Sodium/glucose co‐transporter‐2 (SGLT2) inhibitors, which lower blood glucose by increasing renal glucose elimination, have been shown to reduce the risk of adverse cardiovascular (CV) and renal ...events in type 2 diabetes. This has been ascribed, in part, to haemodynamic changes, body weight reduction and several possible effects on myocardial, endothelial and tubulo‐glomerular functions, as well as to reduced glucotoxicity. This review evaluates evidence that an effect of SGLT2 inhibitors to lower uric acid may also contribute to reduced cardio‐renal risk.
Chronically elevated circulating uric acid concentrations are associated with increased risk of hypertension, CV disease and chronic kidney disease (CKD). The extent to which uric acid contributes to these conditions, either as a cause or an aggravating factor, remains unclear, but interventions that reduce urate production or increase urate excretion in hyperuricaemic patients have consistently improved cardio‐renal prognoses. Uric acid concentrations are often elevated in type 2 diabetes, contributing to the “metabolic syndrome” of CV risk. Treating type 2 diabetes with an SGLT2 inhibitor increases uric acid excretion, reduces circulating uric acid and improves parameters of CV and renal function. This raises the possibility that the lowering of uric acid by SGLT2 inhibition may assist in reducing adverse CV events and slowing progression of CKD in type 2 diabetes. SGLT2 inhibition might also be useful in the treatment of gout and gouty arthritis, especially when co‐existent with diabetes.
Calorie restriction (CR) extends life span in diverse species. Mitochondria play a key role in CR adaptation; however, the molecular details remain elusive. We developed and applied a quantitative ...mass spectrometry method to probe the liver mitochondrial acetyl-proteome during CR versus control diet in mice that were wild-type or lacked the protein deacetylase SIRT3. Quantification of 3,285 acetylation sites—2,193 from mitochondrial proteins—rendered a comprehensive atlas of the acetyl-proteome and enabled global site-specific, relative acetyl occupancy measurements between all four experimental conditions. Bioinformatic and biochemical analyses provided additional support for the effects of specific acetylation on mitochondrial protein function. Our results (1) reveal widespread reprogramming of mitochondrial protein acetylation in response to CR and SIRT3, (2) identify three biochemically distinct classes of acetylation sites, and (3) provide evidence that SIRT3 is a prominent regulator in CR adaptation by coordinately deacetylating proteins involved in diverse pathways of metabolism and mitochondrial maintenance.
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► MS quantifies 1,578 mitochondrial acetyl sites altered during CR and loss of SIRT3 ► SIRT3 functions as a prominent regulator in CR adaptation ► CR and SIRT3 regulate previously unrecognized processes in mitochondria ► We provide an acetylation atlas for understanding mitochondrial regulation in CR
This paper uses the rollout of the first Community Health Centers (CHCs) to study the longer-term health effects of increasing access to primary care. Within ten years, CHCs are associated with a ...reduction in age-adjusted mortality rates of 2 percent among those 50 and older. The implied 7 to 13 percent decrease in one-year mortality risk among beneficiaries amounts to 20 to 40 percent of the 1966 poor/non-poor mortality gap for this age group. Large effects for those 65 and older suggest that increased access to primary care has longer-term benefits, even for populations with near universal health insurance.
Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits ...long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.
Abstract We use novel, large-scale data on 17.5 million Americans to study how a policy-driven increase in economic resources affects children's long-term outcomes. Using the 2000 Census and 2001–13 ...American Community Survey linked to the Social Security Administration's NUMIDENT, we leverage the county-level rollout of the Food Stamps program between 1961 and 1975. We find that children with access to greater economic resources before age five have better outcomes as adults. The treatment-on-the-treated effects show a 6% of a standard deviation improvement in human capital, 3% of a standard deviation increase in economic self-sufficiency, 8% of a standard deviation increase in the quality of neighbourhood of residence, a 1.2-year increase in life expectancy, and a 0.5 percentage-point decrease in likelihood of being incarcerated. These estimates suggest that Food Stamps’ transfer of resources to families is a highly cost-effective investment in young children, yielding a marginal value of public funds of approximately sixty-two.
The selective hydrogenation of nitriles to primary amines using a bench-stable cobalt precatalyst under 4 atm of H2 is reported herein. The catalyst precursor was reduced in situ using NaHBEt3, and ...the resulting Lewis acid formed, BEt3, was found to be integral to the observed catalysis. Mechanistic insights gleaned from para-hydrogen induced polarization (PHIP) transfer NMR studies revealed that the pairwise hydrogenation of nitriles proceeded through a Co(I/III) redox process.
The severity of congenital diaphragmatic hernia (CDH) can be estimated prenatally using observed-to-expected lung-head ratios (by ultrasound) and total fetal lung volumes (by magnetic resonance ...imaging), as well as fetal liver position. Infants with CDH require intensive cardiopulmonary support after birth, including immediate endotracheal intubation and "gentle ventilation," as well as judicious fluid and inotropic support. Pulmonary hypertension, as assessed by echocardiography, may require the use of pulmonary vasodilators and other medical adjuncts or, in severe cases, extracorporeal life support, if available. Open surgical repair of the diaphragmatic defect should usually be delayed until physiologic stability has been achieved, but a failure to perform surgery within the first two weeks of life should prompt a team discussion of priorities with the family. Infants with CDH should undergo long-term, multidisciplinary surveillance that includes standardized neurodevelopmental testing, especially if they are considered high risk (i.e., needing pulmonary support at 30 days, needing a patch repair or requiring extracorporeal life support).
Nearly a century ago it was recognized that radiation absorption by stellar matter controls the internal temperature profiles within stars. Laboratory opacity measurements, however, have never been ...performed at stellar interior conditions, introducing uncertainties in stellar models. A particular problem arose when refined photosphere spectral analysis led to reductions of 30-50 per cent in the inferred amounts of carbon, nitrogen and oxygen in the Sun. Standard solar models using the revised element abundances disagree with helioseismic observations that determine the internal solar structure using acoustic oscillations. This could be resolved if the true mean opacity for the solar interior matter were roughly 15 per cent higher than predicted, because increased opacity compensates for the decreased element abundances. Iron accounts for a quarter of the total opacity at the solar radiation/convection zone boundary. Here we report measurements of wavelength-resolved iron opacity at electron temperatures of 1.9-2.3 million kelvin and electron densities of (0.7-4.0) × 10(22) per cubic centimetre, conditions very similar to those in the solar region that affects the discrepancy the most: the radiation/convection zone boundary. The measured wavelength-dependent opacity is 30-400 per cent higher than predicted. This represents roughly half the change in the mean opacity needed to resolve the solar discrepancy, even though iron is only one of many elements that contribute to opacity.
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