ObjectiveThe relation between early-life rhinovirus (RV) wheezing illness and later onset of wheezing/asthma remains a subject of debate. Therefore, we conducted this meta-analysis to evaluate the association between RV wheezing illness in the first 3 years of life and the subsequent development of wheezing/asthma.DesignSystematic review and meta-analysis.MethodsThe PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases were systematically searched for studies published between 1988 and February 2017, and additional studies were found by searching reference lists of relevant articles. 2 reviewers independently extracted data and assessed the quality of each study. Results were pooled using fixed-effect models or random-effects models as appropriate.ResultsThe meta-analysis included 15 original articles which met the criteria, while 10 articles reported the results of 4 longitudinal cohort studies with different follow-up periods. RV wheezing illness in the first 3 years of life was associated with an increased risk of wheezing/asthma in later life (relative risk (RR)=2.00, 95% CI 1.62 to 2.49, p<0.001). In subgroup analysis by age at follow-up, the association still remained significant in <10 years (RR=2.02, 95% CI 1.70 to 2.39, p<0.001) and ≥10 years (RR=1.92, 95% CI 1.36 to 2.72, p<0.001).ConclusionsThe meta-analysis suggests an association between RV-induced wheezing in the first 3 years of life and the subsequent development of wheezing/asthma. Large-scale and well-designed studies that adequately address concerns for potential confounding factors are required to validate the risk identified in the current meta-analysis.

Sphingosine-1-phosphate (S1P), a bioactive lipid, has been shown to be elevated in the airways of individuals with asthma and modulates the airway smooth muscle cell (ASMC) functions, yet its underlying molecular mechanisms are not completely understood. The aim of the present study is to address this issue. S1P induced yes-associated protein (YAP) dephosphorylation and nuclear localization via the S1PR/Rho-associated protein kinase (ROCK) pathway, and this in turn increased forkhead box M1 (FOXM1) and cyclin D1 expression leading to ASMC proliferation, migration, and contraction. Pretreatment of cells with S1PR antagonist JTE013, S1PR antagonist CAY10444, or ROCK inhibitor Y27632 blocked S1P-induced alterations of YAP, FOXM1, cyclin D1, and ASMC proliferation, migration, and contraction. In addition, prior silencing of YAP or FOXM1 with siRNA reversed the effect of S1P on ASMC functions. Taken together, our study indicates that S1P stimulates ASMC proliferation, migration, and contraction by binding to S1PR and modulating ROCK/YAP/FOXM1 axis and suggests that targeting this pathway might have potential value in the management of asthma.

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In this article, we perform cost-effectiveness analysis on interventions that improve the rate of high school completion. Using the What Works Clearinghouse to select effective interventions, we calculate cost-effectiveness ratios for five youth interventions. We document wide variation in costeffectiveness ratios between programs and between sites within multisite programs, reflecting differences in resource use, program implementation, and target population characteristics. We offer suggestions as to how cost-effectiveness data can be used to inform policymaking, with the goal of improving the efficiency with which public and private resources are employed in education.

The aims of the present study were to examine signaling mechanisms for PDGF-induced pulmonary arterial smooth muscle cells (PASMC) proliferation and to determine the effect of AMPK activation on PDGF-induced PASMC proliferation and its underlying mechanisms. PDGF activated PI3K/Akt/mTOR signaling pathway, and this in turn up-regulated Skp2 and consequently reduced p27 leading to PASMC proliferation. Prior incubation of PASMC with metformin induced a dramatic AMPK activation and significantly blocked PDGF-induced cell proliferation. PASMC lacking AMPKα2 were resistant to the inhibitory effect of metformin on PDGF-induced cell proliferation. Metformin did not affect Akt activation but blocked mTOR phosphorylation in response to PDGF; these were accompanied by the reversion of Skp2 up-regulation and p27 reduction. Our study suggests that the activation of AMPK negatively regulates mTOR activity to suppress PASMC proliferation and therefore has a potential value in the prevention and treatment of pulmonary hypertension by negatively modulating pulmonary vascular remodeling.

Abstract. Evidence suggests that an imbalance between oxidation and antioxidation is involved in the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Activation of AMP-activated protein kinase (AMPK) has been shown to inhibit the occurrence of ALI/ARDS. However, it is unknown whether activation of AMPK benefits ALI/ARDS by restoration of the oxidant and antioxidant balance, and which mechanisms are responsible for this process. The present study aimed to address these issues. Lipopolysaccharide (LPS) induced pronounced pathological changes of ALI in mice; these were accompanied by elevated production of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) compared with control mice. Prior treatment of mice with the AMPK agonist metformin significantly suppressed the LPS-induced development of ALI, reduced the elevation of MDA and increased the activity of SOD. Further analysis indicated that activation of AMPK also stimulated the protein expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and superoxide dismutase 1 (SOD1). This study suggests that activation of AMPK by metformin inhibits oxidative stress by upregulation of PGC1α and SOD1, thereby suppressing the development of ALI/ARDS, and has potential value in the clinical treatment of such conditions.

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The aims of the present study were to examine signaling mechanisms underlying transforming growth factor β1 (TGF-β1)-induced airway smooth muscle cells (ASMCs) proliferation and to determine the effect of adenosine monophosphate-activated protein kinase (AMPK) activation on TGF-β1-induced ASMCs proliferation and its potential mechanisms. TGF-β1 reduced microRNA-206 (miR-206) level by activating Smad2/3, and this in turn up-regulated histone deacetylase 4 (HDAC4) and consequently increased cyclin D1 protein leading to ASMCs proliferation. Prior incubation of ASMCs with metformin induced AMPK activation and blocked TGF-β1-induced cell proliferation. Activation of AMPK slightly attenuated TGF-β1-induced miR-206 suppression, but dramatically suppressed TGF-β1-caused HDAC4 up-expression and significantly increased HDAC4 phosphorylation finally leading to reduction of up-regulated cyclin D1 protein expression. Our study suggests that activation of AMPK modulates miR-206/HDAC4/cyclin D1 signaling pathway, particularly targeting on HDAC4, to suppress ASMCs proliferation and therefore has a potential value in the prevention and treatment of asthma by alleviating airway remodeling.