重症肌无力死亡原因分析及重症肌无力人源化SCID模型的构建和标志物探查

发布时间：2018-04-19 22:12

本文选题：重症肌无力 + 发病年龄　；参考：《华中科技大学》2016年博士论文

【摘要】：目的：调查同济医院住院和门诊的重症肌无力(MG)成人患者的死亡率和相关危险因素。方法：对2013年前就诊的MG患者做了详细的登记,包含起病时间,发病时状态,分级,病程,用药情况,激素,免疫抑制剂的使用,胸腺手术,合并症如心功能不全,高血压,糖尿病,慢性阻塞性肺部疾病,脑中风等。对死亡原因进行分析。采用COX生存分析和K-M曲线分析方法。结果：共收集2195位患者,129位MG患者死亡,病亡率为5.88%,死亡的原因有癌症,MG危象,心肌梗塞,肺部疾病,中风,消化道出血和自杀。65.9%死亡发生在医院,34.1%发生在社区医院。与MG相关危险因素是病程,MG危象,MGFA Ⅲ型和Ⅳ型,乙酰胆碱受体(AchR)抗体水平,胸腺病理,免疫抑制剂的使用(p0.05)。另外,先前的中风,慢性阻塞性肺病(COPD),糖尿病,房颤,高脂血症,心肌梗塞,恶性肿瘤和死亡有相关性(HR分别为3.251,4.173,3.738,3.886,1.945,2.177和14.7,p0.05),外周血管病(PVD),心功能不全,高血压,慢性肾病和吸烟并没有统计学意义(p0.05)。结论：入组时疾病的严重程度,AchR抗体的表达,胸腺病理,和病程是死亡的高危预测因素；合并症,如中风,慢性阻塞性肺部疾病,糖尿病,房颤,高脂血症,心肌梗塞,恶性肿瘤增加MG的死亡风险；免疫抑制剂的使用,胸腺切除手术能降低MG的死亡风险。目的：通过给SCID小鼠注入MG危象患者增殖的T细胞,来阐明T细胞在MG小鼠模型中的作用并检测细胞因子。方法：共32只6-8周雄性SCID小鼠饲养于SPF级动物实验室。环磷酰胺(CTX)按40mg/kg给小鼠腹腔注射,连续4天。从MG危象患者血中分离出的单个核细胞进行增殖(以T细胞为主,少量B细胞)。首次注射CTX第5天后,实验组每周给SCID小鼠腹腔注射培养的2×106淋巴细胞,对照组给予PBS共8次。每位患者淋巴细胞移植到4只小鼠,共4位患者均为MGFA Ⅲ型。并完善小鼠临床评分(Clinical scores),抓力试验(Grip strength),翻笼试验(Inverted screen test),小鼠行肌电图检测后,ELISA法检测抗人乙酰胆碱受体抗体,IL-6和IL-4的水平。结果：实验组共6只小鼠确定为MG模型,临床评分,抓力试验,翻笼试验均差于对照组,6只小鼠的肌电图显示为阳性,乙酰胆碱受体抗体检测实验组高于对照组,而IL-6和IL-4没有统计学意义。结论：MG危象患者T细胞增殖可以诱导出MG人源化SCID小鼠模型,为以后MG危象的个性化治疗奠定基础。目的：磁共振弥漫张量成像(DTI)和磁共振波谱分析(MRS)在肌萎缩侧索硬化病人中的应用。方法：2013年10月到2014年7月19位肌萎缩侧索硬化病人和13位年龄匹配的健康成人完善磁共振检查,包含部分各向异数(FA),表观扩散系数(ADC),N-乙酰天冬氨酸(NAA),胆碱(Cho),和肌酸(Cr)等定量结果。肌萎缩侧索硬化功能评定量表修改版(ALSFRS-R)和疾病进展比例用来评估功能残疾。分析患者和对照组的影像结果,影像和功能残疾的相关性进行统计学分析。结果：双侧皮质运动区的NAA/Cr和皮质脊髓束(CST)的FA值比对照组明显降低。两组的Cho/Cr,纤维长度,纤维体积,ADC和NAA没有统计学意义。ALS患者右侧皮质脊髓束FA(r=0.243, p=0.316);左侧皮质运动区NAA (r=0.095, p=0.699), NAA/Cr (r=0.172,p=0.481);右侧的皮质运动区NAA (r=0.320,p=0.182), NAA/Cr (r=0.193,p=0.492)和ALSFRS-R之间无明显统计学意义。疾病进展比值和FA, NAA,或NAA/Cr没有统计学意义。结论：NAA/Cr和FA能够帮助诊断肌萎缩侧索硬化。大脑局部NAA/Cr和FA值不能够评估ALSFRS-R和疾病进展比值。
[Abstract]:Objective: To investigate the mortality and risk factors for adult patients with myasthenia gravis (MG) in Tongji Hospital. Methods: a detailed registration was made for patients with MG before 2013, including onset time, disease status, classification, course of disease, medication, hormone, use of immunosuppressive agents, thymic surgery, and cardiac function. Incomplete, hypertension, diabetes, chronic obstructive pulmonary disease, stroke and so on. Analysis of the causes of death. Using COX survival analysis and K-M curve analysis. Results: a total of 2195 patients were collected, 129 MG patients died and the death rate was 5.88%, the causes of death were cancer, MG crisis, myocardial infarction, lung disease, stroke, gastrointestinal bleeding and Suicide.65.9% death occurred in the hospital, 34.1% occurred in the community hospital. The risk factors associated with MG were the course of disease, the MG crisis, the MGFA III and IV type, the acetylcholine receptor (AchR) antibody level, the thymus pathology, the use of immunosuppressive agents (P0.05). In addition, the previous stroke, the chronic obstructive pulmonary disease (COPD), diabetes, atrial fibrillation, hyperlipidemia, myocardial infarction There was a correlation between malignant tumor and death (HR 3.251,4.173,3.738,3.886,1.945,2.177 and 14.7, P0.05), peripheral vascular disease (PVD), cardiac insufficiency, hypertension, chronic kidney disease and smoking (P0.05). Conclusion: the severity of the disease, the expression of the AchR antibody, the thymus pathology, and the course of the disease are Gao Weiyu's death. Test factors; complications such as stroke, chronic obstructive pulmonary disease, diabetes, atrial fibrillation, hyperlipidemia, myocardial infarction, and malignant tumor increase the risk of death of MG; immunosuppressive drugs, thymectomy can reduce the risk of MG death. Objective: to clarify the T cells in MG by injecting T cells into the T cells of the MG crisis patients. The function of the mouse model and the detection of cytokine. Methods: a total of 32 6-8 weeks male SCID mice were fed in the SPF animal laboratory. Cyclophosphamide (CTX) was injected into the abdominal cavity of the mice by 40mg/kg for 4 days. The mononuclear cells isolated from the blood of the MG crisis patients were proliferated (with T fine cells and a small amount of B cells). After the first injection of CTX, it was the first day of the injection of CTX. In the experimental group, 2 x 106 lymphocytes were injected into the abdominal cavity of SCID mice, and the control group was given a total of 8 times PBS. Each patient was transplanted into 4 mice. A total of 4 patients were all MGFA III. The clinical score of mice (Clinical scores), grasping test (Grip strength), cage test (Inverted screen test), and electromyography of mice were examined. After test, ELISA method was used to detect the anti human acetylcholine receptor antibody, IL-6 and IL-4 level. Results: 6 mice in the experimental group were determined to be MG model, the clinical score, the grasping test, the cage test were all poor in the control group, the electromyography of 6 mice was positive, the acetylcholine receptor antibody test group was higher than the control group, and the IL-6 and IL-4 did not count the statistics. Conclusion: the proliferation of T cells in MG crisis patients can induce the MG humanized SCID mouse model and lay the foundation for the individualized treatment of MG crisis. Objective: the application of magnetic resonance diffuse tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) in amyotrophic lateral sclerosis patients. Methods: 19 muscular atrophy from October 2013 to July 2014. Sclerosing patients and 13 age matched healthy adults perfected MRI, including partial anisotropy (FA), apparent diffusion coefficient (ADC), N- acetyl aspartic acid (NAA), choline (Cho), and creatine (Cr) quantitative results. The amyotrophic lateral sclerosis function assessment table modified version (ALSFRS-R) and disease progression ratio were used to assess functional disability. Analysis of the images of the patients and the control group, the correlation between the image and the functional disability was statistically analyzed. Results: the FA value of the NAA/Cr and the corticospinal tract (CST) in the bilateral cortical motor area was significantly lower than that of the control group. The two groups of Cho/Cr, fiber length, fiber volume, ADC and NAA were not statistically significant in the right lateral corticospinal tract FA of.ALS patients (r=0 .243, p=0.316); left cortical motor area NAA (r=0.095, p=0.699), NAA/Cr (r=0.172, p=0.481); there is no significant statistical significance between NAA (r=0.320, p=0.182) in the right cortical motor area. Atrophic lateral sclerosis. NAA/Cr and FA values in the brain do not assess the ratio of ALSFRS-R to disease progression.

【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R746.1

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