Proteomics reveals potential non-neuronal cholinergic receptor-effectors in endothelial cells

Aim:

The non-neuronal acetylcholine system (NNAS) in endothelial cells participates in modulating endothelial function, vascular tone, angiogenesis and inflammation, thus plays a critical role in cardiovascular diseases. In this study, we used a proteomic approach to study potential downstream receptor-effectors of NNAS that were involved in regulating cellular function in endothelial cells.

Methods:

Human umbilical vein endothelial cells were incubated in the presence of acetylcholine, oxotremorine, pilocarpine or nicotine at the concentration of 10 μmol/L for 12 h, and the expressed proteins in the cells were separated and identified with two-dimensional electrophoresis (2-DE) and LC-MS. The protein spots with the largest changes were identified by LC-MS. Biowork software was used for database search of the peptide mass fingerprints.

Results:

Over 1200 polypeptides were reproducibly detected in 2-DE with a pH range of 3–10. Acetylcholine, oxotremorine, pilocarpine and nicotine treatment caused 16, 9, 8 and 9 protein spots, respectively, expressed differentially. Four protein spots were identified as destrin, FK506 binding protein 1A (FKBP1A), macrophage migration inhibitory factor (MIF) and profilin-1. Western blotting analyses showed that treatment of the cells with cholinergic agonists significantly decreased the expression of destrin, FKBP1A and MIF, and increased the expression of profilin-1.

Conclusion:

A set of proteins differentially expressed in endothelial cells in response to cholinergic agonists may have important implications for the downstream biological effects of NNAS.     

Changes in Early Serum Metal Ion Levels and Impact on Liver,Kidney, and Immune Markers Following Metal-on-Metal Total Hip Arthroplasty

We retrospectively studied 32 consecutive patients (32 hips) who underwent THA with a Durom large-head, MOM articulation between January 2008 and December 2010. Of the patients who underwent THA using a Trilogy metal on polyethylene prosthesis during the same period, 32 were chosen to form the Trilogy group. 32 volunteers were chosen to form the control group. At the last follow-up, serum metal ion levels, liver and kidney function and host immunologic immune responses were evaluated. The mean Co and Cr levels in the Durom group were 4.33- and 1.95-fold higher than those in the Trilogy group. CD3 +, CD4 + and CD8 + cell levels in the Durom group were significantly decreased. The INF-γ level in the Durom group was significantly higher than that in the Trilogy and control groups.     

模拟高空跳伞着陆状态下踝关节动态角速度与垂直反作用力的测定

 目的 通过模拟高空跳伞着陆训练环境测定不同高度半蹲式跳伞着陆状态下的踝关节角速度、地面垂直反作用力,为预防跳伞着陆踝部损伤提供生物力学依据。方法 募集18名健康志愿者,包括空军地勤人员9名、职业跳伞人员9名。两组受试者身高、体重的差异无统计学意义。受试者分别从30 cm和60 cm高的跳台以半蹲式跳伞着陆并腿姿势跳落到测力台上。高速摄像机记录着陆过程,测定踝关节跖屈角位移及时间、地面垂直反作用力,计算角速度,分析踝关节动态角位移、角速度、垂直作用力与不同高度的相关性。结果 30 cm高度：地勤人员组与跳伞运动员组踝关节角位移分别为25.73°±8.13°、20.05°±12.27°,垂直反作用力分别为（3 372.4±748.6） N、（5 181.5±1 726.2） N,受力时间分别为（0.049±0.015） s、（0.012±0.004） s,缓冲时间分别为（1.397±0.746） s、（1.737±0.451） s,差异均有统计学意义。60 cm高度：地勤人员组与跳伞运动员组踝关节角速度分别为（25.45±15.01） °/s、（16.51±4.18） °/s,垂直反作用力分别为（4 616.0±1124.7） N、（7 119.5±2 307.4） N,受力时间分别为（0.048±0.013） s、（0.015±0.006） s,缓冲时间分别为（0.922±0.347） s、（1.617±0.547） s,差异均有统计学意义。结论 从不同的测试高度跳下,跳伞运动员组的地面垂直反作用力大于地勤人员组,但角速度及角位移小于地勤人员组。对比地勤人员组,跳伞运动员组的受力时间短而缓冲时间更长。     

The efficacy and safety of mirabegron in treating OAB: a systematic review and meta-analysis of phase III trials

Purpose

Mirabegron, a potent and selective β3-adrenoceptor agonist, has been developed for the treatment of overactive bladder (OAB). We carried out a systematic review and meta-analysis to assess the efficacy and safety of the drug for treating OAB.

Methods

A literature review was performed to identify all published randomized double-blind, placebo-controlled phase III trials of mirabegron for the treatment of OAB. The search included the following databases: MEDLINE, EMBASE and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. A systematic review and meta-analysis of phase III trials were conducted.

Results

Four publications involving a total of 5,761 patients were used in the analysis, including four phase III RCTs that compared mirabegron with placebo. We found that mirabegron was effective in treating OAB in our meta-analysis. Co-primary efficacy end points: the mean number of incontinence episodes per 24 h (the standardized mean difference (SMD) = ?0.44, 95 % confidence interval (CI) ?0.59 to ?0.29, p < 0.00001); the mean number of micturitions per 24 h (SMD = ?0.62, 95 % CI ?0.80 to ?0.45, p < 0.00001) and key secondary efficacy end points: mean volume voided per micturition; mean number of urgency episodes per 24 h indicated that mirabegron was more effective than the placebo. Safety assessments included common treatment-emergent adverse events (TEAEs) [OR 1.10, 95 % CI 0.93–1.31, p = 0.25), hypertension, cardiac arrhythmia TEAEs, urinary retention and discontinuations due to adverse event indicated that mirabegron was well tolerated.

Conclusions

This meta-analysis indicates that mirabegron to be an effective and safe treatment for OAB symptoms with a low occurrence of side effects. It offers promise as an effective oral agent for the treatment of OAB with a distinct efficacy/tolerability balance.     

Hilus pulmonis as the center of gravity for AS thoracolumbar kyphosis

Introduction

The sagittal vertical axis (SVA) is a meaningful measurement and widely used for evaluating sagittal balance, and is considered a design standard for surgery, including most ankylosing spondylitis (AS) kyphotic deformity planning. However, recent research indicates that the C7 plumb line is actually not the center of gravity (CG) line. Therefore, whether there is a better radiological marker as the CG of the trunk for AS thoracolumbar kyphosis remains unknown. This research is to investigate a radiological marker for the CG of the trunk in lateral radiographs for AS thoracolumbar kyphosis.

Materials and methods

The center of gravity of an irregular object can be obtained by hanging or supporting it in different points and directions, and the CG will be on the point of intersection. According to this principle of mechanics, we could use the pre- and post-operative hip axis vertical lines to locate the CG of the trunk. We evaluated 38 AS-fixed thoracolumbar kyphotic patients with pedicle subtraction osteotomies. Full-length, free-standing lateral radiographs, including the spine and pelvis, were available for all patients. Pre- and post-operative radiological parameters were measured, including SVA, horizontal distance between hip axis and C7 (HDHC), horizontal distance between hip axis and T5 (HDHT5), horizontal distance between hip axis and T9 (HDHT9), and horizontal distance between hip axis and hilus pulmonis (HDHH). Pre- and post-operative radiological parameter changes were compared by paired samples t tests. The intraclass correlation coefficient (ICC) was used to determine the intra- and interobserver reliabilities of HDHH.

Results

Pre-operative SVA, HDHC, HDHT5, HDHT9, and HDHH values were, respectively, 21.1, 12.7, 3.5, ?3.8, and 2.7 cm, and their post-operative values were, respectively, 9.1, 4.2, ?2.1, ?5.6, and 0.9 cm. Changes in SVA, HDHC, HDHT5, and HDHT9 were significant (p < 0.05), while the change in HDHH was not (p > 0.05). The ICC for overall interobserver reliability was 0.958 (p < 0.001), and it was 0.963 (p < 0.001) for overall intraobserver reliability.

Conclusion

The hilus pulmonis fell approximately on the hip axis both pre- and post-operatively. It was a better marker as the center of gravity of the trunk for deformity planning for AS thoracolumbar kyphosis.     

The N‐terminal fragment of the β‐amyloid precursor protein of Alzheimer's disease (N‐APP) binds to phosphoinositide‐rich domains on the surface of hippocampal neurons

The function of the β‐amyloid precursor protein (APP) of Alzheimer's disease is poorly understood. The secreted ectodomain fragment of APP (sAPPα) can be readily cleaved to produce a small N‐terminal fragment (N‐APP) that contains heparin‐binding and metal‐binding domains and that has been found to have biological activity. In the present study, we examined whether N‐APP can bind to lipids. We found that N‐APP binds selectively to phosphoinositides (PIPs) but poorly to most other lipids. Phosphatidylinositol 4,5‐bisphosphate (PI(4,5)P₂)‐rich microdomains were identified on the extracellular surface of neurons and glia in primary hippocampal cultures. N‐APP bound to neurons and colocalized with PIPs on the cell surface. Furthermore, the binding of N‐APP to neurons increased the level of cell‐surface PI(4,5)P₂ and phosphatidylinositol 3,4,5‐trisphosphate. However, PIPs were not the principal cell‐surface binding site for N‐APP, because N‐APP binding to neurons was not inhibited by a short‐acyl‐chain PIP analogue, and N‐APP did not bind to glial cells which also possessed PI(4,5)P₂ on the cell surface. The data are explained by a model in which N‐APP binds to two distinct components on neurons, one of which is an unidentified receptor and the second of which is a PIP lipid, which binds more weakly to a distinct site within N‐APP. Our data provide further support for the idea that N‐APP may be an important mediator of APP's biological activity. © 2014 Wiley Periodicals, Inc.     

左心室血栓治疗的系统回顾及meta分析

目的 左心室血栓(left ventricular thrombus, LVT)是多种心脏疾病的并发症,血栓脱落可导致后果严重的体循环栓塞,因此及早治疗LVT极为重要。方法 本文分别从抗凝治疗、溶栓治疗、抗血小板治疗、手术治疗4方面对LVT的治疗进行文献检索。在web of science, Ovid,EMBASE,Pubmed和Cochrane数据库应用“左心室血栓”“新型口服抗凝药”“Xa因子抑制剂”,“NOAC”,“DOAC”,“达比加群”,“利伐沙班”,“依度沙班”,“阿哌沙班”“维生素K拮抗剂”和“华法林”作为主题词进行检索。共25篇文章可用于meta分析以比较新型口服抗凝剂(direct oral anticoagulant,DOAC)与维生素K拮抗剂(vitamin K antagonist,VKA)的治疗效果及不良事件的发生率,对目前可检索到的应用肝素、抗血小板药物、溶栓、手术治疗LVT的文章进行系统回顾。结果 DOAC治疗LVT的出血及卒中事件的发生率、全因死亡率低于VKA,而LVT的消失率、严重出血事件的发生率、出现全身栓塞事件的发生率两种治疗方法差异无统计学意义。...