Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes

Background Despite the number of medications for type 2 diabetes, many people with the condition do not achieve good glycaemic control. Some existing glucose-lowering agents have adverse effects such as weight gain or hypoglycaemia. Type 2 diabetes tends to be a progressive disease, and most patients require treatment with combinations of glucose-lowering agents. The sodium glucose co-transporter 2 (SGLT2) receptor inhibitors are a new class of glucose-lowering agents. Objective To assess the clinical effectiveness and safety of the SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. Data sources MEDLINE, Embase, Cochrane Library (all sections); Science Citation Index; trial registries; conference abstracts; drug regulatory authorities; bibliographies of retrieved papers. Inclusion criteria Randomised controlled trials of SGLT2 receptor inhibitors compared with placebo or active comparator in type 2 diabetes in dual or combination therapy. Methods Systematic review. Quality assessment used the Cochrane risk of bias score. Results Seven trials, published in full, assessed dapagliflozin and one assessed canagliflozin. Trial quality appeared good. Dapagliflozin 10 mg reduced HbA1c by −0.54% (weighted mean differences (WMD), 95% CI −0.67 to −0.40) compared to placebo, but there was no difference compared to glipizide. Canagliflozin reduced HbA1c slightly more than sitagliptin (up to −0.21% vs sitagliptin). Both dapagliflozin and canagliflozin led to weight loss (dapagliflozin WMD −1.81 kg (95% CI −2.04 to −1.57), canagliflozin up to −2.3 kg compared to placebo). Limitations Long-term trial extensions suggested that effects were maintained over time. Data on canagliflozin are currently available from only one paper. Costs of the drugs are not known so cost-effectiveness cannot be assessed. More data on safety are needed, with the Food and Drug Administration having concerns about breast and bladder cancers. Conclusions Dapagliflozin appears effective in reducing HbA1c and weight in type 2 diabetes, although more safety data are needed

An Analysis of Private School Closings

We add to the small literature on private school supply by exploring exits of K-12 private schools. We find that the closure of private schools is not an infrequent event, and use national survey data from the National Center for Education Statistics to study closures of private schools. We assume that the probability of an exit is a function of excess supply of private schools over the demand, as well as the school's characteristics such as age, size, and religious affiliation. Our empirical results generally support the implications of the model. Working Paper 07-0

Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer

The myotonic dystrophy-related Cdc42-binding kinases MRCKα and MRCKβ contribute to the regulation of actin-myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphological changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent anti-proliferative effects with greatest activity in hematological cancer cells. Mass spectrometry identified MRCKα S1003 as an autophosphorylation site, enabling development of a phosphorylation-sensitive antibody tool to report on MRCKα status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKα S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy

Acute kidney disease and renal recovery : consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of > 90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum