【特刊综述】雄激素对骨骼肌的作用：对乏力的发展和治疗的意义

雄激素对骨骼肌合成有明显影响,随着年龄增大,雄激素的下降常伴随肌量和肌力的下降。这种肌量和肌功能的下降,被称为少肌症或肌体老化,是老年人体质弱化（男性化减退）进展的关键事项。也是导致快速机能衰退及其不良后果的关键。雄激素水平下降对老年男性体质弱化（男性化减退）的潜在影响和对躯体功能的促进治疗作用无疑已经引起了相当的关注。本综述概述了近期关于肌肉老化、少肌症、老年体质弱化的概念、定义,并评估了关于雄激素和老年体质弱化的研究进展。近期源于观测性和介入性研究的证据强烈支持雄激素对老年男性肌量的作用,但雄激素对肌力和特有的躯体功能的效用并不明确。研究显示,雄激素治疗在老年男性中通常有良好的耐受性,而近期的研究则关注于雄激素的高剂量治疗和对于心血管风险较高人群的治疗。雄激素受体调节剂（SARMs）的初期试验研究显示传统雄激素治疗对于老年患者在肌量和肌功能方面有相同的效用。将来的重要研究方向包括利用这类雄激素治疗并结合适用于不同老年患者群体促进躯体功能的运动训练,同时将更多地关注近期关于激素水平、身体成分及躯体功能间关系的观测性（回顾性）研究。     

Genetic and Molecular Predictors of High Vancomycin MIC in Staphylococcus aureus Bacteremia Isolates

An elevated vancomycin MIC is associated with poor outcomes in Staphylococcus aureus bacteremia (SAB) and is reported in patients with methicillin-susceptible S. aureus (MSSA) bacteremia in the absence of vancomycin treatment. Here, using DNA microarray and phenotype analysis, we investigated the genetic predictors and accessory gene regulator (agr) function and their relationship with elevated vancomycin MIC using blood culture isolates from a multicenter binational cohort of patients with SAB. Specific clonal complexes were associated with elevated (clonal complex 8 [CC8] [P < 0.001]) or low (CC22 [P < 0.001], CC88 [P < 0.001], and CC188 [P = 0.002]) vancomycin MIC. agr dysfunction (P = 0.014) or agr genotype II (P = 0.043) were also associated with an elevated vancomycin MIC. Specific resistance and virulence genes were also linked to an elevated vancomycin MIC, including blaZ (P = 0.002), sea (P < 0.001), clfA (P < 0.001), splA (P = 0.001), and the arginine catabolic mobile element (ACME) locus (P = 0.02). These data suggest that inherent organism characteristics may explain the link between elevated vancomycin MICs and poor outcomes in patients with SAB, regardless of the antibiotic treatment received. A consideration of clonal specificity should be included in future research when attempting to ascertain treatment effects or clinical outcomes.     

GSK3β inhibition and LEF1 upregulation in skeletal muscle following a bout of downhill running

Canonical Wnt signaling is important in skeletal muscle repair but has not been well characterized in response to physiological stimuli. The objective of this study was to assess the effect of downhill running (DHR) on components of Wnt signaling. Young, male C57BL/J6 mice were exposed to DHR. Muscle injury and repair (MCadherin) were measured in soleus. Gene and protein expression of Wnt3a, active β-catenin, GSK3β, and LEF1 were measured in gastrocnemius. Muscle injury increased 6 days post-DHR and MCadherin protein increased 5 days post-DHR. Total and active GSK3β protein decreased 3 days (9-fold and 3.6-fold, respectively) post-DHR. LEF1 protein increased 6 days (5-fold) post-DHR. DHR decreased GSK3β and increased LEF1 protein expression, but did not affect other components of Wnt signaling. Due to their applicability, using models of physiological stimuli such as DHR will provide significant insight into cellular mechanisms within muscle.     

B-cell growth factor receptor expression and B-cell growth factor response of leukemic B cell precursors and B lineage lymphoid progenitor cells

The purpose of this study was to analyze the expression of B cell growth factor (BCGF) receptors and to elucidate the biologic effects of biochemically purified natural BCGF at the B cell precursor stage of human B lineage lymphoid differentiation. The specific binding of radioiodinated high-mol-wt BCGF (125I-HMW-BCGF) and low-molecular-wt BCGF (125I-LMW-BCGF) to fresh marrow blasts from B cell precursor acute lymphoblastic leukemia (ALL) patients was initially investigated. The estimated number of radioiodinated BCGF molecules bound per blast ranged from undetectable to 24.3 X 10(3) for HMW-BCGF, and from 11.5 X 10(3) to 457.8 X 10(3) for LMW-BCGF. In 3H-TdR incorporation assays, 75% of cases showed a significant response to LMW-BCGF with a median stimulation index of 9.3. By comparison, only 33% of cases showed a significant response to HMW-BCGF with a median stimulation index of 2.4. Subsequently, B cell precursor colony assays were performed to assess and compare the biologic effects of BCGF on leukemic B lineage lymphoid progenitor cells. Among 28 cases studied, 57% responded to both HMW-BCGF and LMW-BCGF, 21% responded only to LMW-BCGF, and the remaining cases showed no proliferative response to either growth factor. The response patterns of virtually pure populations of FACS- sorted leukemic B cell precursors were essentially identical to the proliferative responses of unsorted leukemic B-cell precursors. Synergistic effects between HMW-BCGF and LMW-BCGF were observed in 80% of the cases that responded to both. The numbers of cell-bound radioiodinated BCGF molecules, the stimulation indices, as well as the number of B cell precursor colonies in BCGF-stimulated cultures showed a marked interpatient variation. Patients with structural chromosomal abnormalities (SCAs) involving 12p11-13 or patients with a Philadelphia chromosome showed a greater HMW-BCGF response at the level of leukemic progenitor cells than did other patients (P = .02). The LMW-BCGF response was significantly greater for patients with SCA than for patients without SCA (P = .04). The response of leukemic progenitor cells to HMW-BCGF or LMW-BCGF did not correlate with sex, age, disease status, FAB morphology, WBC at diagnosis, or immunophenotype. To our knowledge, this study represents the first detailed analyses of BCGF receptor expression and BCGF effects in B cell precursor ALL. The data presented provide direct evidence for the expression of functional receptors for both HMW-BCGF and LMW-BCGF in B cell precursor ALL.     

Aven‐mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in conventional osteosarcoma

Conventional high‐grade osteosarcoma is the most common primary bone sarcoma, with relatively high incidence in young people. In this study we found that expression of Aven correlates inversely with metastasis‐free survival in osteosarcoma patients and is increased in metastases compared to primary tumours. Aven is an adaptor protein that has been implicated in anti‐apoptotic signalling and serves as an oncoprotein in acute lymphoblastic leukaemia. In osteosarcoma cells, silencing Aven triggered G₂ cell‐cycle arrest; Chk1 protein levels were attenuated and ATR–Chk1 DNA damage response signalling in response to chemotherapy was abolished in Aven‐depleted osteosarcoma cells, while ATM, Chk2 and p53 activation remained intact. Osteosarcoma is notoriously difficult to treat with standard chemotherapy, and we examined whether pharmacological inhibition of the Aven‐controlled ATR–Chk1 response could sensitize osteosarcoma cells to genotoxic compounds. Indeed, pharmacological inhibitors targeting Chk1/Chk2 or those selective for Chk1 synergized with standard chemotherapy in 2D cultures. Likewise, in 3D extracellular matrix‐embedded cultures, Chk1 inhibition led to effective sensitization to chemotherapy. Together, these findings implicate Aven in ATR–Chk1 signalling and point towards Chk1 inhibition as a strategy to sensitize human osteosarcomas to chemotherapy. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

小鼠皮肤超氧化物歧化酶活性与枸杞多糖的干预

目的:观察枸杞多糖对皮肤胶原代谢和自由基产生的影响,探讨其抗皮肤衰老的作用。方法:实验于2005-06/2006-05在广东医学院整形外科研究所完成。①实验材料:清洁级昆明小鼠60只,月龄2个月,体质量16～24g,雌雄各半。②实验分组:将小鼠随机分为正常对照组、衰老模型组和抗衰老模型组,每组20只。③实验干预:模型组每日用D-半乳糖溶液皮下注射制造衰老模型,用量和时间为80mg/(kg·d)7d,120mg/(kg·d)14d,140mg/(kg·d)14d,180mg/(kg·d)7d。正常对照组每日注射同体积的生理盐水。抗衰老模型组在注射D-半乳糖期间以枸杞多糖灌胃,剂量为20mg/(kg·d),正常对照组和衰老组则以同体积的生理盐水代之灌胃。④实验评估:42d后切取小鼠颈背部皮肤,测定超氧化物歧化酶活力、羟脯氨酸和丙二醛含量。结果:56只小鼠进入结果分析(4只死亡)。①小鼠皮肤超氧化物歧化酶活力:与正常对照组相比,衰老组和抗衰老组小鼠皮肤超氧化物歧化酶活力降低,差异有显著性意义(P<0.01);抗衰老组与衰老模型组比较,超氧化物歧化酶活力增加,差异有显著性意义(P<0.01)。②与正常对照组相比,衰老组和抗衰老组小鼠皮肤羟脯氨酸和丙二醛含量增加,差异有显著性意义(P<0.01);抗衰老组与衰老组比较,羟脯氨酸和丙二醛含量均降低,差异有显著性意义(P<0.01)。结论:枸杞多糖改善皮肤老化的作用与提高小鼠皮肤超氧化物歧化酶活力,降低羟脯氨酸、丙二醛含量,影响胶原代谢有关。     

Inter-rater agreement and reliability of the COSMIN (COnsensus-based Standards for the selection of health status Measurement Instruments) Checklist

Background  

The COSMIN checklist is a tool for evaluating the methodological quality of studies on measurement properties of health-related patient-reported outcomes. The aim of this study is to determine the inter-rater agreement and reliability of each item score of the COSMIN checklist (n = 114).     

Meta-analysis: the efficacy of intravenous H2-receptor antagonists in bleeding peptic ulcer

BACKGROUND: Although a previous meta-analysis found that intravenous H2-receptor antagonists were only weakly beneficial in bleeding gastric ulcer and of no benefit in bleeding duodenal ulcer, patients with ulcer bleeding continue to receive such treatment. AIM: To re-evaluate the efficacy of intravenous H2-receptor antagonists in ulcer re-bleeding, surgery and mortality by updating the previous meta-analysis. METHODS: After two independent literature searches, randomized, placebo-controlled trials of intravenous H2-receptor antagonists in bleeding ulcer published between 1984 and 2000 were added to those from the initial meta-analysis. Pooled rates of re-bleeding, surgery and death were re-calculated, together with the relative risk reduction, absolute risk reduction, number needed to treat and Mantel-Haenszel odds ratio. RESULTS: Intravenous H2-receptor antagonists did not significantly reduce re-bleeding, surgery or death in bleeding duodenal ulcer. There were small but significant reductions in re-bleeding, surgery and death in bleeding gastric ulcer; the absolute risk reductions were 7.2%, 6.7% and 3.2%, respectively. CONCLUSIONS: Intravenous H2-receptor antagonists are of no value in bleeding duodenal ulcer, although they may be mildly beneficial in bleeding gastric ulcer. Because proton pump inhibitors have a greater inhibitory effect on gastric acid secretion than H2-receptor antagonists, they may be more effective in ulcer bleeding and should be further evaluated for that indication.     

质子泵抑制剂治疗消化性溃疡出血的系统评价和汇总分析

目的回顾关于质子泵抑制剂治疗溃疡出血患者的随机对照研究，确定该治疗对于死亡率、再出血和外科干预措施的影响。设计系统评价和汇总分析。资料来源包括Cochrane协作网的临床试验注册库、Medline、Embase、手工检索的摘要和制药公司。评价方法在经内镜证实存在溃疡出血并至少有以下事件之一——死亡、再出电、外科干预的患者中，进行随机对照研究，比较质子泵抑制剂与安慰剂或H2受体拮抗剂的疗效。所有临床试验依据方法学质量来进行分级。由2个评定者独立回顾每个临床试验，将分歧按照多数人的意见来统一。结果我们选出了21项随机对照研究，包括2915例患者。质子泵抑制剂治疗对于死亡率没有显著影响[比值比1．11，95％可信区间0．79～1．57；需要治疗的人数（NNT）无法计算]。但是质子泵抑制剂可以降低再出血的发生（0．46，0．33～0．64；NNT为12）和外科治疗的比例（0．59，0．46～0．76；NNT为20）。对其中10项具有高质量方法学的临床试验进行汇总分析，得到相似的结论：死亡率的OR值为0．96（0．46～2．01）；再出血的OR值为0．41（0．25～0．68），NNT为10；外科手术的OR值为0．62（0．46～0．83），NNT为25。结论质子泵抑制剂的治疗可以降低溃疡的再出血风险，减少对外科手术的需要，但患者的总体死亡率没有改善。