Comparative effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors and human glucagon-like peptide-1 (GLP-1) analogue as add-on therapies to sulphonylurea among diabetes patients in the Asia-Pacific region: a systematic review

The prevalence of diabetes mellitus is rising globally, and it induces a substantial public health burden to the healthcare systems. Its optimal control is one of the most significant challenges faced by physicians and policy-makers. Whereas some of the established oral hypoglycaemic drug classes like biguanide, sulphonylureas, thiazolidinediones have been extensively used, the newer agents like dipeptidyl peptidase-4 (DPP-4) inhibitors and the human glucagon-like peptide-1 (GLP-1) analogues have recently emerged as suitable options due to their similar efficacy and favorable side effect profiles. These agents are widely recognized alternatives to the traditional oral hypoglycaemic agents or insulin, especially in conditions where they are contraindicated or unacceptable to patients. Many studies which evaluated their clinical effects, either alone or as add-on agents, were conducted in Western countries. There exist few reviews on their effectiveness in the Asia-Pacific region. The purpose of this systematic review is to address the comparative effectiveness of these new classes of medications as add-on therapies to sulphonylurea drugs among diabetic patients in the Asia-Pacific countries. We conducted a thorough literature search of the MEDLINE and EMBASE from the inception of these databases to August 2013, supplemented by an additional manual search using reference lists from research studies, meta-analyses and review articles as retrieved by the electronic databases. A total of nine randomized controlled trials were identified and described in this article. It was found that DPP-4 inhibitors and GLP-1 analogues were in general effective as add-on therapies to existing sulphonylurea therapies, achieving HbA1c reductions by a magnitude of 0.59–0.90% and 0.77–1.62%, respectively. Few adverse events including hypoglycaemic attacks were reported. Therefore, these two new drug classes represent novel therapies with great potential to be major therapeutic options. Future larger-scale research should be conducted among other Asia-Pacific region to evaluate their efficacy in other ethnic groups

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Treatment of glenohumeral instability in rugby players

Rugby is a high-impact collision sport, with impact forces. Shoulder injuries are common and result in the longest time off sport for any joint injury in rugby. The most common injuries are to the glenohumeral joint with varying degrees of instability. The degree of instability can guide management. The three main types of instability presentations are: (1) frank dislocation, (2) subluxations and (3) subclinical instability with pain and clicking. Understanding the exact mechanism of injury can guide diagnosis with classical patterns of structural injuries. The standard clinical examination in a large, muscular athlete may be normal, so specific tests and techniques are needed to unearth signs of pathology. Taking these factors into consideration, along with the imaging, allows a treatment strategy. However, patient and sport factors need to be also considered, particularly the time of the season and stage of sporting career. Surgery to repair the structural damage should include all lesions found. In chronic, recurrent dislocations with major structural lesions, reconstruction procedures such as the Latarjet procedure yields better outcomes. Rehabilitation should be safe, goal-driven and athlete- specific. Return to sport is dependent on a number of factors, driven by the healing process, sport requirements and extrinsic pressures

Differential Impact of Tetratricopeptide Repeat Proteins on the Steroid Hormone Receptors

Tetratricopeptide repeat (TPR) motif containing co-chaperones of the chaperone Hsp90 are considered control modules that govern activity and specificity of this central folding platform. Steroid receptors are paradigm clients of Hsp90. The influence of some TPR proteins on selected receptors has been described, but a comprehensive analysis of the effects of TPR proteins on all steroid receptors has not been accomplished yet.We compared the influence of the TPR proteins FK506 binding proteins 51 and 52, protein phosphatase-5, C-terminus of Hsp70 interacting protein, cyclophillin 40, hepatitis-virus-B X-associated protein-2, and tetratricopeptide repeat protein-2 on all six steroid hormone receptors in a homogeneous mammalian cell system. To be able to assess each cofactor's effect on the transcriptional activity of on each steroid receptor we employed transient transfection in a reporter gene assay. In addition, we evaluated the interactions of the TPR proteins with the receptors and components of the Hsp90 chaperone heterocomplex by coimmunoprecipitation. In the functional assays, corticosteroid and progesterone receptors displayed the most sensitive and distinct reaction to the TPR proteins. Androgen receptor's activity was moderately impaired by most cofactors, whereas the Estrogen receptors' activity was impaired by most cofactors only to a minor degree. Second, interaction studies revealed that the strongly receptor-interacting co-chaperones were all among the inhibitory proteins. Intriguingly, the TPR-proteins also differentially co-precipitated the heterochaperone complex components Hsp90, Hsp70, and p23, pointing to differences in their modes of action.The results of this comprehensive study provide important insight into chaperoning of diverse client proteins via the combinatorial action of (co)-chaperones. The differential effects of the TPR proteins on steroid receptors bear on all physiological processes related to steroid hormone activity

Is there a difference between child self-ratings and parent proxy-ratings of the quality of life of children with a diagnosis of Attention Deficit Hyperactivity Disorder (ADHD)? A systematic review of the literature

There are contemporary indicators that parent proxy-ratings and child self-ratings of a child’s quality of life (QoL) are not interchangeable. This review examines dual informant studies to assess parent–child agreement on the QoL of children with attention-deficit/hyperactivity disorder. A systematic search of four major databases (PsycINFO, MEDLINE, EMBASE and Cochrane databases) was completed, and related peer-reviewed journals were hand-searched. Studies which reported quantitative QoL ratings for matched parent and child dyads were screened in accordance with relevant inclusion and exclusion criteria. Key findings were extracted from thirteen relevant studies, which were rated for conformity to the recommendations of an adapted version of the STROBE statement guidelines for observational studies. In the majority of studies reviewed, children rated their QoL more highly than their parents. There was some evidence for greater agreement on the physical health domain than psychosocial domains

New insights into the synergism of nucleoside analogs with radiotherapy

Nucleoside analogs have been frequently used in combination with radiotherapy in the clinical setting, as it has long been understood that inhibition of DNA repair pathways is an important means by which many nucleoside analogs synergize. Recent advances in our understanding of the structure and function of deoxycytidine kinase (dCK), a critical enzyme required for the anti-tumor activity for many nucleoside analogs, have clarified the mechanistic role this kinase plays in chemo- and radio-sensitization. A heretofore unrecognized role of dCK in the DNA damage response and cell cycle machinery has helped explain the synergistic effect of these agents with radiotherapy. Since most currently employed nucleoside analogs are primarily activated by dCK, these findings lend fresh impetus to efforts focused on profiling and modulating dCK expression and activity in tumors. In this review we will briefly review the pharmacology and biochemistry of the major nucleoside analogs in clinical use that are activated by dCK. This will be followed by discussions of recent advances in our understanding of dCK activation via post-translational modifications in response to radiation and current strategies aimed at enhancing this activity in cancer cells

Pliocene-Quaternary crustal melting in central and northern Tibet and insights into crustal flow

There is considerable controversy over the nature of geophysically recognized low-velocity-high-conductivity zones (LV-HCZs) within the Tibetan crust, and their role in models for the development of the Tibetan Plateau. Here we report petrological and geochemical data on magmas erupted 4.7-0.3 Myr ago in central and northern Tibet, demonstrating that they were generated by partial melting of crustal rocks at temperatures of 700-1,050°C and pressures of 0.5-1.5 GPa. Thus Pliocene-Quaternary melting of crustal rocks occurred at depths of 15-50 km in areas where the LV-HCZs have been recognized. This provides new petrological evidence that the LV-HCZs are sources of partial melt. It is inferred that crustal melting played a key role in triggering crustal weakening and outward crustal flow in the expansion of the Tibetan Plateau

Controlling waves in space and time for imaging and focusing in complex media

In complex media such as white paint and biological tissue, light encounters nanoscale refractive-index inhomogeneities that cause multiple scattering. Such scattering is usually seen as an impediment to focusing and imaging. However, scientists have recently used strongly scattering materials to focus, shape and compress waves by controlling the many degrees of freedom in the incident waves. This was first demonstrated in the acoustic and microwave domains using time reversal, and is now being performed in the optical realm using spatial light modulators to address the many thousands of spatial degrees of freedom of light. This approach is being used to investigate phenomena such as optical super-resolution and the time reversal of light, thus opening many new avenues for imaging and focusing in turbid medi

High precision determination of the gluon fusion Higgs boson cross-section at the LHC

We present the most precise value for the Higgs boson cross-section in the gluon-fusion production mode at the LHC. Our result is based on a perturbative expansion through N$^3$LO in QCD, in an effective theory where the top-quark is assumed to be infinitely heavy, while all other Standard Model quarks are massless. We combine this result with QCD corrections to the cross-section where all finite quark-mass effects are included exactly through NLO. In addition, electroweak corrections and the first corrections in the inverse mass of the top-quark are incorporated at three loops. We also investigate the effects of threshold resummation, both in the traditional QCD framework and following a SCET approach, which resums a class of $\pi^2$ contributions to all orders. We assess the uncertainty of the cross-section from missing higher-order corrections due to both perturbative QCD effects beyond N$^3$LO and unknown mixed QCD-electroweak effects. In addition, we determine the sensitivity of the cross-section to the choice of parton distribution function (PDF) sets and to the parametric uncertainty in the strong coupling constant and quark masses. For a Higgs mass of $m_H = 125~{\rm GeV}$ and an LHC center-of-mass energy of $13~{\rm TeV}$, our best prediction for the gluon fusion cross-section is \[ \sigma = 48.58\,{\rm pb} {}^{+2.22\, {\rm pb}\, (+4.56\%)}_{-3.27\, {\rm pb}\, (-6.72\%)} \mbox{ (theory)} \pm 1.56 \,{\rm pb}\, (3.20\%) \mbox{ (PDF+$\alpha_s$)} \