WP1130通过抑制NLRP3炎症小体活化缓解小鼠的感染性休克

目的 探究小分子化合物WP1130抑制NLRP3炎症小体活化并缓解感染性休克的作用机制。方法 细胞生物学水平：WP1130预处理小鼠骨髓来源巨噬细胞（BMDM）或人THP-1细胞后,利用多种NLRP3炎症小体活化剂（Nigericin、ATP、MSU、胞内LPS转染）活化NLRP3炎症小体,使用poly A:T活化AIM2炎症小体,通过Western blot和ELISA检测细胞培养上清中caspase-1和IL-1β的分泌水平,确定WP1130对NLRP3炎症小体的抑制效果及其特异性。利用激光共聚焦显微镜观察Nigericin诱导的线粒体损伤情况,探究WP1130是否影响NLRP3炎症小体组装活化的上游信号。动物水平：将SPF级雄性C57BL/6小鼠随机分为3组,即空白对照组（Control组）、感染性休克组（LPS组）、WP1130治疗组（WP1130+LPS组）,ELISA检测小鼠血清和腹腔液中IL-1β、TNF-α的分泌水平。结果 WP1130可剂量依赖性的抑制多种激动剂诱导的NLRP3炎症小体活化（P<0.05）,但对非炎症小体相关炎性因子IL-6、TNF-α的分泌无显著影响（P>0.05）。此外,WP1130对AIM2炎症小体的活化无显著影响（P>0.05）。机制研究表明,WP1130并不影响NLRP3炎症小体组装活化的上游信号线粒体损伤。动物实验结果表明,相较感染性休克组（LPS组）,WP1130治疗组（WP1130+LPS组）小鼠血清和腹腔液中IL-1β的水平显著降低（P<0.05）,而TNF-α的分泌水平无统计学差异（P>0.05）。结论 WP1130能够特异性抑制NLRP3炎症小体活化并缓解LPS诱导的小鼠感染性休克。     

WP 631 and Epo B synergize in SKOV-3 human ovarian cancer cells

Combined therapy is one of the basic methods of treatment different types of cancer. It allows to reduce the side effects of each component while maximizing the therapeutic action. The aim of this study was to evaluate the impact of two new drugs: WP 631 (bisanthracycline) and epothilone B (Epo B), added in combination on the SKOV-3 human ovarian cancer cells.To assess the type of interaction between WP 631 and Epo B isobolografic analysis was applied based on the cytotoxicity of drugs determined by the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolinum bromide) assay. Apoptotic and necrotic cell levels were measured by double staining with Hoechst 33258 and propidium iodide, Annexin V-FITC staining and by using TUNEL assay.The combination of WP 631 and Epo B is more potent than drugs added alone. The quantitative analysis indicated that the major mode of cell death induced by the combination after 72 h treatment was early apoptosis, whereas drugs administered alone generated less intensive apoptosis.The present report demonstrates for the first time that WP 631 and Epo B co-administered synergize in SKOV-3 cell line (Z_ex/Z_th < 1).     

Activation of Stratification Strategies and Results of the interventions on frail patients of Healthcare Services (ASSEHS) DG Sanco Project No. 2013 12 04

To face the challenge of active and healthy ageing (AHA), European Health Systems and services should move towards proactive, anticipatory and integrated care. Health care systems thus need to personalize services, put patients at the centre of care and provide services using the adequate resources. Population health risk management is emphasized through the use of tools to stratify people with chronic diseases according to their risk. Effective screening of frailty is vital for optimizing the care of frail populations at risk. The Activation of Stratification Strategies and Results of the interventions on frail patients of Healthcare Services (ASSEHS) EU project (N° 2013 12 04) is an international effort whose aim is to bring together stratification-related professionals from Health Services, Academia and Research in the EU in order to (i) study current existing health risk stratification strategies and tools, (ii) spread their use and application on frail elderly patients, (iii) minimize deterioration of conditions and/or (iv) prevent emergency or hospital admissions. The analysis of Risk Stratification in different Health Systems will generate conclusions and risk stratification solutions, which will be transferable to a variety of regions in the future. ASSEHS is in line with Area 4 of the B3 Action Plan of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA).     

Changes to level ground transtibial amputee gait with a weighted backpack

Background

Many occupations and hobbies require the use of a weighted pack. To date there has been limited backpack gait studies performed on the amputee population. It is important that we address this knowledge gap in order to further improve individual's quality of living through changes in rehabilitation, and prosthesis development.

Methods

The study population was ten male, unilateral, traumatic, K4-level (ability for prosthetic ambulation with high impact, stress, or energy levels), transtibial amputees. Ten walking trials were collected on level ground; five with a 24.5 kg backpack and five without a backpack. Temporal–spatial parameters and kinematic and kinetic peak values for the ankle, knee, hip, pelvis, and trunk were collected and analyzed for significant differences.

Findings

Temporal–spatial parameters incurred changes that were congruent with the literature on able bodied individuals. Pelvis speeds and range of motion decreased with the pack. Knee flexion during weight acceptance increased, and was supported on the intact limb by increased eccentric knee power during weight acceptance. Hip flexion on both limbs also increased during weight acceptance while wearing the backpack.

Interpretation

The backpack load can be accommodated by people at a K4 functional level for level ground walking. At the prosthetic limb, greater deformation was found at the foot–ankle and further increases in pack weight and higher impact tasks (i.e., jogging) could lead to decreased performance for some prosthetic feet. Gait training programs should focus on removing any gait asymmetries and increasing the strength of both the hip and knee flexors.     

Inhibitory effect of aerosol WP871 on SRS-A mediated bronchoconstriction in the guinea pig in vivo

Slow-reacting substance of anaphylaxis (SRS-A) is an important factor mediating bronchoconstriction in asthma. We developed a guinea pig model for SRS-A mediated bronchoconstriction induced by antigen inhalation. Using this model, we investigated the effect of inhaled WP871, a new anti-allergic drug, on bronchoconstriction. Aerosol WP871 (0.01 and 0.033%) to some extent inhibited the antigen-induced bronchoconstriction in a dose-dependent fashion, but high-dose WP871 (0.1%) inhalation itself produced a non-specific bronchoconstriction. However, aerosol WP871 (0.033%) showed no inhibitory effect on bronchoconstriction caused by direct inhalation of leukotriene C4, a component of SRS-A. These findings indicate that aerosol WP871 does not antagonize SRS-A, but inhibits synthesis and/or release of SRS-A and has some non-specific bronchoconstrictive effect in high concentration.     

Pesticide-induced physiological alterations in certain tissues of a fish, Mystus vittatus

Effect of sublethal concentrations (1/5, 1/10 and 1/15 fractions of 96-h TL50) of thiotox, dichlorvos and carbofuran on acid, alkaline and glucose-6-phosphatase of liver, kidney and gills of Mystus vittatus have been studied. Maximum (62.79%) inhibition of alkaline phosphatase in gills after thiotox (0.00013 mg/l) treatment have been observed. At 0.000045mg/l concentrations of thiotox, a marginal (7.6%) and significant (P less than 0.01) stimulation was observed in hepatic alkaline phosphatase activity.     

Changing outcomes and treatment strategies for wire induced coronary perforations in the era of bivalirudin use

Objectives : The objective of this study is to analyze the clinical outcomes and treatment strategies of coronary wire perforations (WPs) in the era of heparin use compared to the era of bivalirudin use. Background : Percutaneous coronary intervention (PCI) advances have led to progressive decrease in complications. Therefore, complex coronary lesions such as chronic total occlusions and calcified lesions are being attempted with stiff/hydrophilic wires with resultant higher incidence of coronary WP. Methods : A single‐center retrospective data analysis of coronary perforation (CP) for the last 4 years with review of coronary angiograms was done and WPs were identified. A simple classification scheme based on angiographic appearance of CP was made: Type I (“myocardial stain,” with no frank dye extravasation) and type II (“myocardial fan,” with dye extravasation to pericardial cavity or cardiac chambers). Results : Overall incidence of CP was 0.49% (82/16,859). Of these 50 (61%) were caused by WP; 30 occurred with heparin use (Group A) and 20 with bivalirudin use (Group B). WPs always occurred in type B₂/C lesions (100%) and commonly with use of hydrophilic guidewires (70%). Major adverse cardiac events and cardiac tamponade were frequent in group A (50%) and none in group B (0%); P < 0.01. All WP in group B responded to stopping anticoagulation and prolonged balloon inflation, while group A type II perforations frequently required additional interventions (pericardiocentesis, coil embolization). Conclusions : Cardiac tamponade and major adverse cardiac events from WPs were less frequent with bivalirudin use compared to heparin use. This beneficial effect of bivalirudin may be explained on the basis of its short half‐life and reversible thrombin inhibition property. Therefore, bivalirudin may offer a safer alternative for anticoagulation in complex PCI. © 2009 Wiley‐Liss, Inc.     

医院流程再造及临床路径实施中的量化研究

本文通过对医院流程化管理及临床路径研究过程中影响或贯穿整个过程的信息,提出精确化数据化定量分析,通过对个别流程的数据收集,利用计算机软件模拟,以达到揭示、改进流程瓶颈的目的。     

The 4′-O-benzylated doxorubicin analog WP744 overcomes resistance mediated by P-glycoprotein,multidrug resistance protein and breast cancer resistance protein in cell lines and acute myeloid leukemia cells

Summary Background: The synthetic 4’-O-benzylated doxorubicin analog WP744 was designed to abrogate transport by the multidrug resistance (MDR)-associated ATP-binding cassette (ABC) proteins P-glycoprotein (Pgp) and multidrug resistance protein (MRP-1). We compared its uptake and cytotoxicity with those of doxorubicin and daunorubicin in cell lines overexpressing Pgp, MRP-1 or breast cancer resistance protein (BCRP) and in acute myeloid leukemia (AML) cells. Methods: Cellular uptake was studied by flow cytometry and cytotoxicity in 96-h 96-well cultures in cell lines overexpressing Pgp, MRP-1 or wild type (BCRP^R482) or mutant (BCRP^R482T, BCRP^R482G) BCRP and in pre-treatment AML marrow cells. Results: Uptake and cytotoxicity of WP744 were consistently greater than those of doxorubicin and daunorubicin at equimolar concentrations in all cell lines studied and in AML cells. Conclusion: WP744 overcomes transport by Pgp, MRP-1 and BCRP in cell lines and AML cells and is a promising agent for clinical development in AML and other malignancies with broad-spectrum multidrug resistance.