Palmitate-TLR4 signaling regulates the histone demethylase, JMJD3, in macrophages and impairs diabetic wound healing.

Chronic macrophage inflammation is a hallmark of type 2 diabetes (T2D) and linked to the development of secondary diabetic complications. T2D is characterized by excess concentrations of saturated fatty acids (SFA) that activate innate immune inflammatory responses, however, mechanism(s) by which SFAs control inflammation is unknown. Using monocyte-macrophages isolated from human blood and murine models, we demonstrate that palmitate (C16:0), the most abundant circulating SFA in T2D, increases expression of the histone demethylase, Jmjd3. Upregulation of Jmjd3 results in removal of the repressive histone methylation (H3K27me3) mark on NFκB-mediated inflammatory gene promoters driving macrophage-mediated inflammation. We identify that the effects of palmitate are fatty acid specific, as laurate (C12:0) does not regulate Jmjd3 and the associated inflammatory profile. Further, palmitate-induced Jmjd3 expression is controlled via TLR4/MyD88-dependent signaling mechanism, where genetic depletion of TLR4 (Tlr4-/- ) or MyD88 (MyD88-/- ) negated the palmitate-induced changes in Jmjd3 and downstream NFκB-induced inflammation. Pharmacological inhibition of Jmjd3 using a small molecule inhibitor (GSK-J4) reduced macrophage inflammation and improved diabetic wound healing. Together, we conclude that palmitate contributes to the chronic Jmjd3-mediated activation of macrophages in diabetic peripheral tissue and a histone demethylase inhibitor-based therapy may represent a novel treatment for nonhealing diabetic wounds.

Performance management of Clostridium difficile infection in hospitals - The carrot or stick approach?

Public and political pressure for healthcare quality indicator monitoring, specifically healthcare-associated infection (HAI) has intensified the debate regarding the merits of public reporting and target setting as policy approaches. This paper reviews the evidence for these approaches with a focus on HAI, including Clostridium difficile infection (CDI). Healthcare key performance indicators (KPIs) and associated targets have been used widely with little evaluation. While targets are associated with some HAI reductions including CDI, as their control is multi-factorial, it is likely that reductions are due to numerous, concurrent control measures. Targets may help tackle organizational-wide issues that require high level management engagement and have contributed to the increased access and influence of infection control teams. HAI public reporting has also gained traction and is mandatory in many countries despite little scientific evaluation. CDI is one of the KPIs used but there is little consensus as to the best KPI for public reporting. Countries without public reporting have also seen improvements. Using indicator-based strategies rather than evidence-based ones risk improving the KPI but not necessarily quality of care. 'Bottom-up' approaches focussing on quality improvement and innovation generated by front line staff are seen as a lever for sustainable change. Positive deviance, where the resourcefulness and problem solving abilities of staff is harnessed, enables 'bottom-up' changes with process and outcome improvements. As implementation of best practice in healthcare is dependent on behavioural and cultural change, it is most likely that a combination of 'top-down' and 'bottom-up' approaches are required for sustainable improvement. This combined approach was used to improve staff influenza vaccination rates. Regulation may initially direct the spot-light onto infection control needs but true sustainable HAI reduction will only be fostered with concurrent cultural and behavioural shifts in practice and ownership of the HAI burden across clinical, policy and management domains. It will be interesting if this approach will be increasingly used by policy makers, however, irrespective it is clear that there is a need for rigorous evaluation of our HAI policy approaches from this point forward.