Lipid membranes accelerate amyloid formation in the mouse model of AA amyloidosis

Introduction: AA amyloidosis develops as a result of prolonged inflammation and is characterized by deposits of N-terminal proteolytic fragments of the acute phase reactant serum amyloid A (SAA). Macrophages are usually found adjacent to amyloid, suggesting their involvement in the formation and/or degradation of the amyloid fibrils. Furthermore, accumulating evidence suggests that lipid membranes accelerate the fibrillation of different amyloid proteins.

Methods: Using an experimental mouse model of AA amyloidosis, we compared the amyloidogenic effect of liposomes and/or amyloid-enhancing factor (AEF). Inflammation was induced by subcutaneous injection of silver nitrate followed by intravenous injection of liposomes and/or AEF to accelerate amyloid formation.

Results: We showed that liposomes accelerate amyloid formation in inflamed mice, but the amyloidogenic effect of liposomes was weaker compared with AEF. Regardless of the induction method, amyloid deposits were mainly found in the marginal zones of the spleen and coincided with the depletion of marginal zone macrophages, while red pulp macrophages and metallophilic marginal zone macrophages proved insensitive to amyloid deposition.

Conclusions: We conclude that increased intracellular lipid content facilitates AA amyloid fibril formation and show that the mouse model of AA amyloidosis is a suitable system for further mechanistic studies.     

急性心肌梗死患者急诊介入治疗联用替罗非班出血情况分析

目的:分析急性ST段抬高心肌梗死患者急诊直接经皮冠状动脉介入治疗(PCI)联合应用血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂替罗非班时出血并发症的发生情况,探讨发生心肌梗死溶栓治疗临床试验(TIMI)出血事件的相关影响因素。方法:2005年4月至2006年3月,150例急性ST段抬高心肌梗死患者行直接PCI时应用替罗非班,平均年龄57.8±9.6(35～78)岁,男性116例。分析出血并发症发生情况,根据住院期间出血事件是否达到TIMI出血标准将所有患者分为TIMI出血组(n=10)和非TIMI出血组(n=140),分析两组的相关临床和介入治疗情况,以及出血事件对近期临床预后的影响,探讨应用替罗非班发生TIMI出血事件的相关影响因素。结果:在TIMI出血组中,达到轻、重度出血标准的患者分别占总病例的4.7%和2.0%。住院期间随访发现,发生TIMI轻重度出血的患者住院期间死亡/再梗联合事件发生率明显高于非TIMI出血组(分别为40%和3.6%,P<0.01),住院时间延长(P<0.01)。单因素分析显示,发生TIMI出血事件的患者中,女性比率,补救性应用替罗非班比率和术后即刻的活化部分凝血酶原时间较高(P<0.05)。Logistic多因素回归分析提示术后即刻的活化部分凝血酶原时间是急诊PCI治疗应用替罗非班发生TIMI出血事件的独立预测指标(P=0.013,OR=1.458)。结论:急性ST段抬高心肌梗死急诊介入治疗时,联合应用替罗非班存在一定的出血发生率,发生TIMI轻重度出血的患者近期预后不良。较高的活化部分凝血酶原时间是应用替罗非班发生TIMI出血事件的独立危险因素。     

老年2型糖尿病患者胰岛素敏感性与红细胞膜磷脂成分的关系

目的探讨老年2型糖尿病患者红细胞膜磷脂成分与胰岛素敏感性的关系。方法测定32例老年2型糖尿病患者和30例健康老年人红细胞膜磷脂酰胆碱(phosphstidycholine,PC)、磷脂酰丝氨酸(phosphatidylserine,PS)、磷脂酰肌醇(phosphatidtlinostiol,PI)、磷脂酰乙酰胺(phosphatidylethanolamine,PE)、红细胞最大变形指数(maximumdeformationindex,DImax)、最大聚集指数(maximumlaggregationindex,AImax)以及葡萄糖利用常数(glucosedisposalconstantki,KITT值)。结果与对照组比较,2型糖尿病患者KITT值明显下降(P<0.01);DImax降低[(39.15±33.31)%对(36.79±2.50)%,P<0.01];而AImax显著上升[(39.26±4.46)%对(42.25±5.87)%,P<0.05];红细胞膜各磷脂成分磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酰乙酰胺均较健康对照组降低[分别为(202±22)(、136±21)、(10±1)(、194±33)μg/mg蛋白对(184±32)(、112±27)(、8±2)(、171±37)μg/mg蛋白,P<0.01]。结论老年2型糖尿病患者红细胞膜磷脂成分的变化直接影响红细胞功能,引起细胞流变学、血液流变学的异常,增加胰岛素抵抗。     

单核细胞趋化蛋白-1与心力衰竭

炎症是心力衰竭的重要组成部分.然而其导致心力衰竭发生、发展的详细机制仍不清楚.单核细胞趋化蛋白.1是引起慢性炎症的主要趋化因子并且在心力衰竭的发病学中起着重要作用.抗单核细胞趋化蛋白-1将是治疗心力衰竭极有希望的措施.     

Performance of stent thrombosis and bleeding risk scores in out-of-hospital cardiac arrest due to acute coronary syndromes

BackgroundPatients with out-of-hospital cardiac arrest (OHCA) due to acute coronary syndromes (ACS) who undergo percutaneous coronary intervention (PCI) are at high risk of bleeding and thrombosis. While predictive bleeding and stent thrombosis risk scores have been established, their performance in patients with OHCA has not been evaluated.MethodsAll consecutive patients admitted for OHCA due to ACS who underwent PCI between January 2007 and December 2019 were included. The ACTION and CRUSADE bleeding risk scores and the Dangas score for early stent thrombosis risk were calculated for each patient. A C-statistic analysis was performed to assess the performance of these scores.ResultsAmong 386 included patients, 82 patients (21.2%) experienced severe bleeding and 30 patients (7.8%) experienced stent thrombosis. The predictive performance of the ACTION and CRUSADE bleeding risk scores for major bleeding was poor, with areas under the curve (AUCs) of 0.596 and 0.548, respectively. Likewise, the predictive performance of the Dangas stent thrombosis risk score was poor (AUC 0.513). Using multivariable analysis, prolonged low-flow (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.00–1.05; P = 0.025), reduced haematocrit or fibrinogen at admission (OR 0.93, 95% CI 0.88–0.98; P = 0.010 and OR 0.61; 95% CI 0.41–0.89; P = 0.012, respectively) and the use of glycoprotein IIb/IIIa inhibitors (OR 2.10, 95% CI 1.18–3.73; P = 0.011) were independent risk factors for major bleeding.ConclusionThe classic bleeding and stent thrombosis risk scores have poor performance in a population of patients with ACS complicated by OHCA. Other predictive factors might be more pertinent to determine major bleeding and stent thrombosis risks in this specific population.     

Spectrin,red cell shape and deformability

Summary In a companion paper, the shapes of spectrin deficient mouse erythrocytes were described; in contrast to previous assumptions, spherules with tethered microvesicles rather than true spherocytes were found. Thence, spectrin deficient mouse erythrocytes are endowed with an excess of surface area for the given volume but the membrane is assuming a highly positive curvature. Observations during and after the action of enzymes cleaving the red cell surface charge (Neuraminidase, Trypsin, Chymotrypsin) showed that the previously positive membrane curvature, as well as the tendency of the membrane to flow into fingerlike protrusions was completely abolished. The erythrocytes of the spectrin deficient, desialylated mouse erythrocytes assumed a variety of shapes, often discocytic or even stomatocytic, i.e. their membrane presented with negative curvature. However, while these desialylated membranes could be easily deformed (elongated) by shear flow they did not recoil elastically into any definitive configuration after removal of the deforming forces. It is concluded from these observations that spectrin (acting on the inner interface between membrane and cytoplasm) and sialic acid residues (acting on the outer interface between membrane and plasma) exert antagonizing effects on membrane curvature and membrane bending elasticity. Sialic acid residues, strongly charged and situated on the outer side of the cell, produce positive membrane curvature; this observation can most readily be explained by assuming that this mechanical effect is caused by repulsive coulombic forces expanding the outer half of the bilayer. To explain the effect of the spectrin-complex in counteracting positive or in producing negative membrane curvature, a similar expansive coulombic force acting between the highly charged residues has been postulated. Thence, a model for explaining the overall elastic behaviour of the normal mammalian red cell is developed which is based on the assumption of elastic interactions of proteinacous membrane components coupled to the lipid bilayer of the membrane.Supported by Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 109, Project C 7. Dedicated to the memory of the late Professor Marcel Hanns, who not only made possible the measurements of zeta-potential in the present experiments but who, in many discussions of the scientific problems envolved, was very instrumental in shaping the concepts presented in this communication.     

左旋卡尼汀对异丙肾上腺素致心肌损害的影响

目的:观察左旋卡尼汀对异丙肾上腺素致心肌损害的保护作用并探讨其机制。方法:采用大鼠皮下注射异丙肾上腺素造成心肌损害模型。心肌切片,HE染色,光镜下观察心肌损害程度;分离心肌线粒体,测定膜脂流动性（LFU）。结果:注射左旋卡尼汀可减轻心肌损害程度;改善线粒体的损伤,改善LFU。结论:左旋卡尼汀能减轻异丙肾对心肌的损害,对线粒体膜脂流动性损伤具有明显的保护作用。     

Risk Prediction and Comparative Efficacy of Anti-TNF vs Thiopurines,for Preventing Postoperative Recurrence in Crohn's Disease: A Pooled Analysis of 6 Trials

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氧化型低密度脂蛋白促进单核细胞－内皮细胞体外粘附反应

体外培养猪胸主动脉内皮细胞，观察氧化型低密度脂蛋白对内皮细胞－单核细胞体外粘附反应的影响，同时观察氧化型低密庆脂蛋白对内皮细胞表面粘附分子颗粒膜蛋白－１４０及内皮细胞分泌前列环素的影响。结果发现氧化型低密度脂蛋白（０、５０、１００和２００ｍｇ／Ｌ）增加内皮细胞－单核细胞粘附率并呈剂量依赖性，其中以１００ｍｇ／Ｌ作用最强；氧化型低密度脂蛋白（１００ｍｇ／Ｌ）与内皮细胞孵育０．５ｈ，粘附率上升但无显著性，１ｈ后显著升高，３ｈ达高峰，４８ｈ回复接近正常水平。同时发现１００ｍｇ／Ｌ氧化型低密度脂蛋白使内皮细胞表面颗粒膜蛋白－１４０含量从９２．８±４７．６上升到２９３．０±１４０．７μｇ／Ｌ（Ｐ＜０．０５），内皮细胞分泌前列环素量从８４．６±１８．７降低到６．０±３．１ｎｇ／Ｌ（Ｐ＜０．０１）．结果表明氧化型低密度脂蛋白可显著促进单核细胞－内皮细胞粘附，其作用机制可能同内皮细胞表面粘附分子颗粒膜蛋白－１４０增加有关。关键词