Mechanisms of propranolol action in infantile hemangioma

Infantile hemangioma is a common tumor of infancy. Although most hemangiomas spontaneously regress, treatment is indicated based on complications, risk to organ development and function, and disfigurement. The serendipitous discovery of propranolol, a non-selective b-adrenergic receptor blocker, as an effective means to regress hemangiomas has made this a first-line therapy for hemangioma patients. Propranolol has shown remarkable response rates. There are, however, some adverse effects, which include changes in sleep, acrocyanosis, hypotension, and hypoglycemia. Over the last few years, researchers have focused on understanding the mechanisms by which propranolol causes hemangioma regression. This has entailed study of cultured vascular endothelial cells including endothelial cells isolated from hemangioma patients. In this article, we review recent studies offering potential mechanisms of how various cell types found in hemangioma may respond to propranolol

Propranolol inhibits growth of hemangioma-initiating cells but does not induce apoptosis

Background: Infantile hemangioma (IH) is the most common tumor of infancy. The first-line therapy for IH is propranolol, a nonselective β-adrenergic receptor antagonist. However, mechanisms for the therapeutic effect of propranolol and regrowth of IH following cessation of treatment in some cases are not clear. We have recently shown that IH arises from multipotent stem cells. Whether IH stem cells are responsive to propranolol and are selectively targeted is unknown, and this is the focus of this study. Methods: IH stem cells were exposed to propranolol and were assayed for cellular and molecular alterations. We used endothelial cells (ECs) as controls and bone marrow-derived mesenchymal progenitor cells (bm-MPCs) as normal stem/progenitor counterparts to determine selectivity. Results: Our results show that propranolol significantly reduced IH stem cell growth but failed to induce caspase-3 activation. Normal bm-MPCs and mature ECs showed maintained or increased caspase-3 activation and significantly reduced cyclin-D1 levels. We further show that IH stem cells may escape apoptosis by inducing antiapoptotic pathways. Conclusion: This study reveals that propranolol does not induce apoptosis in IH stem cells, which is in contrast with the result for ECs. Escape from apoptosis in IH stem cells may involve induction of antiapoptotic pathways. Copyright © 2014 International Pediatric Research Foundation, Inc

Impact of Cardiorespiratory Fitness on Survival in Men with Low Socioeconomic Status

Aims Although both low socioeconomic status (SES) and poor cardiorespiratory fitness (CRF) are associated with increased chronic disease and heightened mortality, it remains unclear whether moderate-to-high levels of CRF are associated with survival benefits in low SES populations. This study evaluated the hypothesis that SES and CRF predict all-cause mortality and cardiovascular disease mortality and that moderate-to-high levels of CRF may attenuate the association between low SES and increased mortality. Methods This study included 2368 men, who were followed in the Kuopio Ischaemic Heart Disease Study cohort. CRF was directly measured by peak oxygen uptake during progressive exercise testing. SES was characterized using self-reported questionnaires. Results During a 25-year median follow-up, 1116 all-cause mortality and 512 cardiovascular disease mortality events occurred. After adjusting for potential confounders, men with low SES were at increased risks for all-cause mortality (hazard ratio 1.49, 95% confidence interval: 1.30–1.71) and cardiovascular disease mortality (hazard ratio1.38, 1.13–1.69). Higher levels of CRF were associated with lower risks of all-cause mortality (hazard ratio 0.54, 0.45–0.64) and cardiovascular disease mortality (hazard ratio 0.53, 0.40–0.69). In joint associations of SES and CRF with mortality, low SES-unfit had significantly higher risks of all-cause mortality (hazard ratio 2.15, 1.78–2.59) and cardiovascular disease mortality (hazard ratio 1.95, 1.48-2.57), but low SES-fit was not associated with a heightened risk of cardiovascular disease mortality (hazard ratio 1.09, 0.80-1.48) as compared with their high SES-fit counterparts. Conclusion Both SES and CRF were independently associated with subsequent mortality; however, moderate-to-high levels of CRF were not associated with an excess risk of cardiovascular disease mortality in men with low SES.peerReviewe

Eating Behaviours of British University Students: A Cluster Analysis on a Neglected Issue

Unhealthy diet is a primary risk factor for noncommunicable diseases. University student populations are known to engage in health risking lifestyle behaviours including risky eating behaviours. The purpose of this study was to examine eating behaviour patterns in a population of British university students using a two-step cluster analysis. Consumption prevalence of snack, convenience, and fast foods in addition to fruit and vegetables was measured using a self-report “Student Eating Behaviours” questionnaire on 345 undergraduate university students. Four clusters were identified: “risky eating behaviours,” “mixed eating behaviours,” “moderate eating behaviours,” and “favourable eating behaviours.” Nineteen percent of students were categorised as having “favourable eating behaviours” whilst just under a third of students were categorised within the two most risky clusters. Riskier eating behaviour patterns were associated with living on campus and Christian faith. The findings of this study highlight the importance of university microenvironments on eating behaviours in university student populations. Religion as a mediator of eating behaviours is a novel finding

Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria

Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving mitochondrial fission, but exactly how Drp1 is regulated remains unclear. Here, we identified Drosophila Clueless and its mammalian orthologue CLUH as key regulators of Drp1. As with loss of drp1, depletion of clueless or CLUH results in mitochondrial elongation, while as with drp1 overexpression, clueless or CLUH overexpression leads to mitochondrial fragmentation. Importantly, drp1 overexpression rescues adult lethality, tissue disintegration and mitochondrial defects of clueless null mutants in Drosophila. Mechanistically, Clueless and CLUH promote recruitment of Drp1 to mitochondria from the cytosol. This involves CLUH binding to mRNAs encoding Drp1 receptors MiD49 and Mff, and regulation of their translation. Our findings identify a crucial role of Clueless and CLUH in controlling mitochondrial fission through regulation of Drp1