Altered GPM6A/M6 Dosage Impairs Cognition and Causes Phenotypes Responsive to Cholesterol in Human and Drosophila

Glycoprotein M6A (GPM6A) is a neuronal transmembrane protein of the PLP/DM20 (proteolipid protein) family that associates with cholesterol‐rich lipid rafts and promotes filopodia formation. We identified a de novo duplication of the GPM6A gene in a patient with learning disability and behavioral anomalies. Expression analysis in blood lymphocytes showed increased GPM6A levels. An increase of patient‐derived lymphoblastoid cells carrying membrane protrusions supports a functional effect of this duplication. To study the consequences of GPM6A dosage alterations in an intact nervous system, we employed Drosophila melanogaster as a model organism. We found that knockdown of Drosophila M6, the sole member of the PLP family in flies, in the wing, and whole organism causes malformation and lethality, respectively. These phenotypes as well as the protrusions of patient‐derived lymphoblastoid cells with increased GPM6A levels can be alleviated by cholesterol supplementation. Notably, overexpression as well as loss of M6 in neurons specifically compromises long‐term memory in the courtship conditioning paradigm. Our findings thus indicate a critical role of correct GPM6A/M6 levels for cognitive function and support a role of the GPM6A duplication for the patient's phenotype. Together with other recent findings, this study highlights compromised cholesterol homeostasis as a recurrent feature in cognitive phenotypes.     

心脑血管病危险因素与颈动脉粥样硬化的相关性

目的 探讨心脑血管病危险因素与颈动脉粥样硬化的相关性。方法 选择2010年8月～2013年8月健康体检者916例,依据合并危险因素的数量将受试者分为4组,即0个危险因素组（对照组）226例,1个危险因素组239例,2个危险因素组234例,≥3个危险因素组217例。所有受试者均进行颈动脉超声检测及血生化检测。结果 对照组患者斑块发生率为7.52%,1个危险因素组为15.06%,2个危险因素组为23.93%,≥3个危险因素组为45.16%,从对照组到合并≥3个危险因素组斑块发生率显著上升（P<0.01）。4组受试者IMT分别为0.94±0.32 mm、1.12±0.34 mm、1.25±0.33 mm及1.37±0.39 mm,斑块Crouse积分分别为0.24±0.64、0.58±1.21、0.85±1.26及1.32±1.64。从对照组到合并≥3个危险因素组IMT及斑块Crouse积分逐渐增高（P<0.01）。Logistic回归分析显示,1个危险因素组颈动脉粥样硬化斑块发生率为对照组的1.27倍,2个危险因素组为2.31倍,≥3个危险因素组为4.68倍（P<0.01）。结论 危险因素之间对缺血性脑血管病高危人群颈动脉粥样硬化及斑块的发生具有显著的联合协同作用。     

Trends and risk factors of elderly-onset Crohn's disease: A nationwide cohort study

BACKGROUND The incidence of inflammatory bowel disease(IBD)is increasing in Asia.Numerous risk factors associated with IBD development have been investigated.AIM To investigate trends and environmental risk factors of Crohn’s disease(CD)diagnosed in persons aged≥40 years in South Korea.METHODS Using the National Health Insurance Service database,a total of 14060821 persons aged>40 years who underwent national health screening in 2009 were followed up until December 2017.Patients with newly diagnosed CD were enrolled and compared with non-CD cohort.CD was identified according to the International Classification of Diseases 10th revision and the rare/intractable disease registration program codes from the National Health Insurance Service database.The mean follow-up periods was 7.39 years.Age,sex,diabetes,hypertension,smoking,alcohol consumption,regular exercise,body mass index,anemia,chronic kidney disease(CKD)and dyslipidemia were adjusted for in the multivariate analysis model.RESULTS During the follow-up,1337(1.33/100000)patients developed CD.Men in the middle-aged group(40-64 years)had a higher risk than women[adjusted hazard ratio(aHR)1.46,95%confidence interval(CI):1.29-1.66];however,this difference tended to disappear as the age of onset increases.In the middle-aged group,patients with a history of smoking[(aHR 1.46,95%CI:1.19-1.79)and anemia(aHR 1.85,95%CI:1.55-2.20)]had a significantly higher CD risk.In the elderly group(age,≥65 years),ex-smoking and anemia also increased the CD risk(aHR 1.68,95%CI:1.22-2.30)and 1.84(95%CI:1.47-2.30,respectively).Especially in the middle-aged group,those with CKD had a statistically elevated CD risk(aHR 1.37,95%CI:1.05-1.79).Alcohol consumption and higher body mass index showed negative association trend with CD incidence in both of the age groups.[Middle-aged:aHR 0.77(95%CI:0.66-0.89)and aHR 0.73(95% CI:0.63-0.84),respectively][Elderly-group:aHR 0.57(95% CI:0.42-0.78)and aHR 0.84(95%CI 0.67-1.04),respectively].For regular physical activity and dyslipidemia,negative correlation between CD incidences was proved only in the middle-aged group[aHR 0.88(95%CI:0.77-0.89)and aHR 0.81(95%CI:0.68-0.96),respectively].CONCLUSION History of cigarette smoking,anemia,underweight and CKD are possible risk factors for CD in Asians aged>40 years.     

单中心冠心病患者对危险因素认知程度及控制现状的调查

目的分析我院门诊及住院的冠心病患者危险因素认知程度及控制现状。方法设计冠心病危险因素认知调查表,由经培训的调查员使用统一的调查表对患者进行面对面的问卷调查,分析2012—2014年我院门诊及住院诊治的经冠状动脉造影检查确诊的冠心病患者1 127例,所有患者均详细询问病史,检测血脂、血糖、糖化血红蛋白水平,行口服葡萄糖耐量试验,测量身高和体质量。结果 926例(82.2%)的患者认为应规律服用冠心病二级预防药物。患者对高血压是冠心病的危险因素知晓率最高,为65.22%(735/1127);对常见的4种危险因素全部知晓率为9.58%(108/1 127);经过住院宣教,出院后危险因素检出和控制情况:住院时吸烟的患者375例(33.27%),随访时下降至93例(8.25%)(P=0.002);住院时908例高血压患者中398例(43.83%)血压控制,随访时上升至662例(72.91%)(P=0.021);住院时共有757例(67.17%)血脂异常者,随访时下降至256例(22.72%)(P=0.002);住院时检出糖代谢异常者466例(41.35%),随访时检出672例(59.63%)(P=0.026)。结论本中心冠心病患者对疾病认知程度不甚理想,冠心病危险因素整体控制不佳,医务人员应进一步加强对患者冠心病二级预防的宣传教育。     

脑白质高信号对帕金森病运动症状和认知损害的影响

目的探讨脑白质高信号(WMH)对帕金森病(PD)运动症状和认知损害的影响。方法回顾性纳入315例PD患者,根据Fazekas量表评分分为轻度WMH组191例,中度WMH组74例,重度WMH组50例。收集脑血管病相关危险因素,Hoehn-Yahr(H-Y)分级、世界运动障碍协会统一帕金森病评定量表第三部分(MDS-UPDRSⅢ)总分及震颤、强直、运动迟缓、步态姿势异常评分评估运动症状,用简易智能状态检查量表(MMSE)、蒙特利尔认知评估量表(MoCA)评估认知功能,用汉密尔顿抑郁量表(HAMD)、汉密尔顿焦虑量表(HAMA)评估情绪,用3T MRI及Fazekas量表评估WMH程度,用Spearman相关和多元线性回归分析。结果 3组年龄、起病年龄、病程、MMSE和MoCA评分比较,有统计学差异(P<0.05,P<0.01)。3组H-Y分级、MDS-UPDRSⅢ总分、震颤、强直、运动迟缓、步态姿势异常、HAMA、HAMD评分及体位性低血压比例比较,无统计学差异(P>0.05)。多元线性回归分析校正年龄、病程、起病年龄、MoCA、同型半胱氨酸、缺血性脑卒中、高血压、吸烟、性别、体质量指数和心脏病等因素后,WMH与MMSE仍显著相关(β=-0.183,95%CI:-0.134^-0.007,P=0.029)。脑室旁WMH(r=-0.246,P=0.000;r=-0.235,P=0.000)和深部WMH(r=-0.192,P=0.001;r=-0.187,P=0.001)与MMSE和MoCA呈显著负相关。WMH与PD运动症状不相关(P>0.05)。结论 WMH对PD认知损害影响明显,临床需警惕PD伴发WMH,脑血管病二级预防可能对PD患者认知减退有潜在预防作用。     

老年人抗γ氨基丁酸B型受体脑炎的临床特点

目的探讨老年人抗γ氨基丁酸B型(GABA-B)受体脑炎的临床特点。方法回顾性分析10例老年抗GABA-B受体脑炎患者临床资料,采用改良的Rankin量表(mRS)评分进行预后评估。结果10例患者主要临床表现包括痫性发作(100%)、精神行为异常(100%),认知障碍(100%),意识障碍(80%)。头颅MRI异常7例,以累及颞叶、海马、岛叶、杏仁体及扣带回等边缘系统,其中3例同时累及非边缘系统(包括额叶、放射冠)。胸部CT示肺部占位性病变3例。10例均给予免疫调节治疗。出院6个月后电话随访,死亡2例,预后不良4例,预后良好4例。结论老年抗GABA-B受体脑炎患者以痫性发作、精神行为异常、认知障碍为主要表现;头颅MRI以边缘系统异常信号多见;易合并有肿瘤,需注意肿瘤筛查及定期跟踪随访;免疫调节及抗肿瘤为主要治疗方法,预后较差。     

缺血性脑小血管病患者凝血标志物及同型半胱氨酸与血管性认知障碍的相关性

目的探讨缺血性脑小血管病(CSVD)患者凝血标志物与血管性认知障碍的相关性。方法连续入选缺血性CSVD患者300例,根据简易智能状态检查量表评分分为认知正常组106例和认知障碍组194例,认知障碍组又分为轻度组102例、中度组59例和重度组33例。选取同期门诊健康体检者60例作为对照组。测定血浆血栓调节蛋白(TM)、组织因子途径抑制物(TFPI)及同型半胱氨酸(Hcy)水平,比较各项差异。结果与对照组比较,认知正常组和认知障碍组TM及Hcy升高,TFPI降低(P<0.05);且认知障碍组较认知正常组TM及Hcy更高[(32.6±30.2)μg/Lvs(21.7±14.5)μg/L,(19.3±15.2)μmo L/Lvs(14.0±6.0)μmo L/L],TFPI更低[(110.3±28.2)mmol/L vs(136.8±47.9)mmol/L,P<0.05]。血浆TFPI和Hcy与患者发生认知功能障碍独立相关(P=0.000)。与轻度组比较,中度组和重度组Hcy及TM升高,TFPI降低(P<0.05);重度组较中度组变化更明显(P<0.05)。认知功能评分及不同认知域损害均与血浆TM及Hcy呈负相关,与血浆TFPI呈正相关(P<0.05,P<0.01)。结论TFPI、TM及Hcy与缺血性CSVD患者认知障碍发生、发展过程中的内皮细胞损伤有关。     

急性缺血性脑卒中后认知障碍患者精神行为症状的特征性分析

目的探讨急性缺血性脑卒中后认知障碍(PSCI)患者精神行为症状(BPS)发生的特征。方法纳入2018年1月~2019年5月苏北人民医院神经内科住院的急性脑梗死患者105例,PSCI患者73例分为脑卒中后痴呆(PSD)组28例和脑卒中后认知障碍非痴呆(PSCI-ND)组45例,脑卒中后非认知障碍(非PSCI)组32例。PSCI患者又分为BPS组50例和非BPS组23例。根据英国牛津郡社区脑卒中规划分型,将急性脑梗死患者分为部分前循环梗死型(PACI)、后循环梗死型和腔隙性脑梗死型(LACI)。认知功能评估采用简易智能状态检查量表(MMSE)和蒙特利尔认知评估量表(MoCA),BPS评估采用神经精神问卷(NPI)。评价患者日常生活活动能力量表(ADL),并收集相关临床资料。结果PSD组和PSCI-ND组NIHSS评分、NPI总分、BPS发生率均明显高于非PSCI组,教育年限明显低于非PSCI组(P<0.05)。PSD组年龄明显高于PSCI-ND组(P<0.05)。BPS组ADL总分、MMSE总分和MoCA总分明显低于非BPS组[(86.90±10.50)分vs(92.61±10.10)分,P=0.032;(24.39±2.13)分vs(20.36±4.27)分,P=0.000;(17.04±4.23)分vs(22.00±2.65)分,P=0.000]。与非BPS组比较,BPS组PACI发生率明显升高(52.0%vs 4.3%,P=0.000),LACI发生率明显降低(20.0%vs 56.5%,P=0.002)。PSD组和PSCI-ND组幻觉、激越、抑郁、淡漠、异常运动和睡眠行为障碍比例明显高于非PSCI组(P<0.05)。PSD组激越、抑郁、淡漠和睡眠行为障碍比例明显高于PSCI-ND组(P<0.05)。结论PSCI患者较易出现BPS,其认知水平不同BPS发生率及表现不同,揭示了PSCI的临床异质性特点,为PSCI的治疗提供临床依据。     

原发性胆汁性肝硬化发病相关危险因素研究进展

原发性胆汁性肝硬化（PBC）是一种原因不明的自身免疫性肝病,多见于中年女性。在已知的诸多发病危险因素中,人口学因素、环境因素和遗传因素以及家族史、吸烟史和尿路感染等一直为人们所重视。近年来,随着研究的深入,特别是全基因组关联研究（GWAS）技术的应用,发现了一些可能导致该病的危险基因,如人类白细胞抗原基因、白细胞介素（IL）-12和X染色体单体等。今后,还需要大量的样本和GWAS数据来验证这一说法,以期从基因水平上阐述该病的发病机制。     

原发性肝癌术后早期复发的危险因素分析

目的：探讨原发性肝癌（PLC）患者术后早期复发的危险因素。方法在51例 PLC 患者,选取17项临床和组织病理学参数,分析 PLC 术后早期复发的相关因素。结果发现血清 AST 水平（P〈0.001）、是否伴有肝硬化（P〈0.001）、肿瘤包膜是否完整（P=0.003）和血管侵犯（P=0.006）与早期复发相关;通过 Kaplan-Meier 法和 Cox 风险比例模型筛选发现有肝硬化（风险比=2.865,95%可信区间为1.846~8.466,P〈0.001）、肿瘤包膜缺失（风险比=3.357,95%可信区间为1.526~6.949,P=0.002）和血管侵犯（风险比=2.230,95%可信区间为1.094~4.548,P=0.027）是 PLC 术后早期复发的独立危险因素。结论对于有肝硬化、肿瘤包膜缺失和伴有血管侵犯等危险因素的 PLC 患者,术后应加强随访,以期及早发现肿瘤复发并给予及时的治疗。