培多普利抑制心肌重构的动物实验研究

目的:本研究采用Wistar大鼠冠脉结扎心梗后心衰模型,以培多普利作为观察药物,探讨肾素血管紧张素系统(RAS)在心肌重构中的地位和血管紧张素转换酶抑制剂(ACEI)对心肌重构的干预作用.方法:将Wistar大鼠分为梗塞组、梗塞治疗组和假术组.梗塞组结扎左冠状动脉,梗塞治疗组在前者基础上用培多普利治疗2mg/kg/天,假手术组不结扎左冠状动脉.三月后测血流动力学参数,血液及组织内血管紧张素Ⅱ(AngⅡ)含量、血管紧张素转换酶(ACE)活性和观察组织形态学变化.结果:三月后,与假术组相比,梗塞组出现了克血性心衰(DHF)的血流动力学改变;心肌局部AngⅡ含量、ACE活性显著差增高,但血液AngⅡ含量和ACE活性无明显改变;心脏重量指数显著上升;残存心肌细胞肥大,间质增生,胶原蛋白沉积.培多普利可以改善血流动力学参数,减少AngⅡ的生成、抑制ACE活性并减轻心肌细胞肥大、间质增生和胶原蛋白沉积的程度.结论:心肌组织局部的RAS参与了心肌重构的病理生理过程,血液RAS与心肌重构无显著相关,ACEI可以有效地防治心肌重构及心衰.     

AAV8 transduction capacity is reduced by prior exposure to endosome-like pH conditions

Adeno-associated virus(AAV) is an essential instrument in the neuroscientist's toolkit, which allows delivery of DNA to provide labeling with fluorescent proteins or genetic instructions to regulate gene expression. In the field of neural regeneration, the transduction of neurons enables the observation and regulation of axon growth and regeneration, and in the future will likely be a mechanism for delivering molecular therapies to promote sprouting and regeneration after central nervous system injury. Traditional formulations of AAV preparations permit efficient viral transduction under physiologic conditions, but an improved understanding of the mechanistic limitations of AAV transduction may facilitate production of more resilient AAV strains for investigative and therapeutic purposes. We studied AAV transduction in the context of prior exposure of AAV serotype 8(AAV8) to environmental p H within the range encountered during endosomal endocytosis(p H 7.4 to p H 4.4), during which low p H-triggered structural and autoproteolytic changes to the viral capsid are believed to be necessary for endosome escape and virus uncoating. Due to the fundamental nature of these processes, we hypothesized that premature exposure of AAV8 particles to acidic p H would decrease viral transduction of HT1080 cells in vitro, as measured by fluorescent reporter gene expression using high-content imaging analysis. We found that increasingly acidic incubation conditions were associated with concomitant reductions in transduction efficiency, and that quantitative levels of reporter gene expression in transduced cells were similarly decreased. The biggest decrease in transduction occurred between p H 7.4 and p H 6.4, suggesting the possible co-occurrence of a p H-associated event and viral inactivation within that range. Taken together, these findings indicate that exposure of AAV8 to acidic p H for as little as 1 hour is deleterious to transduction ability. Future studies are necessary to understand the p H-associated causative mechanisms involved. This study was approved by the University of Miami Institutional Animal Care and Use Committee, USA(Protocol #18-108-LF) on July 12, 2018.     

Massive Plasmodium falciparum visceral sequestration: a cause of maternal death in Africa

Sequestration of Plasmodium falciparum-infected erythrocytes (PfIE) in the capillaries of the central nervous system (CNS) is the pathognomonic feature of cerebral malaria, a condition frequently leading to death. Sequestration of PfIE in the placental intervillous spaces is the characteristic feature of malaria in pregnancy and is associated with low birthweight and prematurity. Although both patterns of sequestration are thought to result from the expression of different parasite proteins involved in cytoadhesion to human receptors, scant information exists on whether both conditions can coexist and whether this can lead to death. We conducted a prospective autopsy study including all consecutive pregnancy-related deaths in a tertiary-level referral hospital in Maputo, Mozambique, between October 2002 and December 2006. Extensive sampling of all major viscera was performed. All cases showing parasites in any of the viscera were included in the analysis. From 317 complete autopsies PfIEs were identified in ten women (3.2%). All cases showed massive accumulation of PfIE in small capillaries of the CNS but also in most visceral capillaries (heart, lung, kidney, uterus). Placental tissue, available in four cases, showed a massive accumulation of maternal PfIE in the intervillous space. Coma (six women) and dyspnoea (five women) were the most frequent presenting clinical symptoms. In conclusion, massive visceral sequestration of PfIE with significant involvement of the CNS is an infrequent but definite direct cause of maternal death in endemic areas of Africa. The PfIE sequestered in cerebral capillaries and the placenta coexist in these fatal cases.     

陈其华从痰辨治癌痛临床经验

介绍陈其华教授从痰辨治癌痛的临床经验.我国恶性肿瘤的发生率及病死率逐年升高,癌痛是恶性肿瘤中晚期最多见,同时也是严重降低患者生活质量的临床表现之一.虽然现阶段临床应用"三阶梯止痛方案"能够在短时间缓解癌痛程度,但因患者耐受、相关医疗法规以及人为性因素等的影响使恶性肿瘤癌痛的远期控制难以取得满意效果.湖南中医药大学第一附属医院陈其华教授结合自身数十年的临床实践经验提出"肿瘤痰证学说",认为癌痛主要为痰导致的"不通则痛""不荣则痛",临证时治疗癌痛应以"消痰止痛"为原则,同时谨遵陈实功"内外合参"学术思想,注重整体与局部辨证,权衡疾病虚实主次,参以引经药物直达病所,每获良效,另举验案以飨同道.     

Associations of 25‐Hydroxyvitamin D and 1,25‐Dihydroxyvitamin D With Bone Mineral Density,Bone Mineral Density Change,and Incident Nonvertebral Fracture

Relationships between 1,25‐dihydroxyvitamin D (1,25(OH)₂D) and skeletal outcomes are uncertain. We examined the associations of 1,25(OH)₂D with bone mineral density (BMD), BMD change, and incident non‐vertebral fractures in a cohort of older men and compared them with those of 25‐hydroxyvitamin D (25OHD). The study population included 1000 men (aged 74.6 ± 6.2 years) in the Osteoporotic Fractures in Men (MrOS) study, of which 537 men had longitudinal dual‐energy X‐ray absorptiometry (DXA) data (4.5 years of follow‐up). A case‐cohort design and Cox proportional hazards models were used to test the association between vitamin D metabolite levels and incident nonvertebral and hip fractures. Linear regression models were used to estimate the association between vitamin D measures and baseline BMD and BMD change. Interactions between 25OHD and 1,25(OH)₂D were tested for each outcome. Over an average follow‐up of 5.1 years, 432 men experienced incident nonvertebral fractures, including 81 hip fractures. Higher 25OHD was associated with higher baseline BMD, slower BMD loss, and lower hip fracture risk. Conversely, men with higher 1,25(OH)₂D had lower baseline BMD. 1,25(OH)₂D was not associated with BMD loss or nonvertebral fracture. Compared with higher levels of calcitriol, the risk of hip fracture was higher in men with the lowest 1,25(OH)₂D levels (8.70 to 51.60 pg/mL) after adjustment for baseline hip BMD (hazard ratio [HR] = 1.99, 95% confidence interval [CI] 1.19–3.33). Adjustment of 1,25(OH)₂D data for 25OHD (and vice versa) had little effect on the associations observed but did attenuate the hip fracture association of both vitamin D metabolites. In older men, higher 1,25(OH)₂D was associated with lower baseline BMD but was not related to the rate of bone loss or nonvertebral fracture risk. However, with BMD adjustment, a protective association for hip fracture was found with higher 1,25(OH)₂D. The associations of 25OHD with skeletal outcomes were generally stronger than those for 1,25(OH)₂D. These results do not support the hypothesis that measures of 1,25(OH)₂D improve the ability to predict adverse skeletal outcomes when 25OHD measures are available. © 2015 American Society for Bone and Mineral Research.     

Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays

Tumoral cells in Hodgkin lymphoma (HL) display an increased growth fraction and diminished apoptosis, implying a profound disturbance of the cell cycle and apoptosis regulation. However, limitations of molecular techniques have prevented the analysis of the tumor suppressor pathways and cell-cycle checkpoints. Tissue microarray (TMA) is a powerful tool for analyzing a large number of molecular variables in a large series of tumors, although the feasibility of this technique has not yet been demonstrated in heterogeneous tumors. The expression of 29 genes regulating the cell cycle and apoptosis were analyzed by immunohistochemistry and in situ hybridization in 288 HL biopsies using TMA. The sensitivity of the technique was validated by comparing the results with those obtained in standard tissue sections. The results revealed multiple alterations in different pathways and checkpoints, including G1/S and G2/M transition and apoptosis. Striking findings were the overexpression of cyclin E, CDK2, CDK6, STAT3, Hdm2, Bcl2, Bcl-X(L), survivin, and NF-kappaB proteins. A multiparametric analysis identified proteins associated with increased growth fraction (Hdm2, p53, p21, Rb, cyclins A, B1, D3, and E, CDK2, CDK6, SKP2, Bcl-X(L), survivin, STAT1, and STAT3), and proteins associated with apoptosis (NF-kappaB, STAT1, and RB). The analysis also demonstrated that Epstein-Barr virus (EBV)-positive cases displayed a characteristic profile, confirming the pathogenic role of EBV in HL. Survival probability depends on multiple biologic factors, including overexpression of Bcl2, p53, Bax, Bcl-X(L), MIB1, and apoptotic index. In conclusion, Hodgkin and Reed-Sternberg cells harbor concurrent and overlapping alterations in the major tumor suppressor pathways and cell-cycle checkpoints. This appears to determine the viability of the tumoral cells and the clinical outcome.     

Vitamin D Receptor Genetic Polymorphism Is Significantly Associated With Decreased Risk of Hypertension in a Chinese Han Population

The aim of this study was to investigate the association of vitamin D receptor (VDR) gene polymorphism and hypertension in a Chinese Han population. The authors genotyped 3 tagSNPs (rs11574129, rs2228570, and rs739837) of the VDR gene using TaqMan assays in a case‐control study including 2409 patients with hypertension and 3063 controls. The results showed that rs2228570 presented statistical correlations with decreased risk of male hypertension after adjustment for confounding factors, odds ratios (ORs) and 95% confidence intervals (CIs) of additive, dominant, and recessive models were 0.828 (0.74–0.927), 0.75 (0.631–0.89), and 0.816 (0.67–0.995), and P values were .001, .001, and .044, respectively. Significant associations were found in the smoking population and ORs (95% CIs) of additive and dominant models were 0.81 (0.69–0.952) and 0.71 (0.552–0.913) (P values .011 and .008), respectively, after adjustment for covariates. Quantitative trait analysis indicated that the untreated cases with TT genotype of rs2228570 showed higher systolic blood pressure compared with the TC/CC genotype (P=.015). Our findings suggest that VDR genetic polymorphism rs2228570 is significantly associated with the decreased risk of hypertension in Chinese men and smokers.     

Comparison of Carbon Supports in Anion Exchange Membrane Fuel Cells

Anion exchange membrane fuel cells (AEMFCs) are attractive alternatives to proton exchange membrane fuel cells due to their ability to employ nonprecious metals as catalysts, reducing the cost of AEMFC devices. This paper presents an experimental exploration of the carbon support material effects on AEMFC performance. The silver (Ag) nanoparticles supported on three types of carbon materials including acetylene carbon (AC), carbon black (CB), and multiwalled carbon nanotube (MWCNT)—Ag/AC, Ag/CB, and Ag/MWCNT, respectively—were prepared using the wet impregnation method. The silver loading in the catalysts was designed as 60 wt.% during the synthesizing process, which was examined using thermogravimetric analysis. The elemental composition of the prepared Ag/AC, Ag/CB, and Ag/MWCNT catalysts was confirmed using X-ray diffraction analysis. The nanoparticle size of Ag attached on carbon particles or carbon nanotubes, as observed by scanning electron microscopy (SEM), was around 50 nm. For the performance tests of a single AEMFC, the obtained results indicate that the maximum power density using Ag/MWCNT as the cathode catalyst (356.5 mW·cm⁻²) was higher than that using Ag/AC (329.3 mW·cm⁻²) and Ag/CB (256.6 mW·cm⁻²). The better cell performance obtained using a MWCNT support can be ascribed to the higher electrical conductivity and the larger electrochemical active surface area calculated from cyclic voltammetry measurements.