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We determined the role of p38 mitogen-activated protein kinase (MAPK), 72-kDa heat shock protein (HSP72), and antioxidant enzymes in whole body heat stress (HS)-induced cardioprotection in mouse hearts. Adult male mice were treated with either HS or anesthesia only. At 0.5, 48, 72, or 120 h later, the hearts were subjected to 20 min of global ischemia and 30 min of reperfusion in Langendorff mode. A significant protection against ischemia-reperfusion injury was observed 48 h after HS as demonstrated by: 1) reduction in infarct size; 2) decrease in leakage of lactate dehydrogenase; and 3) enhanced postischemic ventricular contractile function. No such protection was observed at other post-HS time points. HS caused an ~25% increase in phosphorylated c-Jun [NH.sub.2]-terminal kinase (JNK) but not p38 MAPK in the heart during the first 2-h post-HS time period. Cardioprotection was abolished by the MAPK inhibitor SB-203580, which also partially suppressed the HS-induced JNK phosphorylation. The protective effect was associated with a two- to threefold increase in HSP72 protein accumulation, but not antioxidant enzyme activities (catalase and Cu/Zn and Mn SOD) in the myocardium. Although HSP72 levels remained high 72 h after HS, the cardioprotection had already disappeared. We conclude that HS induces a transient delayed cardioprotection at 48 h after thermal stress in mice which appears to be mediated via a MAPK-signaling pathway. ischemia; reperfusion; signal transduction; antioxidants; myocardial preconditioning

Purpose To determine aspects of the design of pediatric registries that contribute to the success of registries conducted as a postmarketing study following approval of drugs or biological products by the US Food and Drug Administration. Methods Pediatric registries for drugs and biological products were identified by searching the US Food and Drug Administration Postmarketing Requirements and Commitments database. Based on the recruitment of patients, the meeting of predetermined deadlines, and the submission of data, we classified studies as successful, unsuccessful, or unevaluable. Design aspects of successful and unsuccessful registries were examined for commonalities. Results Thirty-eight studies were identified, and ten registries met the criteria for successful. Four (40%) successful registries utilized a registry established prior to product approval, and six (60%) were disease-based. Among unsuccessful registries, none were disease-based or utilized a pre-existing registry. Conclusions Characteristics identified as more common to successful registries included utilizing a disease-based registry and a registry established prior to product approval. Future studies might examine a larger sample of registries to see if these aspects consistently result in successful studies. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Severe Mg2+ deficiency provokes pro-oxidative and pro-inflammatory changes, and also has been shown to be pro-apoptotic in thymus and certain cell cultures. In this study we examined the extent that chronic severe dietary Mg2+ deficiency induces apoptosis in the heart. Sprague-Dawley rats were fed during three weeks with normal (25 mM, Mg-control) or magnesium deficient (2.25 mM, Mg-deficient) diets, after which, hearts were harvested and frozen. DNA fragmentation was examined in heart tissue sections, and while < 1% of nuclei were positive for apoptosis in Mg-control rat tissue, over 32% of nuclei gave positive for Klenow fragments in hearts from Mg-deficient rats. Caspase 3 activity measurements in heart homogenates showed a 3.9-fold increase in enzyme activity in Mg-deficient rat hearts compared to Mg-controls (p < 0.002); and furthermore, western blot analysis of cleaved PARP (caspase 3 substrate), showed a 4.6-fold increase of cleaved PARP in Mg-deficient rat hearts (p < 0.002). In summary, our data indicate that chronic Mg2+ deficiency induces apoptosis of myocardium in vivo.

Inducible nitric oxide synthase (iNOS) mediates late preconditioning (PC) induced by ischemia and pharmacological agents. Since alpha -adrenoceptor (alpha -AR) stimulation is one of the key triggers of PC, we hypothesized that activation of this receptor may induce delayed cardioprotective effect via iNOS-sensitive mechanisms. Adult male ICR mice were treated i.p. with either vehicle/inhibitors or phenylephrine (10 mg/kg) and subjected to 30 min of global ischemia and 30 min reperfusion in Langendorff mode 24 h later. 5-Methyl-urapidil (3 mg/kg) and chloroethylclonidine (3 mg/kg) were injected 15 min prior to phenylephrine to block alpha -AR(1A) and alpha -AR(1B) receptors respectively. S-Methylisothiourea (3 mg/kg), an iNOS inhibitor, was given 60 min prior to ischemia in phenylephrine-pretreated mice. Preischemic NO(x) was measured using a chemoluminescence reaction. Phenylephrine treatment reduced infarct size from 31.10 +/- 0.79% (vehicle) to 14.24 +/- 0.84% (P<0.001). Chloroethylclonidine blocked the effect of phenylephrine (infarct size 31.31 +/- 1.69%) but 5-methyl-urapidil (17.72 +/- 1.25%) did not. Phenylephrine-induced delayed cardioprotection was abolished by S-methylisothiourea and absent in iNOS knockout mice. Baseline NO(x) content was significantly increased in phenylephrine and 5-methyl-urapidil+phenylephrine treated hearts, but remained at baseline levels in hearts treated with chloroethylclonidine, 5-methyl-urapidil or S-methylisothiourea. Western blot analysis revealed a 1.8-fold increase in iNOS with phenylephrine, which was inhibited by chloroethylclonidine but not by 5-methyl-urapidil. We conclude that phenylephrine-induced delayed PC is mediated by selective activation of alpha-AR(1B). Enhanced iNOS expression concomitant with increased NO synthesis, as well as pharmacological blockade and absence of cardioprotection in iNOS knockout mice suggests an essential role of NO in phenylephrine triggered late PC., (Copyright 2002 Academic Press.)