单纯肥胖者与代谢综合征患者血管内皮功能的比较

目的:比较单纯肥胖者与代谢综合征患者的血管内皮功能。方法:观察对象来自石家庄市2000-09/2001-06参加社区健康体检者。①体质量指数≥25kg/m2的超重/肥胖者中,单纯肥胖组295例,代谢综合征组219例,另选172例体质量指数<25kg/m2的健康人作为对照。②将肥胖者按体质量指数分为轻度肥胖(25～29.9kg/m2)和重度肥胖(≥30kg/m2),按腰围分为腹部脂肪轻度堆积(男<104cm,女<88cm)和重度堆积(男≥104cm,女≥88cm)。③血管内皮舒张功能测定:所有受试者采用NAS-1000HF彩超诊断系统测定反应性充血时及含服硝酸甘油后肱动脉内径的变化。结果:686例受试者全部进入结果分析。①单纯肥胖组和代谢综合征组体质量指数、腰围、臀围和腰臀比均高于对照组(P<0.01～0.001),其中体质量指数和臀围在男女间比较差异不显著,腰围和腰臀比男性高于女性(P<0.05),而男性代谢综合征组又高于男性单纯肥胖组(P<0.05)。②血管内皮舒张功能检测显示,反应性充血时,单纯肥胖组和代谢综合征组相对于基础血管内径变化的百分率均低于对照组[(7.79±3.93)%,(5.54±4.46)%,(11.25±3.98)%,P<0.05～0.01];代谢综合征组男性低于单纯肥胖组男性(P<0.05);男性代谢综合征组重度肥胖者低于轻度肥胖者(P<0.05);单纯肥胖组男性重度脂肪堆积低于男性轻度脂肪堆积者(P<0.05),代谢综合征组无论男女,重度脂肪堆积均低于轻度脂肪堆积者(P<0.05)。结论:①单纯肥胖者已存在血管内皮功能异常,而代谢综合征患者中内皮功能损伤程度更显著,并且与腹部脂肪堆积密切相关。②代谢综合征患者中男性血管内皮功能损伤较女性更明显。     

Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology

Neurofibrillary tangles (NFTs) are composed of abnormal aggregates of the cytoskeletal protein tau. Together with amyloid beta (Abeta) plaques and neuronal and synaptic loss, NFTs constitute the primary pathological hallmarks of Alzheimer disease (AD). Recent evidence also suggests that caspases are activated early in the progression of AD and may play a role in neuronal loss and NFT pathology. Here we demonstrate that tau is cleaved at D421 (DeltaTau) by executioner caspases. Following caspase-cleavage, DeltaTau facilitates nucleation-dependent filament formation and readily adopts a conformational change recognized by the early pathological tau marker MC1. DeltaTau can be phosphorylated by glycogen synthase kinase-3beta and subsequently recognized by the NFT antibody PHF-1. In transgenic mice and AD brains, DeltaTau associates with both early and late markers of NFTs and is correlated with cognitive decline. Additionally, DeltaTau colocalizes with Abeta(1-42) and is induced by Abeta(1-42) in vitro. Collectively, our data imply that Abeta accumulation triggers caspase activation, leading to caspase-cleavage of tau, and that this is an early event that may precede hyperphosphorylation in the evolution of AD tangle pathology. These results suggest that therapeutics aimed at inhibiting tau caspase-cleavage may prove beneficial not only in preventing NFT formation, but also in slowing cognitive decline.     

Melatonin promotes survival of nonvascularized fat grafts and enhances the viability and migration of human adipose‐derived stem cells via down‐regulation of acute inflammatory cytokines

Nonvascularized fat grafting is a valuable technique for soft tissue reconstruction but poor survival of fat in the host environment remains a problem. A process known as cell‐assisted transfer is used to enhance fat graft retention by adding stromal vascular fraction, an adipose‐derived stem cell (ASC) rich content to lipoaspirate. We have recently shown that the use of melatonin, a reactive oxygen species scavenger, protects human ASCs from hydrogen peroxide‐induced oxidative stress and cell death in vitro but its role as a pharmacological adjunct in clinical fat grafting has not been studied. Herein, the effect of melatonin was examined on human ASCs in vitro using survival and functional assays including the MTT assay, CellTox Green assay, monolayer scratch assay as well as a human cytokine chemoluminescence, and tumour necrosis factor‐α assay. Further, the effect of melatonin‐treated fat grafts was tested in vivo with a murine model. Haematoxylin and eosin staining, perilipin and CD31 immunostaining were performed with morphometric analysis of adipose tissue. The results demonstrate that, in vitro, the addition of melatonin to ASCs significantly improved their cell‐viability, promoted cell migration and preserved membrane integrity as compared to controls. In addition, it induced a potent anti‐inflammatory response by downregulating acute inflammatory cytokines particularly tumour necrosis factor‐α. For the first time, it is demonstrated in vivo that melatonin enhances fat graft volume retention by reducing inflammation and increasing the percentage of adipose volume within fat grafts with comparable volumes to that of cell‐assisted lipotransfer. Based on these novel findings, melatonin may be a useful pharmacological adjunct in clinical fat grafting.     

Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage: an updated systemic review and meta-analysis

Introduction  

Previous meta-analyses of magnesium sulphate infusion in the treatment of aneurysmal subarachnoid hemorrhage (SAH) have become outdated due to recently published clinical trials. Our aim was thus to perform an up-to-date systemic review and meta-analysis of published data on the use of magnesium sulphate infusion in aneurysmal SAH patients.     

The evidence for the use of recombinant factor VIIa in massive bleeding: development of a transfusion policy framework

summary .  A review of the recent randomized control trial evidence of the use of recombinant factor VIIa (rFVIIa) in massive bleeding. rFVIIa is a recombinant genetically engineered clotting factor that has been used for the management of haemophilia patients with inhibitors. There has been increasing use in patients with massive bleeding, even when there is no underlying coagulation disorder present. In November 2006, the Canadian National Advisory Committee on Blood and Blood Products engaged in a consultation and review process with several leading Canadian experts to review and discuss the current evidence up to November 2006. There is little evidence to support the routine use of rFVIIa in massive bleeding on review of 13 randomized controlled trials. rFVIIa should only be considered as part of a transfusion policy framework for massive bleeding after all other transfusion and supportive measures are considered. An example of a policy framework is presented.     

Oncoproteomics of hepatocellular carcinoma: from cancer markers' discovery to functional pathways.

Hepatocellular carcinoma (HCC) is a heterogeneous cancer with no promising treatment and remains one of the most prevailing and lethal malignancies in the world. Researchers in many biological areas now routinely identify and characterize protein markers by a mass spectrometry-based proteomic approach, a method that has been commonly used to discover diagnostic biomarkers for cancer detection. The proteomic research platforms span from the classical two-dimensional polyacrylamide gel electrophoresis (2-DE) to the latest Protein Chip or array technology, which are often integrated with the MALDI (matrix-assisted laser-desorption ionization), SELDI (surface-enhanced laser desorption/ionization) or tandem mass spectrometry (MS/MS). New advances on quantitative proteomic analysis (e.g. SILAC, ICAT, and ITRAQ) and multidimensional protein identification technology (MudPIT) have greatly enhanced the capability of proteomic methods to study the expressions, modifications and functions of protein markers. The present article reviews the latest proteomic development and discovery of biomarkers in HCC that may provide insights into the underlying mechanisms of hepatocarcinogenesis and the readiness of biomarkers for clinical uses.     

Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates

RNAi is a powerful method for suppressing gene expression that has tremendous potential for therapeutic applications. However, because endogenous RNAi plays a role in normal cellular functions, delivery and expression of siRNAs must be balanced with safety. Here we report successful stable expression in primates of siRNAs directed to chemokine (c-c motif) receptor 5 (CCR5) introduced through CD34+ hematopoietic stem/progenitor cell transplant. After hematopoietic reconstitution, to date 14 months after transplant, we observe stably marked lymphocytes expressing siRNAs and consistent down-regulation of chemokine (c-c motif) receptor 5 expression. The marked cells are less susceptible to simian immunodeficiency virus infection ex vivo. These studies provide a successful demonstration that siRNAs can be used together with hematopoietic stem cell transplant to stably modulate gene expression in primates and potentially treat blood diseases such as HIV-1.     

Desmopressin induces endothelial P-selectin expression and leukocyte rolling in postcapillary venules

Desmopressin, (DDAVP; 1-desamino-8-D-arginine vasopressin) increases the release and activity of von Willebrand factor (vWF); however, its effects on the other major constituent of endothelial Weibel-Palade bodies, P-selectin, has not been investigated. DDAVP-induced P-selectin expression may explain DDAVP's efficacy in bleeding disorders in which vWF levels are normal. Therefore, the objective of this study is to assess the effect of DDAVP on P-selectin expression on endothelial cells of postcapillary venules in vivo and on human umbilical vein endothelium in vitro, and to determine whether DDAVP has direct effects on leukocyte behavior in postcapillary venules. DDAVP (0.1 and 1.0 microgram/mL) induced a significant but transient increase in P- selectin expression on human umbilical vein endothelial cells as well as on rat and human platelets. Immunohistochemical analysis of rat postcapillary venules showed that in contrast to saline, DDAVP injection (1 microgram/kg, intravenous) induced significant endothelial P-selectin expression. DDAVP administration also induced a rapid and significant increase in leukocyte rolling in rat mesenteric venules in vivo. This response was entirely dependent on P-selectin, as an anti-P- selectin antibody rapidly reversed the DDAVP-induced increase in leukocyte rolling. DDAVP induced leukocyte rolling in medium (20 to 40 microns) and large (> 40 microns), but not small (< 20 microns), postcapillary venules. In animals that were treated with DDAVP, there was a steady and significant increase in leukocyte adhesion. This study shows that DDAVP can directly induce P-selectin expression on endothelium in vitro and in vivo and that the latter response is capable of supporting prolonged leukocyte rolling in rat postcapillary venules.