Recent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously reported that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase (AMPK) in immortalised cell lines and murine hepatocytes. As AMPK has anti-inflammatory actions in vascular cells, we examined whether SGLT2 inhibitors attenuated inflammatory signalling in cultured human endothelial cells. Incubation with clinically-relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin activated AMPK and inhibited IL-1β-stimulated adhesion of pro-monocytic U937 cells and secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1). Inhibition of MCP-1 secretion was attenuated by expression of dominant-negative AMPK and was mimicked by the direct AMPK activator, A769662. Stimulation of cells with either canagliflozin or A769662 had no effect on IL-1β-stimulated cell surface levels of adhesion molecules or nuclear factor-κB signalling. Despite these identical effects of canagliflozin and A769662, IL-1β-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but not A769662, whereas IL-1β-stimulated c-jun N-terminal kinase phosphorylation was inhibited by A769662, but not canagliflozin. These data indicate that clinically-relevant canagliflozin concentrations directly inhibit endothelial pro-inflammatory chemokine/cytokine secretion by AMPK-dependent and -independent mechanisms without affecting early IL-1β signalling.

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A patient with sea-blue histiocytosis in spleen and bone marrow with an accompanying hyperlipidaemia is described. The hyperlipidaemia was due to an increase in "free" cholesterol, lecithin, and triglycerides. Despite these findings lecithin-cholesterol acyl transferase activity was normal. Although the precise biochemical defect was not identified, there was a failure of transport of cholesterol from chylomicrons in vitro. We propose that the sea-blue histiocyte is a marker, in some cases, of abnormal lipid metabolism.

In a 5-year period, 11 cases of farmer's lung were seen in Caithness giving a prevalence in the total population of 7.8 per 100,000 per year and in the farming population, 110 per 100,000 per year. A serological survey of 50 healthy farmers revealed 4 with anti-complementary reactions in the complement fixation test for M.faeni and none with positive gel diffusion tests for F.L.H. precipitins. The prevalence of this disease may have a correlation with rainfall.

Excitation-contraction coupling in the heart critically depends on the function of ryanodine receptors (RyRs). While advances in single-molecule localization microscopy (SMLM) have allowed 2D visualization of RyRs at the nanoscale level, the precise cellular localisation of RyRs in 3D in both health and disease has yet to be characterized. We presently utilised our recently developed 3D direct stochastic optical reconstruction microscopy (3D dSTORM) method to quantify the subcellular distribution of RyRs in normal and failing (post-infarction) rat cardiomyocytes, hypothesizing that breakup of RyR clusters may contribute to dysregulated Ca 2þ homeostasis during heart failure. We specifically examined the nanoscale arrangement of two subpopulations of RyRs: sarcolemmaassociated surface clusters and transverse tubule-associated interior clusters. Using 3D dSTORM, we observed a clear difference between surface and interior RyR cluster size in normal cardiomyocytes (13.550.6 and 16.050.7 RyRs/ cluster, respectively, p<0.05). In failing cardiomyocytes, both surface and interior RyR cluster sizes were significantly reduced when compared to normal cells (9.750.7 and 10.550.6 RyRs/cluster, respectively, p<0.05). Interestingly, post-infarct non-failing cardiomyocytes only exhibited reduced cluster size within the cell interior (10.250.6 RyRs/cluster, p<0.05 vs normal), suggesting that RyR dispersion may initially occur at these sites. Ca 2þ release units (CRUs), which are functional groups of RyR clusters responsible for the cooperative generation of Ca 2þ sparks, contained significantly fewer RyRs in failing cells (surface: 20.650.8 vs. 17.051.1 RyRs/CRU in failing, p<0.05; interior: 24.250.9 vs. 18.351.0 RyRs/CRU in failing, p<0.05) and exhibited more dispersed organization. These alterations were paralleled by an observed slowing of Ca 2þ spark kinetics and greater RyR Ca 2þ leak in failing cells. Together, our results identify disassembly of RyR clusters as a novel mechanism underlying impaired cardiomyocyte Ca 2þ homeostasis in heart failure.