Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.

The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta-adrenergic receptor (betaAR) blockade. This was once viewed as counterintuitive, because acute administration causes myocardial depression. Cardiac myocytes from failing hearts show changes in betaAR signaling and excitation-contraction coupling that can impair cardiac contractility, but the role of these abnormalities in the progression of heart failure is controversial. We therefore tested the impact of different manipulations that increase contractility on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy. High-level overexpression of the beta(2)AR caused rapidly progressive cardiac failure in this model. In contrast, phospholamban ablation prevented systolic dysfunction and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice. Cardiac expression of a peptide inhibitor of the betaAR kinase 1 not only prevented systolic dysfunction and exercise intolerance but also decreased cardiac remodeling and hypertrophic gene expression. These three manipulations of cardiac contractility had distinct effects on disease progression, suggesting that selective modulation of particular aspects of betaAR signaling or excitation-contraction coupling can provide therapeutic benefit.

The relationship between blood IL-12p40 level and melanoma progression

© 2014 UICC.Cytokines such as Interleukin (IL)212p70 ("IL-12") and IL-23 can influence tumor progression. We tested the hypothesis that blood levels of IL-12p40, the common subunit of both cytokines, are associated with melanoma progression. Blood from 2,048 white melanoma patients were collected at a single institution between March 1998 and March 2011. Plasma levels of IL-12p40 were determined for 573 patients (discovery), 249 patients (Validation 1) and 244 patients (Validation 2). Per 10-unit change of IL-12p40 level was used to investigate associations with melanoma patient outcome among all patients or among patients with early or advanced stage. Among stage I/II melanoma patients in the pooled data set, after adjustment for sex, age, stage and blood draw time from diagnosis, elevated IL-12p40 was associated with melanoma recurrence [hazard ratio (HR)51.04 per 10-unit increase in IL-12p40, 95% CI 1.02-1.06, p58.48 × 10-5]; Elevated IL-12p40 was also associated with a poorer melanoma specific survival (HR51.06, 95% CI 1.03-1.09, p53.35 × 10-5) and overall survival (HR51.05, 95% CI 1.03-1.08, p58.78 × 10-7) in multivariate analysis. Among stage III/IV melanoma patients in the pooled data set, no significant association was detected between elevated IL-12p40 and overall survival, or with melanoma specific survival, with or without adjustment for the above covariates. Early stage melanoma patients with elevated IL-12p40 levels are more likely to develop disease recurrence and have a poorer survival. Further investigation with a larger sample size will be needed to determine the role of IL-12p40 in advanced stage melanoma patients.

Prevalence, Incidence and Progression of Myopia in Singaporean Adolescents

The Singapore Cohort Study of the Risk Factors for myopia (SCORM) is a longitudinal school-based study that recruited 1979 children, aged 7 to 9 years old between 1999 and 2001, who were re-examined as adolescents in 2006 and 2007. This current study is to determine the prevalence, incidence and progression of myopia among Singapore teenagers and describe any trend in the SCORM study.

At each visit, participants underwent comprehensive eye examinations that included cycloplegic autorefraction and ocular biometry measurements. The prevalence of myopia (SE<-0.5D) and high myopia (SE<-6.0D) among Singapore teenagers aged 11-18 years old was 69.1% [95% confidence interval (CI) 66.5-71.7] and 7.1% (95% CI 5.8-8.7), respectively, with the highest prevalence in people of Chinese ethnicity (p<0.001). The annual incidence was 13.7% (95% CI 9.8-17.6). Males had twice the incidence of females (p=0.043), and adolescents with longer axial lengths (p<0.001) and deeper vitreous chamber (p<0.001) had higher myopia incidence. Annual myopia progression was -0.32 Diopters (D) (SD=0.40), with no difference by age, race or gender. However, adolescents with higher myopia levels at 2006 had significantly faster myopia progression rates (p<0.001).

Myopia prevalence in Singapore teenagers, especially Singapore Chinese teenagers, is one of the highest in the world. In adolescents, there is still a high rate of new onset and rapid progression of myopia. These findings indicate that adolescence may still represent a viable period for intervention programs to mitigate myopia onset and progression.