Glucocorticoid levels rise dramatically in late gestation to mature foetal organs in readiness for postnatal life. Immature heart function may compromise survival. Cardiomyocyte glucocorticoid receptor (GR) is required for the structural and functional maturation of the foetal heart in vivo, yet the molecular mechanisms are largely unknown. Here we asked if GR activation in foetal cardiomyocytes in vitro elicits similar maturational changes. We show that physiologically relevant glucocorticoid levels improve contractility of primary-mouse-foetal cardiomyocytes, promote Z-disc assembly and the appearance of mature myofibrils, and increase mitochondrial activity. Genes induced in vitro mimic those induced in vivo and include PGC-1α, a critical regulator of cardiac mitochondrial capacity. SiRNA-mediated abrogation of the glucocorticoid induction of PGC-1α in vitro abolished the effect of glucocorticoid on myofibril structure and mitochondrial oxygen consumption. Using RNA sequencing we identified a number of transcriptional regulators, including PGC-1α, induced as primary targets of GR in foetal cardiomyocytes. These data demonstrate that PGC-1α is a key mediator of glucocorticoid-induced maturation of foetal cardiomyocyte structure and identify other candidate transcriptional regulators that may play critical roles in the transition of the foetal to neonatal heart.

Analysis 17.1. Comparison 17 Honey products versus alternatives, Outcome 1 Complete healing at 12 weeks. . . . Analysis 17.2. Comparison 17 Honey products versus alternatives, Outcome 2 Incidence of ulcer infection during the 12week trial period.

Background. Collaborative care is an effective intervention for depression which includes both organizational and patient-level intervention components. The effect in the UK is unknown, as is whether cluster-or patient-randomization would be the most appropriate design for a Phase III clinical trial.Method. We undertook a Phase II patient-level randomized controlled trial in primary care, nested within a clusterrandomized trial. Depressed participants were randomized to ' collaborative care' -case manager-coordinated medication support and brief psychological treatment, enhanced specialist and GP communication -or a usual care control. The primary outcome was symptoms of depression (PHQ-9).Results. We recruited 114 participants, 41 to the intervention group, 38 to the patient-randomized control group and 35 to the cluster-randomized control group. For the intervention compared to the cluster control the PHQ-9 effect size was 0.63 (95 % CI 0.18-1.07). There was evidence of substantial contamination between intervention and patient-randomized control participants with less difference between the intervention group and patient-randomized control group (x2.99, 95 % CI x7.56 to 1.58, p=0.186) than between the intervention and cluster-randomized control group (x4.64, 95 % CI x7.93 to x1.35, p=0.008). The intra-class correlation coefficient for our primary outcome was 0.06 (95 % CI 0.00-0.32).Conclusions. Collaborative care is a potentially powerful organizational intervention for improving depression treatment in UK primary care, the effect of which is probably partly mediated through the organizational aspects of the intervention. A large Phase III cluster-randomized trial is required to provide the most methodologically accurate test of these initial encouraging findings.

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