Icosapent ethyl for dyslipidaemia in patients with diabetes and coronary artery disease: Act now to reduce it

The risk of atherosclerotic cardiovascular disease (ASCVD) can be significantly reduced in patients with diabetes who are undergoing low-density lipoprotein cholesterol-reducing therapies. However, the elevated triglyceride levels seen in diabetic dyslipidaemia can contribute to residual ASCVD risk. Icosapent ethyl (IPE) has recently been shown to substantially reduce major cardiovascular events in high-risk patients with hypertriglyceridaemia who are undergoing statin therapy. In a real-world study of patients with diabetes and acute coronary syndrome (ACS), 17.1% were found to be eligible for treatment with IPE based on Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) criteria. A significant proportion of patients with diabetes and ACS merit receiving IPE therapy, with important implications for evolving clinical practice guidelines and best standard of care.     

Neoadjuvant chemoradiotherapy for patients with high-risk extremity and truncal sarcomas: A 10-year single institution retrospective study

BackgroundPatients with large, high-grade extremity and truncal soft tissue sarcomas (STS) are at considerable risk for recurrence. A regimen of pre-operative chemotherapy consisting of mesna, adriamycin, ifosfamide and dacarbazine (MAID), interdigitated with radiotherapy (RT), followed by resection and post-operative chemotherapy with or without RT, has demonstrated high rates of local and distant control. The goal of this study is to assess outcomes in a recent cohort of patients treated on this regimen.MethodsWe retrospectively reviewed records of 66 consecutive patients with STS of the extremity or trunk who were treated with the aforementioned regimen from May 2000 to April 2011. Clinicopathologic characteristics and patient outcomes were analysed.ResultsSixty-six patients were analysed and were equally divided between grade 2 and 3 tumours. Margins were negative in 57 (89%) patients and positive in seven (11%) patients. At a median follow-up of 46 months, there were six (9%) locoregional and 20 (30%) distant recurrences. The locoregional and distant 5-year recurrence-free survival (RFS) rates were 91% and 64%, respectively. The 5-year overall (OS) and disease-specific survival rates were 86% and 89%, respectively. There were no treatment-related deaths or secondary myelodysplasias. Thirty-four (52%) patients had grade 3 or 4 acute haematologic chemotherapy-related toxicity. There were no statistically significant predictors of OS or RFS.ConclusionsFor a contemporary cohort of patients with high-risk extremity and truncal STS, a regimen of neoadjuvant chemoradiotherapy and surgery continues to result in high rates of survival with tolerable short- and long-term toxicity.     

脑源性神经营养因子对周围神经修复与再生的促进效应

目的:观察脑源性神经营养因子对周围神经损伤修复与再生的作用。方法:实验于2000-06/2002-08在大连医科大学神经解剖研究室完成。取健康SD大鼠24只,体质量180～200g,雌雄各半。腹腔内麻醉后,暴露左、右侧坐骨神经,在距梨状肌出口侧1.0cm处切除5mm长的坐骨神经,两断端用硅胶管桥接形成神经再生室。局部用药右侧再生室内注入0.5mL脑源性神经营养因子作为实验组,左侧再生室内注入生理盐水0.5mL作为对照组,观察局部应用脑源性神经营养因子对神经再生的影响。实验评估:术后9周对动物进行损伤肢体行为功能评价、小腿三头肌湿重测定、轴突计算机图像分析轴突数目及直径。结果:纳入SD大鼠24只,均进入结果分析。①各组动物精神状态及行为变化:对照组大鼠第3～4周时出现脱趾、溃疡加剧至第9周仍无愈合及减轻迹象。实验组于第4～5周时溃疡相继愈合,至9周时基本恢复正常。②小腿三头肌湿重测定:实验组明显重于对照组,差异显著[(0.677±0.112),(0.546±0.155)g,P<0.01]。③轴突计算机图像分析轴突计数及直径:实验组均高于对照组,差异显著[轴突数目:(2.361±0.180)×103,(1.757±0.113)×103个,P<0.01;轴突直径:(0.800±0.120),(0.530±0.170)μm,P<0.01]。结论:局部应用脑源性神经营养因子对周围神经再生有明显的促进作用。     

The ontogeny of key endoplasmic reticulum proteins in human embryonic and fetal red blood cells

Recently, using immunohistochemical methods, we surprisingly found that endoplasmic reticulum glucose-6-phosphatase is present in human embryonic and fetal red blood cells (RBCs) but not in adult RBCs. The fact that an endoplasmic reticulum enzyme, whose major site of expression in adults is the liver, is present in human embryonic and fetal RBCs, particularly nucleated cells, indicated that it would be sensible to determine whether these cells also contain other endoplasmic reticulum enzyme systems normally found in adult liver. Therefore, we have studied the expression of other endoplasmic reticulum proteins and found that human embryonic and fetal RBC precursors contain other protein components of the glucose-6- phosphatase system, ie, the phosphate and glucose transport proteins as well as other enzymes (eg, uridine diphosphate- glucuronosyltransferases, cytochrome P450 isozymes, nicotinamide adenine dinucleotide phosphate cytochrome P450 oxidoreductase, and prostaglandin H synthase). In addition, we also found the predominantly cytosolic markers 15-hydroxyprostaglandin dehydrogenase, prostaglandins PGE2 and 13,14-dihydro-15-keto-PGE2. The expression of key enzymes that control glucose production, detoxification of endobiotics and xenobiotics, and the regulation of prostaglandin levels in embryonic and early fetal RBCs means that these cells may have an important role in protecting the developing conceptus before it establishes an efficient circulation and before all tissues fully express their normal complement of these enzymes.     

In vitro characterization of chicken bone marrow-derived dendritic cells following infection with very virulent infectious bursal disease virus

Infectious bursal disease is caused by infectious bursal disease virus (IBDV), an immunosuppressive virus that targets immune cells such as B cells and macrophages. However, the involvement of dendritic cells (DCs) during IBDV infection is not well understood. In this study the in vitro effects of live and inactivated very virulent IBDV (vvIBDV) UPM0081 on bone marrow-derived DCs (BM-DC) were characterized and compared with BM-DC treated with lipopolysaccharide (LPS). Morphologically, BM-DC treated with LPS and vvIBDV showed stellate shape when compared to immature BM-DC. In addition, LPS-treated and both live and inactivated vvIBDV-infected BM-DC expressed high levels of double positive CD86 and major histocompatibility complex class II antigens (>20%). vvIBDV-infected BM-DC showed significantly higher numbers of apoptotic cells compared to LPS. Replication of vvIBDV was detected in the infected BM-DC as evidenced by the increased expression of VP3 and VP4 IBDV antigens based on flow cytometry, real-time polymerase chain reaction and immunofluorescence tests. Levels of different immune-related genes such as interleukin-1β (IL-1β), CXCLi2 (IL-8), IL-18, interferon gamma (IFN-γ, IL-12α, CCR7 and Toll-like receptor-3 (TLR3) were measured after LPS and vvIBDV treatments. However, marked differences were noticed in the onset and intensity of the gene expression between these two treatment groups. LPS was far more potent than live and inactivated vvIBDV in inducing the expression of IL-1β, IL-18 and CCR7 while expression of Th1-like cytokines, IFN-γ and IL-12α were significantly increased in the live vvIBDV treatment group. Meanwhile, the expression of TLR3 was increased in live vvIBDV-infected BM-DC as compared to control. Inactivated vvIBDV-treated BM-DC failed to stimulate IFN-γ, IL-12α and TLR3 expressions. This study suggested that BM-DC may serve as another target cells during IBDV infection which require further confirmation via in vivo studies.     

Higher serum free testosterone is associated with better cognitive function in older men, while total testosterone is not. The Health In Men Study

Objective To determine the relationship of total and free serum testosterone to cognitive performance in older men. Design Cross‐sectional study of a population‐based sample. Participants A total of 2932 men aged 70–89 years. Measurements Cognitive function was assessed using the Standardized Mini‐Mental State Examination (SMMSE). Early morning sera were assayed for total testosterone, SHBG and LH. Free testosterone was calculated using the Vermeulen method. Results There were weak positive correlations between SMMSE score and serum free testosterone (Spearman's rho = 0·06, P = 0·001) and total testosterone (r = 0·04, P = 0·027), and a weak negative correlation with LH (r = ?0·07, P < 0·001). Men with SMMSE scores in the top quintile had higher serum free testosterone compared with those in the lowest quintile [median (interquartile range, IQR): 278 (228–335) vs. 262 (212–320) pmol/l, P = 0·003], but similar total testosterone [15·2 (11·9–18·8) vs. 14·8 (11·6–18·3) nmol/l, P = 0·118]. Increasing age, non‐English‐speaking background, lower educational attainment, presence of clinically significant depressive symptoms, and cardiovascular morbidity were associated with the lowest cognitive performance quintile. After their effects were taken into account in a multivariate analysis, serum free testosterone ≥ 210 pmol/l was associated with reduced likelihood of poor cognitive performance on the SMMSE [odds ratio (OR) 0·71, 95% confidence interval (CI) 0·52–0·97]. Conclusions In community‐dwelling older men, serum free testosterone ≥ 210 pmol/l is associated with better cognitive performance. In this context, calculated free testosterone seems to be a more informative measure of androgen status than total testosterone. Studies examining the contribution of androgens to age‐related cognitive decline should incorporate an assessment of free testosterone concentration.     

Protease inhibitors differentially regulate tumor necrosis factor- induced apoptosis, nuclear factor-kappa B activation, cytotoxicity, and differentiation

We investigated the effect of various protease inhibitors on several tumor necrosis factor (TNF)-mediated cellular responses. Treatment of a human myelogenous leukemia cell line, ML-1a, with TNF in the presence of cycloheximide triggers endonucleolytic activity and apoptotic cell death within 90 minutes. The general serine protease inhibitor diisopropyl fluorophosphate (DFP) and the chymotrypsin-like protease inhibitor N-tosyl-L-lysyl chloromethyl ketone (TPCK) completely abrogated TNF-induced DNA fragmentation and the formation of apoptotic bodies. However, 13 other protease inhibitors, including serine protease inhibitors, did not. The addition of TPCK to cells 30 minutes after TNF treatment completely inhibited the cytokine action, indicating that TPCK-sensitive proteases are not involved in the early stages of signal transduction. TNF is cytotoxic and induces differentiation in ML-1a cells after a 3-day incubation. TPCK had no effect on the TNF-induced cytotoxicity and differentiation, indicating that TPCK-sensitive proteases are specific for DNA fragmentation. TPCK also blocked TNF-induced activation of nuclear factor (NF)-kappa B. The dose-response and the time-course of the inhibitor, however, indicated that the site of action of TPCK for NF-kappa B activation and for DNA fragmentation are quite distinct. Therefore, we conclude that TNF activates two distinct TPCK-sensitive pathways, one leading to apoptosis and the other to NF-kappa B activation.