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The transition from paediatric to adult medicine involves risks of poor patient outcomes and of significant losses of patients to follow up. The research aimed to analyse the implementation in an initial cohort of patients of a new programme of transition to adult care based on a case management approach.A longitudinal study of the case management approach to transition, initiated in a university hospital in France in September 2016.Patients with the endocrine or metabolic disease diagnosed during childhood and transferred to adult care were included. The transition programme includes three steps based on case management: liaising with paediatric services, personalising care pathways, and liaising with structures outside the hospital (general practitioners, agencies in the educational and social sector).The cohort included 500 patients, with malignant brain tumour (n= 56 (11%)), obesity (n= 55 (11%)), type 1 diabetes (n= 54 (11%)), or other disease (n= 335 (67%)). Their median age at transfer was 19, and the sex ratio was 0.5. At median 21 months of follow-up, 439 (88%) had a regular follow-up in or outside the hospital, 47 (9%) had irregular follow-up (absence at the last appointment or no appointment scheduled within the time recommended), 4 had stopped care on doctor’s advice, 4 had died, 3 had moved, and 3 had refused care. The programme involved 9615 case management actions; 7% of patients required more than 50 actions. Patients requiring most support were usually those affected by a rare genetic form of obesity.Case managers successfully addressed the complex needs of patients. Over time, the cohort will provide unprecedented long-term outcome results for patients with various conditions who experienced this form of transition.

After the thrombus formation in cardiac cavities or coronaries, the serine protease thrombin is produced and can therefore reach the myocardial tissue by the active process of extravasation and binds to the G protein-coupled protease-activated receptor-1 (PAR1) expressed in human myocardium. The role of PAR1 was investigated in the thrombin effect on sodium current (INa). INawas recorded in freshly isolated human atrial myocytes by the whole-cell patch-clamp method. Action potentials (AP) were recorded in guinea pig ventricular tissue by the conventional glass microelectrode technique. Thrombin-activated PAR1 induced a tetrodotoxin-blocked persistent sodium current, INaP, in a concentration-dependent manner with an apparent EC50of 28 U/ml. The PAR1 agonist peptide SFLLR-NH2(50 μM) was able to mimic PAR1-thrombin action, whereas PAR1 antagonists N3-cyclopropyl-7-((4-(1-methylethyl)-phenyl)methyl)-7H-pyrrolo(3,2-f)quinazoline-1,3-diamine (SCH 203099; 10 μM) and 1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-3-hydroxy-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanone (ER 112787) (1 μM), completely inhibited it. The activated PAR1 involves the calcium-independent phospholipase-A2signaling pathway because two inhibitors of this cascade, bromoenol lactone (50 μM) and haloenol lactone suicide substrate (50 μM), block PAR1-thrombin-induced INaP.Asa consequence of INaPactivation, in guinea pig right ventricle papillary muscle, action potential duration (APD) were significantly increased by 20% and 15% under the respective action of 32 U/ml thrombin and 50 μM SFLLR-NH2, and these increases in APD were prevented by 1 μM tetrodotoxin or markedly reduced by application of 1 μM SCH 203099 or ER 112787. Thrombin, through PAR1 activation, increases persistent component of the Na+current resulting in an uncontrolled sodium influx into the cardiomyocyte, which can contribute to cellular injuries observed during cardiac ischemia.

After the thrombus formation in cardiac cavities or coronaries, the serine protease thrombin is produced and can therefore reach the myocardial tissue by the active process of extravasation and binds to the G protein-coupled protease-activated receptor-1 (PAR1) expressed in human myocardium. The role of PAR1 was investigated in the thrombin effect on sodium current (INa). INawas recorded in freshly isolated human atrial myocytes by the whole-cell patch-clamp method. Action potentials (AP) were recorded in guinea pig ventricular tissue by the conventional glass microelectrode technique. Thrombin-activated PAR1 induced a tetrodotoxin-blocked persistent sodium current, INaP, in a concentration-dependent manner with an apparent EC50of 28 U/ml. The PAR1 agonist peptide SFLLR-NH2(50 µM) was able to mimic PAR1-thrombin action, whereas PAR1 antagonists N3-cyclopropyl-7-((4-(1-methylethyl)-phenyl)methyl)-7H-pyrrolo(3,2-f)quinazoline-1,3-diamine (SCH 203099; 10 µM) and 1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-3-hydroxy-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanone (ER 112787) (1 µM), completely inhibited it. The activated PAR1 involves the calcium-independent phospholipase-A2signaling pathway because two inhibitors of this cascade, bromoenol lactone (50 µM) and haloenol lactone suicide substrate (50 µM), block PAR1-thrombin-induced INaP.Asa consequence of INaPactivation, in guinea pig right ventricle papillary muscle, action potential duration (APD) were significantly increased by 20% and 15% under the respective action of 32 U/ml thrombin and 50 µM SFLLR-NH2, and these increases in APD were prevented by 1 µM tetrodotoxin or markedly reduced by application of 1 µM SCH 203099 or ER 112787. Thrombin, through PAR1 activation, increases persistent component of the Na+current resulting in an uncontrolled sodium influx into the cardiomyocyte, which can contribute to cellular injuries observed during cardiac ischemia.

An efficient gene delivery system is a prerequisite for myocardial gene therapy. Among the various procedures studied so far, catheter-based percutaneous gene delivery to the myocardium through the coronary vessels seems the most relevant to routine clinical practice; however, the optimal conditions remain to be determined. We selectively infused adenoviral vectors encoding luciferase (1 × 109 PFU) or β-galactosidase (1 × 1010 PFU) into coronary arteries of adult rabbits in various experimental conditions. Coronary artery occlusion for 30 sec, during and after adenovirus delivery, was required to observe luciferase activity in the target area of the circumflex artery (4.0 ± 1.0 × 105 vs. 1.1 ± 0.2 × 104 RLU/mg with and without coronary occlusion, respectively, p < 0.01, and 1.0 ± 0.1 × 103 RLU/mg using nonselective infusion). When adenoviruses were delivered using high-pressure infusion (82 ± 12 vs. 415 ± 25 mmHg before and during infusion, respectively, p < 0.01), luciferase activity increased to 8.5 ± 2.5 × 105 RLU/mg (p < 0.05 vs coronary occlusion alone). Coronary venous sinus occlusion with saline buffer retroinfusion starting before and during anterograde adenovirus delivery resulted in a further 4.7-fold increase in luciferase activity (4.4 ± 0.8 × 106 RLU/mg, p < 0.01) with 5-25% blue-stained myocytes in the target area, compared with 0-5% with the other procedures. Histamine or VEGF-A165 pretreatment, used to increase vascular permeability, slightly increased gene transfer efficiency (8.5 ± 2.0 × 105 and 9.0 ± 2.5 × 105 RLU/mg respectively, p < 0.05 vs. coronary occlusion alone). We conclude that catheter-mediated adenoviral gene transfer to cardiac myocytes through coronary vessels can be a very efficient procedure for myocardial gene therapy, particularly when the vector residence time and perfusion pressure in the vessels are increased.

OBJECTIVES

Background:There are increasing evidences for strong links between metabolic disorders and cardiac diseases such as diabetes and cardiomyopathy or obesity and atrial fibrillation. These epidemiologic observations may not be due to just shared co-morbidities but also from direct impacts of metabolic disorders on myocardium Here, we examined the impact of high fat diet (HFD) induced obesity on atrial properties in mice.Methods:Eight weeks old C57Bl/6J mice were subjected to 2 or 4 months of HFD (60% fat) or normal diet (ND, 4% fat). Metabolomic and lipidomic analysis were performed on whole left atria. Mitochondrial respiration was studied in situ in saponin-permeabilized atrial muscle fibres using a Clarke electrode. Basal mitochondrial respiration rate (in the presence of pyruvate/malate 1/4 mM, without ADP) was measured after addition of 2 mM ADP. Action potential (AP) were recorded in left atrial trabeculae using glass microelectrode technique. Rapid burst atrial pacing were delivered using a trans-esophageal probe to induced AF in anesthetized animals. Potassium currents were recorded in isolated atrial myocytes using the whole cell or perforated patch clamp configurations.Results:In HFD mice, metabolomic analysis indicated an increased consumption of free fatty acid by the beta-oxidation and an accumulation of long chain fatty acid. Whereas no change in mitochondria respiration capacity was observed between ND and HFD, palmitoyl-CoA was the main mitochondria substrate in the latter. APs were shorter in HFD versus ND mice and more sensitive to the K ATP channel blocker, glibenclamide. This atrial electrical remodeling was associated with a higher atrial vulnerability to AF as indicated by longer AF episodes compared to ND mice. In perforated but not whole cell, patch clamped atrial myocytes, the K-ATP component of the potassium current was enhanced in HFD mice (at +70 mV: 0.41?0.12 pA/pF in HFD vs0.13?0.08 pA/pF in ND, P<0.05).Conclusions:High fat diet induces the shift from carbon hydrate to a beta oxidation metabolism of atrial myocardium together with mitochondria respiration changes. This oxidative metabolic alteration is associated with an atrial electrical remodeling