The hepatic compensatory response to elevated systemic sulfide promotes diabetes.

Impaired hepatic glucose and lipid metabolism are hallmarks of type 2 diabetes. Increased sulfide production or sulfide donor compounds may beneficially regulate hepatic metabolism. Disposal of sulfide through the sulfide oxidation pathway (SOP) is critical for maintaining sulfide within a safe physiological range. We show that mice lacking the liver- enriched mitochondrial SOP enzyme thiosulfate sulfurtransferase (Tst-/- mice) exhibit high circulating sulfide, increased gluconeogenesis, hypertriglyceridemia, and fatty liver. Unexpectedly, hepatic sulfide levels are normal in Tst-/- mice because of exaggerated induction of sulfide disposal, with associated suppression of global protein persulfidation and nuclear respiratory factor 2 target protein levels. Hepatic proteomic and persulfidomic profiles converge on gluconeogenesis and lipid metabolism, revealing a selective deficit in medium-chain fatty acid oxidation in Tst-/- mice. We reveal a critical role of TST in hepatic metabolism that has implications for sulfide donor strategies in the context of metabolic disease.

MRI safety management in patients with cardiac implantable electronic devices: Utilizing failure mode and effects analysis for risk optimization.

INTRODUCTION: Cardiac implantable electronic devices (CIEDs) are increasing in prevalence. Exposing patients with CIEDs to magnetic resonance imaging (MRI) can lead to adverse outcomes. This has led certain radiology departments to not accept MRI referrals related to patients with CIEDs. Patients with MR-conditional CIEDs can be safely scanned under specific conditions. Our institution has accepted such referrals since 2014. The aim of this study was to systematically identify and reduce risk in our CIED-MRI protocol using failure mode and effects analysis (FMEA). METHODS: A multidisciplinary FMEA team was assembled and included senior stakeholders from the CIED-MRI protocol. A process map was constructed followed by risk analysis and scoring. Targeted interventions were formulated and implemented; high-risk failure modes were prioritized. A new process map and protocol were drafted and repeat risk analysis was performed. Monitoring and re-evaluation of the CIED-MRI pathway were instigated at departmental quality assurance (QA) meetings. RESULTS: Interventions included direct CIED characterization using wireless technology pre-MRI, CIED programming and reprogramming in the MRI suite before and immediately after MRI reducing device downtime and continuous patient monitoring during MRI by a cardiac physiologist. The cumulative risk priority number (RPN) decreased from 1190 pre-FMEA to 492 post-FMEA. DISCUSSION: Despite the risk of exposing CIEDs to the MR environment, patients with MR-conditional CIEDs can be safely scanned with an appropriate multidisciplinary support. We found FMEA an indispensable tool in identifying and minimizing risk with no adverse events recorded since FMEA recommendations were implemented.

The uncoupling of monocyte-platelet interactions from the induction of proinflammatory signaling in monocytes.

Induction of an inflammatory monocyte phenotype by activated platelets is implicated in the pathogenesis of inflammatory diseases, including atherosclerosis. In this study, we investigated the early signaling events associated with this platelet-induced inflammatory phenotype. We report that coculture of human monocytes with activated platelets induces phosphorylation of Akt, together with rapid mobilization of intracellular Ca(2+), and show that these signaling events can be uncoupled from monocyte binding to activated platelets. Specifically, Ab-inhibition studies and incubation of monocytes with activated platelet supernatant highlighted a role for secreted product(s) of activated platelets. We also identified a role for pertussis toxin-sensitive G protein-coupled receptors and excluded key candidates platelet-activating factor receptor and CCR5. Our results suggest that inhibition of monocyte-platelet interactions via PSGL-1 or P-selectin is not sufficient to prevent platelet-mediated monocyte activation in an inflammatory context. These findings have important implications for the development of therapeutics to treat diseases in which platelet-monocyte complexes are implicated in pathogenesis.

Effects of home-based resistance training and neuromuscular electrical stimulation in knee osteoarthritis: a randomized controlled trial.

BACKGROUND: Quadriceps femoris muscle (QFM) weakness is a feature of knee osteoarthritis (OA) and exercise programs that strengthen this muscle group can improve function, disability and pain. Traditional supervised resistance exercise is however resource intensive and dependent on good adherence which can be challenging to achieve in patients with significant knee OA. Because of the limitations of traditional exercise programs, interest has been shown in the use of neuromuscular electrical stimulation (NMES) to strengthen the QFM. We conducted a single-blind, prospective randomized controlled study to compare the effects of home-based resistance training (RT) and NMES on patients with moderate to severe knee OA. METHODS: 41 patients aged 55 to 75 years were randomised to 6 week programs of RT, NMES or a control group receiving standard care. The primary outcome was functional capacity measured using a walk test, stair climb test and chair rise test. Additional outcomes were self-reported disability, quadriceps strength and cross-sectional area. Outcomes were assessed pre- and post-intervention and at 6 weeks post-intervention (weeks 1, 8 and 14 respectively). RESULTS: There were similar, significant improvements in functional capacity for the RT and NMES groups at week 8 compared to week 1 (p ≤ 0.001) and compared to the control group (p < 0.005), and the improvements were maintained at week 14 (p ≤ 0.001). Cross sectional area of the QFM increased in both training groups (NMES: +5.4%; RT: +4.3%; p = 0.404). Adherence was 91% and 83% in the NMES and RT groups respectively (p = 0.324). CONCLUSIONS: Home-based NMES is an acceptable alternative to exercise therapy in the management of knee OA, producing similar improvements in functional capacity. TRIAL REGISTRATION: Current Controlled Trials ISRCTN85231954.