Baseline Lower Extremity Strength and Subsequent Decline in Functional Performance at 6‐Year Follow‐Up in Persons with Lower Extremity Peripheral Arterial Disease

OBJECTIVES: To evaluate associations between baseline lower extremity strength and decline in functional performance over 6 years of follow‐up in men and women with lower extremity peripheral arterial disease (PAD). DESIGN: Prospective observational study. SETTING: Three Chicago‐area hospitals. PARTICIPANTS: Three hundred seventy‐four men and women with PAD. MEASUREMENTS: Baseline isometric hip extension, hip flexion, knee flexion, and knee extension strength were measured using a musculoskeletal fitness evaluation chair. Usual and fastest‐paced 4‐m walking speed, 6‐minute walk, and Short Physical Performance Battery (SPPB) were assessed at baseline and annually thereafter. Analyses were adjusted for age, sex, race, ankle–brachial index (ABI), comorbidities, and other confounders. RESULTS: In women with PAD, weaker baseline hip and knee flexion strength were associated with faster average annual decline in usual‐pace 4‐m walking speed (P trend <.001 and .02, respectively) and SPPB (P trend=.02 and .01, respectively). In women, weaker hip extension strength was associated with faster decline in usual‐pace 4‐m walking speed and SPPB (P trend=.01 and <.01, respectively). There were no significant associations between baseline strength and decline in 6‐minute walk in women. There were no significant associations between any baseline strength measure and functional decline in men. CONCLUSION: Weaker baseline leg strength is associated with faster functional decline in nonendurance measures of functional performance in women with PAD but not in men with PAD.     

Carvastatin suppresses intimal thickening of rabbit carotid artery after balloon catheter injury probably through the inhibition of vascular smooth muscle cell proliferation and migration

In order to test whether a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor has an anti-atherogenic activity, the effects of carvastatin, a newly developed potent inhibitor, and pravastatin were examined on the intimal thickening of the artery after the endothelial denudation induced by balloon catheter injury. Rabbits were divided into four groups; control, pravastatin-treated (20 mg kg^-1 day^-1) and two of carvastatin-treated groups (10 or 20 mg kg^-1 day^-1     

Effects of portal vein arterialization on liver regeneration after partial hepatectomy in the rat

Although portal venous supply is considered essential to preserve hepatic integrity, in this study, effects of portal arterialization on liver regeneration were evaluated in a rat model of partial hepatectomy (PH). Ninety-six Lewis rats were randomly assigned to four groups of 24 rats each: PH only (group 1), PH with either venous or arterialized portal supply (groups 2 and 3, respectively), and PH without portal supply (group 4). Liver regeneration rate (LRR), 5-bromo-2-deoxyuridine (BrdU) labeling index, and liver biological characteristics were assessed on days 1, 2, 3, and 7. Compared with group 1, all tested rats had a marked body weight loss after surgery, and only rats in group 4 showed no signs of recovery on day 7. With maintained portal inflow (groups 1, 2, and 3), LRRs increased steadily to day-7 values of 89.2% [plusmn] 11.8%, 81.4% [plusmn] 8%, and 77.4% [plusmn] 9.4%, respectively (P = not significant), and 24-hour peak values of BrdU labeling index were 159 [plusmn] 26, 157 [plusmn] 42, and 149 [plusmn] 48, respectively (P = not significant). Conversely, rats deprived of portal supply (group 4) showed profound inhibition of these two parameters (14 [plusmn] 13; P [lt ] .01;32.1% [plusmn] 7.7%; P [lt ] .001, respectively). These results indicate that proper portal blood supply is essential to initiate and maintain liver regeneration after PH. With an equivalent portal inflow rate of either venous or arterial source, the hepatic regeneration response can be sustained. (Liver Transpl 2002;8:146-152.)     

Painful gains: missense mutations in SCN9A and idiopathic small nerve fibre neuropathy

Gain of function Nav1.7 mutations in idiopathic small fibre neuropathy Faber et al. (2012) Annals of Neurology 71: 26-39.     

Role of ATL-derived factor (ADF) in the normal and abnormal cellular activation: Involvement of dithiol related reduction

HTLV-I transformed T cells not only express a large number of interleukin-2 receptors (IL-2R/p55(Tac)), but also produce an IL-2R/Tac inducer named ATL-derived factor (ADF). We have cloned the ADF cDNA and found that ADF production in human lymphocytes can be enhanced by cellular activators such as mitogens or phorbol esters. Recombinant ADF produced by E. coli was shown to have growth-promoting activity in combination with interleukin-2 or suboptimal mitogenic stimuli on several lymphoid cells including human PBMCs, besides the originally reported IL-2R/Tac inducing activity. Homology analysis revealed an unexpected structural relationship between ADF and dithiol-reducing enzyme, thioredoxin, which had been characterized originally in prokaryotic system. Recombinant ADF also has a reducing activity, suggesting the presence of still unknown features of ADF action in vivo. The requirement of dithiol reduction in the biological activities of ADF, together with the possible involvement of ADF production in the normal and abnormal activation of human cells are discussed.     

An accelerated rabies vaccine schedule based on toll-like receptor 3 (TLR3) agonist PIKA adjuvant augments rabies virus specific antibody and T cell response in healthy adult volunteers

BackgroundRabies is a fatal disease where post-exposure prophylaxis (PEP) is crucial in preventing infection. However, deaths even after appropriate PEP, have been reported. The PIKA Rabies vaccine adjuvant is a TLR3 agonist that activates B and T cells leading to a robust immune response.MethodsWe conducted a phase I, open label, randomized study in healthy adults to assess the safety and immunogenicity of the PIKA Rabies vaccine and an accelerated vaccine regimen. Thirty-seven subjects were randomized into 3 groups: control vaccine classic regimen, PIKA vaccine classic regimen and PIKA vaccine accelerated regimen. Subjects were followed up for safety, rabies virus neutralizing antibodies (RVNA) and T cell responses.ResultsBoth the control and PIKA Rabies vaccine were well tolerated. All adverse events (AEs) were mild and self-limiting. Seventy-five percent of subjects in the PIKA accelerated regimen achieved a RVNA titer ⩾0.5 IU/mL on day 7, compared to 53.9% in the PIKA classic regimen (p = 0.411) and 16.7% in control vaccine classic regimen (p = 0.012). The PIKA rabies vaccine elicited multi-specific rabies CD4 mediated T cell response already detectable ex vivo at day 7 after vaccination and that was maintained at day 42.ConclusionThe investigational PIKA rabies vaccine was well tolerated and more immunogenic than the commercially available vaccine in healthy adults.Clinical trial registry: The study was registered with clinicaltrials.gov NCT02657161.     

单中心非瓣膜性心房颤动患者抗栓现状分析及建议

背景　非瓣膜性心房颤动（NVAF）是临床常见的心律失常疾病,脑卒中是心房颤动（简称房颤）最常见的危害之一。目前临床研究主要集中在房颤合并冠心病抗栓方案或抗栓达标情况探讨方面,对于不同用药方案之间远期安全性及有效性的研究少有报道。目的　对房颤各抗栓方案有效性及安全性、各年龄组用药方案及1年内房颤相关终点事件进行对比分析。方法　选取2018年1-10月于广东省中医院心血管科住院的NVAF患者354例为研究对象,记录患者的性别、年龄、房颤类型（阵发性、永久性、持续性、长程持续性）、合并症﹝脑卒中/短暂性脑缺血发作（TIA）、心力衰竭、高血压、糖尿病、冠心病、高脂血症﹞、肌钙蛋白T（cTnT）、卒中风险评分（CHA2DS2-VASc评分）、出血风险评分（HAS-BLED评分）及随访1年内血栓栓塞事件、出血事件、全因死亡及再入院情况。按抗栓方案不同分为无抗栓组（42例）、阿司匹林组（21例）、氯吡格雷组（51例）、联合组（25例）、华法林组（49例）、达比加群组（89例）、利伐沙班组（77例）,按年龄不同分为<65岁（60例）、65~75岁（92例）、>75岁（202例）,并比较不同抗栓方案及年龄间各项指标有无差异。结果　联合组男性占比高于无抗栓组,华法林组年龄小于氯吡格雷组,利伐沙班组阵发性房颤占比低于联合组,无抗栓组、华法林组冠心病占比低于氯吡格雷组、联合组,联合组冠心病占比高于利伐沙班组、达比加群组,联合组cTnT水平高于无抗栓组、阿司匹林组、氯吡格雷组、华法林组、利伐沙班组、达比加群组,氯吡格雷组HAS-BLED评分高于达比加群组（P<0.05）。不同抗栓方案治疗 1年内总血栓栓塞事件发生率比较,差异有统计学意义（χ2=12.404,P=0.054）,全因死亡率比较,差异无统计学意义（χ2=9.925,P=0.128）。不同抗栓方案治疗1年内总出血事件发生率比较,差异有统计学意义（χ2=14.420,P=0.019）。不同年龄段患者再入院率比较,差异有统计学意义（P<0.05）。结论　早期识别房颤并行抗栓治疗在预防血栓栓塞方面具有重要意义。抗栓首选新型口服抗凝药物（NOAC）或者华法林,NOAC在预防血栓形成及出血方面不劣于华法林,但需注意消化道出血风险。对于高龄房颤患者,抗凝更需个体化。     

Reversibility and Pathohistological Basis of Left Ventricular Remodeling in Hibernating Myocardium

The phenomenon of left ventricular (LV) remodeling with dilatation, wall thinning, and increased muscle mass has previously been reported in pigs with 7-day myocardial hibernation. This study investigated cellular and extracellular basis and reversibility of the structural LV remodeling with hibernating myocardium. Five groups of pigs were included: Group A: 7-day myocardial hibernation with a fixed coronary stenosis; Group B: 7-day hibernation with subsequent 3-week reperfusion by release of the stenosis; Group C: control group with sham operation; Group D: 24-hour myocardial hibernation to define structural mechanism of initial wall thinning in the hibernating region without confounding factors of cell loss or hypertrophy, Group E: 4-week myocardial hibernation to exclude the possibility of spontaneous regression of LV remodeling with hibernation. LAD flow decreased by 38 ± 12% (p < 0.01) with a significant decrease in systolic wall thickening at 7 days of hibernation with severe coronary stenosis (Group A). End-diastolic wall thickness decreased by 19% (p < 0.01) accompanied by a decrease in myocyte number across the wall (44%) and in myocyte density (24%), a significant increase in myocyte width (17%), a mild increase in interstitial tissues in hibernating region, and significant increases in LV diastolic volume and in LV mass at 7 days. After reperfusion (Group B), LV volume decreased, LV ejection fraction improved, and myocyte hypertrophy regressed with a decreased LV mass index without a significant change in interstitial tissue. LV remodeling progressed with further increases in LV volume, mass, and interstitial fibrosis in 4-week hibernation. In pigs undergoing 24 hours of myocardial hibernation (Group D), end-diastolic LV wall thickness decreased significantly in the hibernating region with a proportional decrease in the transmural myocyte number but without changes in myocyte width, myocyte density, or interstitial tissues. Therefore, progressive gross LV remodeling associated with hibernating myocardium is accompanied by increasing myocyte hypertrophy and interstitial fibrosis. In hibernating myocardial region, wall thinning is proportional to a decreased myocyte number across the LV wall, indicating slippage of myocytes as a preponderant mechanism for the wall thinning. Myocyte hypertrophy develops within 7 days in hibernating myocardium, causing an increase in LV mass. These changes are partially reversible after reperfusion.