Randomised controlled trial of a mobile phone infant resuscitation guide.

AIM: The aim of this study was to develop a mobile phone resuscitation guide (MPRG) and to evaluate its use during simulated resuscitation of a mannequin. METHODS: An MPRG was developed using EpiSurveyor. A randomised controlled trial was performed in school-going children aged 15-16 years. All subjects were taught infant CPR skills using the American Heart Association Infant CPR Anytime. Two weeks later, the students were randomised to use of MPRG or not, and their CPR skills were re-assessed. The assessment was conducted using previously validated checklists. RESULTS: Twenty-one students participated in this trial. The MPRG group performed notably better in the areas of calling emergency services (80% vs. 36.4%, P = 0.044), completing sufficient CPR cycles (90% vs. 45.5%, P = 0.047) and following the correct CPR sequence (60% vs. 9.1%, P = 0.013). No difference in resuscitation skills of participants was observed. CONCLUSIONS: We have shown that participants were more likely to call emergency services if they were using the MPRG. Further trials are needed to investigate the utility of mobile phone guides and whether or not they can reduce the time taken to contact emergency services as well as if they can sustain correct CPR sequence in an in-vivo setting.

Three decades of quality improvement in electroconvulsive therapy: exploring the role of accreditation.

OBJECTIVES: This study aims to track electroconvulsive therapy (ECT) clinics' compliance with standards for the administration of ECT before and after the introduction of the Electroconvulsive Therapy Accreditation Service (ECTAS) in 2003. METHODS: Three audits on the practice of ECT were retrospectively analyzed, and ECTAS data from 2004 to 2011 were prospectively analyzed. Overall compliance with 10 ECT audit standards was presented in 2 ways: annually and for each of the 3 waves of accreditation. RESULTS: There have been continuing improvements since the introduction of the accreditation service in compliance with all 10 ECT audit standards whether measured annually or by accreditation cycle, although these improvements have not been linked to changes in clinical outcomes. CONCLUSIONS: Although improvements in ECT delivery have coincided with the accreditation service, other factors may have also contributed.

TGF-beta1-Induced MAPK activation promotes collagen synthesis, nodule formation, redox stress and cellular senescence in porcine aortic valve interstitial cells.

BACKGROUND AND AIM OF THE STUDY: Aortic valve stenosis is a major cause of valve replacement, particularly in the elderly. TGF-beta1 is upregulated in stenotic valves and induces calcification and collagen synthesis in cultured valve interstitial cells. It has been shown previously that TGF-beta1 increases reactive oxygen species (ROS) in these cells in association with calcifying nodule formation, but the cellular signaling pathways responsible for these TGF-beta1-induced effects are not well defined. METHODS: Cultured porcine aortic valve interstitial cells were used to investigate the effects of inhibitors of TGF-beta1 signaling pathways on 3H-proline incorporation into the extracellular matrix, the peak number of calcifying nodules formed, redox stress as dichlorofluorescein diacetate (DCF-DA) fluorescence, and senescence-associated beta-galactosidase staining. RESULTS: Nodule formation and proline incorporation were inhibited by SB431542, implicating the Smad pathway, by SB203580, implicating the P38 MAPK pathway, and by U0126, implicating the Mekl/2/Erk1/2 pathway in both processes. Fasudil, an inhibitor of the Rho kinase pathway, was selective in inhibiting nodule formation but not proline incorporation. It was verified that Smad2 phosphorylation, Erk1/2 phosphorylation and p38 MAPK phosphorylation were all induced by TGF-beta1, with Smad 2 phosphorylation peaking at 1-2 h and MAPK phosphorylation at 24-48 h. The effect of TGF-beta1 on phosphorylation of Smad 2 was inhibited by SB431542, on the phosphorylation of p38 MAPK was inhibited by SB203580, and on the phosphorylation of Erk1/2 was inhibited by U0126. ROS generation in response to TGF-beta1, measured as 2,7-dichlorofluorescein-diacetate fluorescence, was inhibited significantly by SB203580 and U0126, implicating both the p38 MAPK and Mekl/2/Erk1/2 signaling pathways. Both pathways also mediated TGF-beta1-induced cellular senescence which was localized to cellular aggregates and mature nodules. CONCLUSION: These data imply that the inhibition of either Smad or MAPK signaling pathways may have a therapeutic benefit in ameliorating the adverse pathological changes associated with aortic valve stenosis.

Inhibition of calcifying nodule formation in cultured porcine aortic valve cells by nitric oxide donors.

Calcific aortic stenosis displays some similarities to atherosclerosis including evidence of endothelial dysfunction. Whether nitric oxide (NO), which is produced by valvular endothelium, has direct protective effects extending to calcification processes in aortic valve cells has not previously been examined. In vitro calcifying nodules in porcine aortic valve interstitial cell cultures, formed in response to transforming growth factor-beta1 (TGF-beta1) 5 ng/ml, were inhibited by NO donors DETA-NONOate 5-100 microM, and sodium nitroprusside (SNP) 3 microM. Raising intracellular cGMP concentrations, via 8-bromo cGMP 1 mM or via brain natiuretic peptide and C-type natiuretic peptide 0.1 microM, inhibited TGF-beta1-induced nodule formation, potentially implicating the cGMP pathway in the NO effect. Stimulation of interstitial cells with substance P or calcium ionophone (A23187) caused NO release and increased intracellular cGMP respectively. However in the presence of TGF-beta1 basal levels of NO production via nitric oxide synthase (NOS) were insufficient to affect nodule formation. Increased dihydroethidium (DHE) fluorescence in response to TGF-beta1, which was inhibited by DETA-NONOate and TEMPOL, suggested a role for intracellular superoxide in TGF-beta1 signalling. Moreover, nodule formation was suppressed by superoxide scavengers TEMPOL, hydralazine and polyethylene glycol-superoxide dismutase (PEG-SOD), but not SOD. In conclusion, NO donors, or agents raising intracellular cGMP levels, may protect aortic valve interstitial cells from early events leading to calcification.

Effect of the anti-anginal agent, perhexiline, on neutrophil, valvular and vascular superoxide formation.

The prophylactic anti-anginal agent, perhexiline, may also be effective in acute coronary syndromes and advanced aortic valvular stenosis, conditions associated with enhanced inflammation. Its potential effects on superoxide formation via NADPH oxidase were measured by lucigenin-mediated chemiluminescence. Perhexiline inhibited superoxide formation in intact neutrophils stimulated with formyl Met Leu Phe (fMLP) 4 muM or with phorbol myristate acetate (PMA) 162 nM - IC50 2.3 microM (1.5-3.6), n=4. Sub-unit assembly of NADPH oxidase by PMA was unaffected by pretreatment with perhexiline 2 microM, a concentration which reduced superoxide formation by 44+/-5% (n=4) in intact neutrophils. Perhexiline inhibited preassembled neutrophil NADPH oxidase and that in membranes of pig valve interstitial cells, human umbilical vein endothelial cells (HUVECs) and cardiac fibroblasts, but not that in rat aorta (rings or membrane preparations). These data imply that perhexiline inhibits the phagocytic NADPH oxidase directly, and that pig aortic valvular interstitial cells possess a similar enzyme, a conclusion supported by immunohistochemical localisation of the gp91phox subunit in these cells. However further study is required to clarify the effect of perhexiline on different NADPH oxidase isoforms particularly in the vasculature.

Dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium.

The antianginal agent perhexiline inhibits rat cardiac carnitine palmitoyltransferase-1 (CPT-1) and CPT-2, key enzymes for mitochondrial transport of long-chain fatty acids. We tested the hypothesis that perhexiline, in therapeutic concentrations (2 microM), inhibits palmitate oxidation and enhances glucose oxidation in isolated rat cardiomyocytes and in the working rat heart, thereby increasing efficiency of oxygen utilization. In isolated cardiomyocytes, perhexiline (2 microM) exerted no acute effects on palmitate oxidation, but after 48 hours pre-exposure oxidation was inhibited by perhexiline (2 to 10 microM) by 15% to 35% (P < 0.0002). In non-ischemic working rat hearts (3%BSA, 0.4 mM palmitate, 11 mM glucose, 100 microU/mL insulin) perhexiline (2 microM) had no significant acute effect on cardiac efficiency, palmitate or glucose oxidation, but 24 hours pretreatment with transdermal perhexiline increased cardiac work (by 29%, P < 0.05) and cardiac efficiency (by 30%, P < 0.02) without significant effects on palmitate oxidation. The selective CPT-1 inhibitor oxfenicine (2 mM) inhibited palmitate oxidation and enhanced glucose oxidation, but failed to enhance cardiac efficiency. In conclusion, in the non-ischemic working rat heart, perhexiline increases myocardial efficiency by a mechanism(s) that is largely or entirely independent of its effects on CPT. Effects on cardiac efficiency during ischemia, and with changes in fatty acid oxidation after longer perhexiline pretreatment remain to be determined.

Differential production of adrenal steroids by purified cells of the human adrenal cortex is relative rather than absolute.

OBJECTIVES: The adrenal cortex produces aldosterone, cortisol and androgens in response to ACTH and angiotensin II. To define the differential response of morphologically distinct cells of the adrenal cortex, we examined the phenotypical and functional characteristics of human adrenocortical cells. RESULTS: Tumour growth factor-beta receptor-1 (TGFbeta-R1) and CYP-11 were found to be expressed predominantly in the zona fasciculata, whereas human leukocyte antigen (HLA-DR) and CYP-17 were localised to the zona reticularis. The angiotensin II receptor, AT-1, was found to be predominantly expressed in the zona glomerulosa. Adrenocortical cells, separated by density, yielded two distinct fractions which displayed differential growth patterns. Lipid-rich cells of fraction I expressed TGFbeta-R1 and produced significantly more cortisol relative to androstenedione than unseparated or fraction II cells, whereas lipid-poor cells of fraction II expressed HLA-DR and produced more androstenedione relative to cortisol in the presence of ACTH. Aldosterone production by fraction II was significantly greater than fraction I or unseparated cells. TGFbeta-R1-positive fasciculata-type cells separated into fraction I and HLA-DR-positive cells consistent with reticularis cells separated into fraction II. Aldosterone-producing cells indicative of glomerulosa cells separated into fraction II. CONCLUSIONS: Our findings are consistent with the concept that all adrenocortical cells are capable of producing a range of steroids, but the relative production of cortisol, androgen and aldosterone differs.