Primed neutrophil infiltrations into multiple organs in child physical abuse cases: A preliminary study

Physical abuse of the elderly induces a massive primed neutrophil infiltration into the lung and liver through chemotaxis by interleukin (IL)-8, similar to cases of traumatic or hemorrhagic shock. Here, we used immunohistochemical analyses to investigate this infiltration in cases of physically abused children. In addition, we examined the expression of neutrophil elastase (NE) as the inflammatory mediator and α1-antitrypsin (AAT) as the elastase inhibitor. The number of neutrophils in the abuse cases was increased significantly in the heart, lung, liver, and kidney, compared with that of control cases. IL-8-positive cells and NE-positive cells in all organs of abuse cases were significantly greater than those in control cases. Large quantities of oxidized AAT, which fails to inactivate NE and results in tissue damage, was detected in the liver of abuse cases. Neutrophil infiltration showed positive correlation with the degree of systemic accumulation of non-fatal injuries caused by repetitive abusive behavior. Although further investigation using more autopsy samples is necessary, results of our preliminary study indicate that massive neutrophil infiltration induced by IL-8 in multiple organs is a new complementary diagnostic indicator of physical abuse in children. Moreover, the demonstration of NE-positive cells and oxidized AAT provides firm evidence of tissue damage.     

Age as a Critical Determinant of Atrial Fibrillation: A Two-sided Relationship

The incidence of atrial fibrillation (AF), the most common sustained arrhythmia and a major public health burden, increases exponentially with age. However, mechanisms underlying this long-recognized association remain incompletely understood. Experimental and human studies have demonstrated the involvement of aging in several arrhythmogenic processes, including atrial electrical and structural remodelling, disturbed calcium homeostasis, and enhanced atrial ectopic activity/increased vulnerability to re-entry induction. Given this wide range of putative mechanisms, the task of delineating the specific effects of aging responsible for AF promotion is not simple, as aging is itself associated with increasing prevalence of a host of AF-predisposing conditions, including heart failure, coronary artery disease, and hypertension. Although we usually think of old age promoting AF, there is also evidence that young age may actually have a protective effect against AF occurrence. For example, the low AF incidence among populations of young patients with significant structural congenital heart disease and substantial atrial enlargement/remodelling suggests that younger age might protect against fibrillation in the diseased atrium; efforts at understating how younger age may prevent AF might be helpful in elucidating missing mechanistic links between AF and age. The goal of this paper is to review the epidemiologic and pathophysiologic evidence regarding mechanisms underlying age-related AF. Although the therapeutic options for AF have recently improved, major gaps still remain and a better understanding of the special relationship between age and AF may be important for the identification of new targets for therapeutic innovation.     

The synergistic antitumor activity of 3-(2-nitrophenyl) propionic acid-paclitaxel nanoparticles (NPPA-PTX NPs) and anti-PD-L1 antibody inducing immunogenic cell death

Cancer immunotherapy is a strategy that is moving to the frontier of cancer treatment in the current decade. In this study, we show evidence that 3-(2-nitrophenyl) propionic acid-paclitaxel nanoparticles (NPPA-PTX NPs), act as immunogenic cell death (ICD) inducers, stimulating an antitumor response which results in synergistic antitumor activity by combining anti-PD-L1 antibody (aPD-L1) in vivo. To investigate the antitumor immunity induced by NPPA-PTX NPs, the expression of both ICD marker calreticulin (CRT) and high mobility group box 1 (HMGB1) were analyzed. In addition, the antitumor activity of NPPA-PTX NPs combined with aPD-L1 in vivo was also investigated. The immune response was also measured through quantitation of the infiltration of T cells and the secretion of pro-inflammatory cytokines. The results demonstrate that NPPA-PTX NPs induce ICD of MDA-MB-231 and 4T1 cells through upregulation of CRT and HMGB1, reactivating the antitumor immunity via recruitment of infiltrating CD3+, CD4+, CD8+ T cells, secreting IFN-γ, TNF-α, and the enhanced antitumor activity by combining with aPD-L1. These data suggest that the combined therapy has a synergistic antitumor activity and has the potential to be developed into a novel therapeutic regimen for cancer patients.     

不同时机给药对原发性痛经模型小鼠雌激素受体、缩宫素受体的影响

目的观察不同时机给药对原发性痛经模型小鼠雌激素受体(ER-α)和缩宫素受体(OTR)的影响。方法将km小鼠按体重分层随机分为:JQF动情周期给药组、JQF第4天给药组(JQF剂量均为0.218 g/kg)、元胡止痛片组(0.1 g/kg)、模型组和正常组。除正常组外每日皮下注射苯甲酸雌二醇0.2 mg/只,连续6 d。采用Western blot和Real-time PCR分别检测1周期给药和3周期连续给药对ER-α和OTR蛋白与m RNA表达的影响。结果与模型组比较,JQF动情周期给药组与第4天给药组ER-α和OTR蛋白、m RNA的表达均呈现显著下调(P<0.01)。动情周期给药组和第4天给药组组间比较无差异,3周期连续给药实验结果与1周期一致。结论不同时机给药对原发性痛经模型小鼠ER-α和OTR蛋白、m RNA表达有相同的抑制作用。     

Cardiovascular Efficacy and Safety of PCSK9 Inhibitors: Systematic Review and Meta-analysis Including the ODYSSEY OUTCOMES Trial

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are efficacious lipid-lowering agents, but more precise estimates of their effects on major adverse cardiovascular events (MACE), mortality, and safety are needed. We systematically reviewed and meta-analyzed randomized controlled trials with durations ≥ 6 months comparing MACE, mortality, and safety with PCSK9 inhibitors vs control. We searched CENTRAL, Embase, MedLine and the grey literature to November 7, 2018. From 2048 articles, we included 23 trials (n = 60,723). PCSK9 inhibitors reduced MACE (relative risk, 0.83; 95% confidence interval, 0.78-0.88), but did not clearly reduce mortality (relative risk, 0.93; 95% confidence interval, 0.85-1.02) or increase adverse events. In conclusion, PCSK9 inhibitors reduce nonfatal MACE, are well tolerated, but effects on mortality remain unclear.