Aim: Most guidelines recommend metformin as first‐line therapy in patients with type 2 diabetes. However, the choice of a second‐line drug lacks consistent consensus. We aimed to assess available ...information of antidiabetic drugs added to metformin on the change in glycated haemoglobin A1c (A1C), risk of hypoglycaemia and change in body weight.
Methods: PubMed and Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) written in English through December 2011. We analysed direct and indirect comparisons of different treatments using Bayesian network meta‐analysis.
Results: Thirty‐nine RCTs involving 17 860 individuals were included. Glucagon‐like peptide‐1 (GLP‐1) analogues resulted in greater decrease in A1C compared with sulfonylureas, glinides, thiazolidinediones, α‐glucosidase inhibitors and DPP‐4 inhibitors −0.20% (95% CI −0.34 to −0.04%), −0.31% (95% CI −0.61 to −0.02%), −0.20% (95% CI −0.38 to −0.00), −0.36% (95% CI −0.64 to −0.07%), −0.32% (95% CI −0.47 to −0.17%), respectively and was comparable with basal insulin and biphasic insulin. A1C decrease was greater for sulfonylureas compared with DPP‐4 inhibitors −0.12% (−0.23 to −0.03%), and for biphasic insulin compared with glinides (−0.36%; 95% CI −0.82 to −0.11%). Compared with placebo, the risk of hypoglycaemia was increased in the sulfonylureas, glinides, basal insulin and biphasic insulin. Weight increase was seen with sulfonylureas, glinides, thiazolidinediones, basal insulin and biphasic insulin, and weight loss was seen with α‐glucosidase inhibitors and GLP‐1 analogues.
Conclusions: Biphasic insulin, GLP‐1 analogues and basal insulin were ranked the top three drugs in terms of A1C reduction. GLP‐1 analogues did not increase the risk of hypoglycaemia and resulted in a significant decrease in body weight. Most oral antidiabetic drugs had similar effects on A1C, but some agents had a lower risk of hypoglycaemia and body weight gain.
An effective method to control the rate of perovskite crystallization by incorporating rationally chosen additives into the perovskite precursor solutions is demonstrated. The processing additives ...simultaneously facilitate nucleation and modulate the kinetics of crystal growth during crystallization, leading to much smoother perovskite morphology with improved coverage area and crystal uniformity. As a result, it enables very high PCE (∼12%) planar‐heterojunction solar cells to be fabricated through the low‐temperature solution processes (under 150 °C). This study opens up a new direction for optimizing perovskite active layer properties to expand device performance ceilings.
A comprehensive morphological study was used to elucidate chloride’s role in CH3NH3PbI3–x Cl x film evolution on a conducting polymer, PEDOT:PSS. Complex ion equilibria and aggregation in solution, ...as well as the role they play in nucleation, are found to ultimately be responsible for the unique morphological diversity observed in perovskite films grown in the presence of the chloride ion. An intermediate phase that is generated upon deposition and initial annealing templates continued self-assembly in the case of CH3NH3PbI3–x Cl x . In the absence of chloride, the film growth of CH3NH3PbI3 is directed by substrate interfacial energy. By employing the through-plane TEM analysis, we gain detailed insight into the unique crystallographic textures, grain structures, and elemental distributions across the breadth of films grown from precursor solutions with different chemistries. The lattice coherence seen in morphologies generated under the influence of chloride provides a physical rational for the enhancement in carrier diffusion length and lifetime.
Background
Obesity accelerates and exacerbates the age-related changes on muscle function and exercise capacity. In addition, the middle-aged population is often overlooked when talking about the ...prevention of sarcopenia. This study investigated the effects of exercise alone or in combination with a high-protein diet on muscle function and physical fitness in middle-aged obese adults.
Materials and methods
Sixty-nine middle-aged (501–64 years old) obese adults were randomly assigned to one of the following groups: control group (C; n=23), exercise group (E; n=23) or exercise plus high-protein group (EP; n=23). Individuals within the E and EP groups received 12 weeks of exercise training; whereas, the individuals in the EP group also received a highprotein diet intervention (1.6g/kg/day). Individuals within the C group were asked to maintain their lifestyle for 12 weeks. Participants were evaluated before and after the intervention. Outcome measures included maximal exercise capacity, muscle function and functional physical performance. Analysis of covariance was used to determine the effects of the intervention.
Results
After the intervention, the E and EP groups had greater maximal work rate, peak oxygen consumption, and muscle power during muscle contractions at 180°/sec than that in the C group (P<0.05). The EP group, but not the E group, showed significant improvement in the sit-to-stand test and climbing stairs test than the C group after the intervention (P<0.05). Within group comparisons showed that the anaerobic threshold only increased in the EP group (+12% from pre-test).
Conclusions
For middle-aged obese adults, exercise with a high-protein diet not only improved muscle power and exercise capacity but also enhanced their functional physical performance.
A simple, low temperature solution process for Pb/Sn binary‐metal perovskite planar‐heterojunction solar cells is demonstrated. Sn inclusion substantially influences the band‐gap, crystallization ...kinetics, and thin‐film formation leading to a broadened light absorption and enhanced film coverage on ITO/PEDOT:PSS. As a result, the optimized device shows a PCE exceeding 10%, which is the best result for binary‐metal perovskite solar cells so far.
Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear ...whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy.
(G2019S) mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Twelve- to sixteen-month-old (G2019S) LRRK2 ...transgenic mice prepared by us displayed progressive degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurons and parkinsonism phenotypes of motor dysfunction. LRRK2 is a member of mixed lineage kinase subfamily of mitogen-activated protein kinase kinase kinases (MAPKKKs). We hypothesized that (G2019S) mutation augmented LRRK2 kinase activity, leading to overphosphorylation of downstream MAPK kinase (MKK) and resulting in activation of neuronal death signal pathway. Consistent with our hypothesis, (G2019S) LRRK2 expressed in HEK 293 cells exhibited an augmented kinase activity of phosphorylating MAPK kinase 4 (MKK4) at Ser(257), and protein expression of active phospho-MKK4(Ser257) was upregulated in the SN of (G2019S) LRRK2 transgenic mice. Protein level of active phospho-JNK(Thr183/Tyr185) and phospho-c-Jun(Ser63), downstream targets of phospho-MKK4(Ser257), was increased in the SN of (G2019S) LRRK2 mice. Upregulated mRNA expression of pro-apoptotic Bim and FasL, target genes of phospho-c-Jun(Ser63), and formation of active caspase-9, caspase-8 and caspase-3 were also observed in the SN of (G2019S) LRRK2 transgenic mice. Our results suggest that mutant (G2019S) LRRK2 activates MKK4-JNK-c-Jun pathway in the SN and causes the resulting degeneration of SNpc dopaminergic neurons in PD transgenic mice.
Spinal muscular atrophy (SMA) is a major genetic cause of death in childhood characterized by marked muscle weakness. To investigate mechanisms underlying motor impairment in SMA, we examined the ...spinal and neuromuscular circuitry governing hindlimb ambulatory behavior in SMA model mice (SMNΔ7). In the neuromuscular circuitry, we found that nearly all neuromuscular junctions (NMJs) in hindlimb muscles of SMNΔ7 mice remained fully innervated at the disease end stage and were capable of eliciting muscle contraction, despite a modest reduction in quantal content. In the spinal circuitry, we observed a ∼28% loss of synapses onto spinal motoneurons in the lateral column of lumbar segments 3-5, and a significant reduction in proprioceptive sensory neurons, which may contribute to the 50% reduction in vesicular glutamate transporter 1(VGLUT1)-positive synapses onto SMNΔ7 motoneurons. In addition, there was an increase in the association of activated microglia with SMNΔ7 motoneurons. Together, our results present a novel concept that synaptic defects occur at multiple levels of the spinal and neuromuscular circuitry in SMNΔ7 mice, and that proprioceptive spinal synapses could be a potential target for SMA therapy.
The black hole (BH)-bulge correlations have greatly influenced the last decade of efforts to understand galaxy evolution. Current knowledge of these correlations is limited predominantly to high BH ...masses (M{sub BH{approx}}>10{sup 8} M{sub sun}) that can be measured using direct stellar, gas, and maser kinematics. These objects, however, do not represent the demographics of more typical L < L* galaxies. This study transcends prior limitations to probe BHs that are an order of magnitude lower in mass, using BH mass measurements derived from the dynamics of H{sub 2}O megamasers in circumnuclear disks. The masers trace the Keplerian rotation of circumnuclear molecular disks starting at radii of a few tenths of a pc from the central BH. Modeling of the rotation curves, presented by Kuo et al., yields BH masses with exquisite precision. We present stellar velocity dispersion measurements for a sample of nine megamaser disk galaxies based on long-slit observations using the B and C spectrograph on the Dupont telescope and the Dual Imaging Spectrograph on the 3.5 m telescope at Apache Point. We also perform bulge-to-disk decomposition of a subset of five of these galaxies with Sloan Digital Sky Survey imaging. The maser galaxies as a group fall below the M{sub BH}-{sigma}{sub *} relation defined by elliptical galaxies. We show, now with very precise BH mass measurements, that the low-scatter power-law relation between M{sub BH} and {sigma}{sub *} seen in elliptical galaxies is not universal. The elliptical galaxy M{sub BH}-{sigma}{sub *} relation cannot be used to derive the BH mass function at low mass or the zero point for active BH masses. The processes (perhaps BH self-regulation or minor merging) that operate at higher mass have not effectively established an M{sub BH}-{sigma}{sub *} relation in this low-mass regime.
Summary
Chronic kidney disease (CKD)-related osteoporosis is a major complication in patients with CKD, conferring a higher risk of adverse outcomes. We found that among those with diabetic kidney ...disease, this complication increased the risk of incident frailty, an important mediator of adverse outcomes.
Introduction
Renal osteodystrophy and chronic kidney disease (CKD)-related osteoporosis increases complications for patients with diabetic kidney disease (DKD). Since musculoskeletal degeneration is central to frailty development, we investigated the relationship between baseline osteoporosis and the subsequent frailty risk in patients with DKD.
Methods
From the Longitudinal Cohort of Diabetes Patients in Taiwan (
n
= 840,000), we identified 12,027 patients having DKD with osteoporosis and 24,054 propensity score-matched controls having DKD but without osteoporosis. The primary endpoint was incident frailty on the basis of a modified FRAIL scale. Patients were prospectively followed-up until the development of endpoints or the end of this study. The Kaplan-Meier technique and Cox proportional hazard regression were used to analyze the association between osteoporosis at baseline and incident frailty in these patients.
Results
The mean age of the DKD patients was 67.2 years, with 55.4% female and a 12.6% prevalence of osteoporosis at baseline. After 3.5 ± 2.2 years of follow up, the incidence rate of frailty in patients having DKD with osteoporosis was higher than that in DKD patients without (6.6 vs. 5.7 per 1000 patient-year,
p
= 0.04). A Cox proportional hazard regression showed that after accounting for age, gender, obesity, comorbidities, and medications, patients having DKD with osteoporosis had a significantly higher risk of developing frailty (hazard ratio, 1.19; 95% confidence interval, 1.02–1.38) than those without osteoporosis.
Conclusions
CKD-related osteoporosis is associated with a higher risk of incident frailty in patients with DKD.
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