Platelet adhesion to collagen type IV under flow conditions

Collagen type IV is a sheet-forming collagen and a major constituent of the vessel wall. To find out which conditions are important for platelet adhesion to collagen type IV, we performed perfusion studies with anticoagulated blood in parallel plate perfusion chambers. The role of divalent cations was investigated by using plasmas with variable concentrations of Mg2+ and Ca2+ ions. When Mg2+ concentration was decreased from 2.00 mmol/L to 0.25 mmol/L at a fixed Ca2+ concentration of 1.25 mmol/L, platelet coverage on the collagen type IV surface decreased from 22.8% +/- 1.8% (n = 4) to 4.6% +/- 0.6% (n = 4) at a shear rate of 1,600 s-1. Also, platelet aggregate formation on collagen type IV was strongly impaired. A monoclonal antibody against the glycoprotein (Gp) Ib receptor and von Willebrand factor (vWF)- depleted plasma reduced the platelet coverage to collagen type IV to, respectively, 10% and 45% of the control value. Electron microscopy showed that vWF was only present between platelets and between the platelet and the collagen type IV surface, but did not bind elsewhere to collagen type IV. These data indicate that collagen type IV is a reactive collagen for platelets. Differences in physiologic plasma magnesium concentrations may in part explain the differences in platelet reactivity to collagen type IV between individuals, and perhaps contribute to differences in the risk for thrombosis.     

16层螺旋CT血管造影对冠状动脉狭窄的评价

目的:分析16层螺旋CT血管造影(MSCTA)无创性评价冠状动脉(冠脉)狭窄的价值.方法:80例临床初诊疑为冠心病,既往无冠脉成形术和搭桥术史的患者,行冠脉16层MSCTA后(其中9例在CT扫描前心率超过80次/min的患者应用了β受体阻滞剂),回顾性重建心电门控轴位图像,并分别采用容积成像、多平面重建、曲面重建、最大密度投影等后处理方法,对所有冠脉及其分支进行重建,统计可供临床评价的、管径≥1.5 mm的冠脉段,以选择性冠脉造影(SCA)为标准,对比分析MSCTA诊断冠脉显著性狭窄(管腔平均直径缩小>50%)的准确性.结果:94%(989/1056)的冠脉节段和94%(290/310)的冠脉主支可供评价,(6%)67/1056段不能评价的主要原因分别为:心脏运动伪影39段,致密钙化20段和管腔显影不良8段.除外不能评价的冠脉,按节段和主支分类,与SCA相比,MSCTA诊断冠脉显著性狭窄的差异无统计学意义,其敏感性、特异性、阳性和阴性预期值分别为93%、99%、87%、99%和95%、98%、91%及99%.结论:在患者心率<80次/min时,16层MSCTA即可获得较好的图像质量用于评价冠脉并判断其狭窄程度,是一种值得临床医生信赖的检查冠脉有无狭窄的无创伤性方法.     

Stem cell factor and interleukin-7 synergize to enhance early myelopoiesis in vitro

Interleukin-7 (IL-7) has been shown to be a critical factor in murine lymphoid development. It stimulates pre-B cells to divide in the absence of stroma cells and it is an important growth regulator of immature and mature T cells. IL-7 has been shown to synergize with stem cell factor (SCF) to provide a potent growth stimulus for pre-B cells. However, the combined effects of IL-7 and SCF on murine primitive hematopoietic cells in vitro have not been established. In the present study, the effects of recombinant rat (rr) SCF and recombinant human (rh) IL-7 on primitive murine bone marrow progenitors (Lin-Sca1+) were investigated in single-cell cloning experiments. rhIL-7 alone had no proliferative effect on Lin-Sca1+ cells, but in a dose-dependent manner directly enhanced rrSCF-induced colony formation, with an average increase in colony numbers of 2.7-fold. Interestingly, the cells formed in response to SCF and IL-7 were predominantly mature granulocytes. Thus, SCF and IL-7 synergize to stimulate early myelopoiesis in vitro.     

Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds

Recent experimental evidence suggests that transcellular propagation of fibrillar protein aggregates drives the progression of neurodegenerative diseases in a prion-like manner. This phenomenon is now well described in cell and animal models and involves the release of protein aggregates into the extracellular space. Free aggregates then enter neighboring cells to seed further fibrillization. The mechanism by which aggregated extracellular proteins such as tau and α-synuclein bind and enter cells to trigger intracellular fibril formation is unknown. Prior work indicates that prion protein aggregates bind heparan sulfate proteoglycans (HSPGs) on the cell surface to transmit pathologic processes. Here, we find that tau fibril uptake also occurs via HSPG binding. This is blocked in cultured cells and primary neurons by heparin, chlorate, heparinase, and genetic knockdown of a key HSPG synthetic enzyme, Ext1. Interference with tau binding to HSPGs prevents recombinant tau fibrils from inducing intracellular aggregation and blocks transcellular aggregate propagation. In vivo, a heparin mimetic, F6, blocks neuronal uptake of stereotactically injected tau fibrils. Finally, uptake and seeding by α-synuclein fibrils, but not huntingtin fibrils, occurs by the same mechanism as tau. This work suggests a unifying mechanism of cell uptake and propagation for tauopathy and synucleinopathy.Alzheimer’s disease (AD), frontotemporal dementia, and other tauopathies feature conversion of soluble, native tau protein into filamentous aggregates. In AD, tau pathology and its associated neural atrophy do not distribute randomly throughout the brain, but progress in association with neural networks (1–4), implying a role for connectivity and the transcellular movement of a pathological agent (1, 2, 4, 5). Prior studies by our laboratory and others have demonstrated that internalized tau aggregates can trigger fibrillization of native tau protein (6–11). We have previously observed that tau aggregates propagate the misfolded state among cells in culture via release of fibrils into the extracellular space. These aggregates trigger further fibrillization by direct protein–protein contact with native tau in the recipient cells (12). Thus, fibrillar tau appears to spread pathologic processes by mechanisms fundamentally similar to prion pathogenesis. Although the phenomenology is now well described, the basic mechanisms that mediate transcellular propagation of tau aggregation remain unknown, including the mechanism of aggregate uptake to seed intracellular fibrillization. Infectious prion protein is known to bind heparan sulfate proteoglycans (HSPGs) on the cell surface, a requirement for propagation of the pathological conformation (13, 14). This study elucidates a mechanism whereby tau aggregates bind HSPGs to stimulate cell uptake via macropinocytosis and seed further aggregation. Further, we find that HSPGs also mediate uptake and seeding of α-synuclein fibrils, but not huntingtin fibrils, consistent with a unifying mechanism for two major classes of neurodegenerative disease.     

On the nature of personal narratives of high quality

This investigation explores the discourse devices associated with high-quality personal narratives. The study examined normative characteristics of 11 high-quality personal narratives of a frightening experience identified (from a larger set of 72 narratives) for their effectiveness in engaging the audience. Lay ratings and an ethnographic interview with seven of the excellent storytellers further characterized the stories and validated their selection. Narratives of both African Americans and Caucasians were represented, and were similar in nature. The excellent narratives were longer, conveyed more fearful topics, and were more dramatic than average narratives. Drama was achieved through direct speech, prosodic shifts, voice changes, inclusion of multiple characters, repetition, and syntactic and semantic parallelism. Illustrative narrative excerpts are provided. This study illustrates the potential in pairing holistic and analytical approaches to narrative analysis.     

A novel locus for autosomal recessive primary torsion dystonia (DYT17) maps to 20p11.22–q13.12

Primary torsion dystonia is a clinically and genetically heterogeneous group of movement disorders. Fifteen different types of dystonia have been described to date, of whom 14 loci have been mapped, but only seven genes identified. Several different modes of inheritance have been described, including autosomal dominant transmission with reduced penetrance (12 loci), recessive X-linked (one locus), and autosomal recessive transmission (three loci). In this study, we describe the localization of a novel form of autosomal recessive, primary focal torsion dystonia using a genomewide search in a large consanguineous Lebanese family with three affected individuals. Homozygosity mapping with 382 microsatellite markers was conducted. Linkage analysis and haplotype construction allowed us to identify a novel locus designated as DYT17, within a 20.5-Mb interval on chromosome 20. Of the 270 known genes spread on this interval, 27 candidate genes were tested and excluded as responsible for the disease. Fine mapping by identification of other dystonia families linked to chromosome 20 and sequencing of candidate genes in the refined interval is required in order to identify the causative gene in DYT17.