下方肝肿瘤热消融治疗中的临床应用价值。方法 重建患者上腹部CT图像，选取有代表性的3个矢状面和1个冠状面作为标准层面，在各层面建立膈下标准病灶模型，并采用足头向穿刺路径进行模拟穿刺。测量各平面上膈肌高度、穿刺路径长度及间距。采用可到达性评价模拟穿刺时穿刺针分布于标准病灶中的最理想的位置情况。结果 纳入86例患者行测量研究，多数患者矢状2、3面的膈肌高度低于2cm，仅分别对平面内1511%的病灶e和813%的病灶f进行了测量。标准病灶a、b、c、d、b’的完全到达比例分别为5243%、6097%、3837%、5294%、6353%，中位路径长度分别为1039cm、1337cm（背侧，腹侧1266cm）、1315cm、888cm、1126cm，中位穿刺路径间距分别为21cm、209cm（背侧，214cm腹侧）、206cm、211cm、2145cm。结论 采用足头向穿刺路径进行穿刺，标准病灶a、b、d、b’有较高的完全到达比例，穿刺宽容度较高，有进一步在临床中应用的价值。标准病灶c的完全到达率不高。标准病灶e、f需要采用该路径穿刺的比例不高。     

Berberine Induces Cell Apoptosis through Cytochrome C/Apoptotic Protease-Activating Factor 1/Caspase-3 and Apoptosis Inducing Factor Pathway in Mouse Insulinoma Cells

Objective: To investigate apoptotic effects of berberine, a significant alkaloids component existing in Rhizoma coptidis, and its possible acting mechanism in insulinoma cells. Methods: Different concentrations of berberine were used to treat mouse insulinoma(MIN6) cells for various period of time. The viability and apoptosis of the cells were analyzed using methylthiazolyldiphenvl-tetrazolium bromide assay, flow cytometry and enzyme-linked immuno sorbent assay. Changes in the relating pro-and anti-apoptosis proteins were detected by western-blotting. Results: The half-maximal inhibitory concentration(IC50) of berberine was 5.7 μmol/L on MIN6 cells viability for 16 h. Berberine caused a 20% reduction(P0.05) in cell number after only 4-h incubation; which reached 50% after 24 h(P0.01). Berberine treatment for 16 h significantly increased the level of DNA fragmentation. The flow cytometry showed the apoptotic rate increased 2.9-and 4.6-fold after treating with berberine(5 μmol/L) for 8 and 16 h, while 3-and 8.7-fold after 10 μmol/L treatment for 8 and 16 h(P0.01). Berberine treatment dramatically elevated the expression ratio of Bax to Bcl-2. Meanwhile, berberine notably increased the apoptosis-inducing factors and cytochrome C transforming from the mitochondria to the cytoplasm. Apoptotic protease-activating factor 1(Apaf-1) was subsequently activated after cytochrome C release. Furthermore, caspase-3 and poly adenosine diphosphate-ribose polymerase were also activated to trigger apoptosis cascade. Conclusion: High concentration(5 and 10 μmol/L) of berberine could induce the apoptosis of MIN6 cells through cytochrome C/Apaf-1/caspase-3 and apoptosis inducing factor(AIF) pathway.     

补骨脂酚通过MAPK途径诱导人肝癌HepG2细胞凋亡的研究

目的:研究补骨脂酚对人肝癌细胞凋亡的影响及其作用机制。方法:应用噻唑蓝法（MTT法）和倒置显微镜技术考察补骨脂酚对HepG2细胞生长的影响；采用荧光显微镜观察补骨脂酚处理后细胞凋亡；利用蛋白免疫印迹法检测补骨脂酚对HepG2细胞中凋亡相关蛋白及MAPK家族蛋白表达的影响；引入MAPK家族蛋白抑制剂考察生长抑制率和凋亡相关蛋白表达的变化。结果:补骨脂酚可以剂量依赖性地抑制人肝癌HepG2细胞增殖，其生长抑制作用明显强于临床上常用的抗肿瘤药5-氟尿嘧啶，并且补骨脂酚对人正常肝L02细胞具有较低的毒性。进一步研究发现，补骨脂酚可以诱导HepG2细胞发生凋亡。此外，MAPK家族参与到补骨脂酚诱导的HepG2细胞凋亡过程中，补骨脂酚可以剂量依赖性激活JNK的表达发挥促凋亡的作用，同时抑制了ERK促存活通路，然而对p38无明显影响。结论:本研究首次阐明了补骨脂酚诱导人肝癌HepG2细胞生长抑制作用机制，为进一步的临床应用提供了理论依据。