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 Ca2+, 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.

Introduction Cardiac Implantable Electronic Devices (CIEDs) are increasing in prevalence. Exposing patients with CIEDs to 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 performed. Monitoring and re-evaluation of the CIED-MRI pathway were instigated at departmental QA meetings. Results Interventions included direct CIED characterisation 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 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 appropriate multidisciplinary support. We found FMEA an indispensable tool in identifying and minimizing risk with no adverse events recorded since FMEA recommendations were implemented.

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46Impaired hepatic glucose and lipid metabolism are hallmarks of type-2 diabetes. 47 Increased sulfide production from cysteine, or sulfide-donor compounds, may 48 beneficially regulate hepatic metabolism. Disposal of sulfide through the sulfide 49 oxidation pathway (SOP) is critical for maintaining sulfide within a safe physiological 50 range. We show that mice lacking the liver-enriched mitochondrial SOP enzyme 51 thiosulfate sulfur-transferase (Tst -/mice) exhibit high circulating sulfide, increased 52 gluconeogenesis, hypertriglyceridemia and fatty liver, despite whole-body insulin-53 sensitisation. Unexpectedly, hepatic sulfide levels were normal in Tst -/mice, a result 54 of homeostatic induction of mitochondrial sulfide disposal and glutathione excretion 55 associated with net suppression of protein persulfidation and nuclear respiratory factor-56 2 target proteins. Proteomic and persulfidomic profiling converged on hepatic lipid 57 metabolism, revealing a deficit in medium-chain fatty acid oxidation in Tst -/mice. In 58 conclusion our findings have implications for sulfide-donor strategies in the context of liver 59 function and metabolic disease.60 61 2016;65(10):3171-3184.

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