Background: Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. It is caused by mutations/deletions of the survival motor neuron 1 (SMN1) gene and is typified by the loss of spinal cord motor neurons, muscular atrophy, and in severe cases, death. The SMN protein is ubiquitously expressed and various cellular- and tissue-specific functions have been investigated to explain the specific motor neuron loss in SMA. We have previously shown that the RhoA/Rho kinase (ROCK) pathway is misregulated in cellular and animal SMA models, and that inhibition of ROCK with the chemical Y-27632 significantly increased the lifespan of a mouse model of SMA. In the present study, we evaluated the therapeutic potential of the clinically approved ROCK inhibitor fasudil. Methods: Fasudil was administered by oral gavage from post-natal day 3 to 21 at a concentration of 30 mg/kg twice daily. The effects of fasudil on lifespan and SMA pathological hallmarks of the SMA mice were assessed and compared to vehicle-treated mice. For the Kaplan-Meier survival analysis, the log-rank test was used and survival curves were considered significantly different at P < 0.05. For the remaining analyses, the Student's two-tail t test for paired variables and one-way analysis of variance (ANOVA) were used to test for differences between samples and data were considered significantly different at P < 0.05. Results: Fasudil significantly improves survival of SMA mice. This dramatic phenotypic improvement is not mediated by an up-regulation of Smn protein or via preservation of motor neurons. However, fasudil administration results in a significant increase in muscle fiber and postsynaptic endplate size, and restores normal expression of markers of skeletal muscle development, suggesting that the beneficial effects of fasudil could be muscle-specific. Conclusions: Our work underscores the importance of muscle as a therapeutic target in SMA and highlights the beneficial potential of ROCK inhibitors as a therapeutic strategy for SMA and for other degenerative diseases characterized by muscular atrophy and postsynaptic immaturity.

The study aimed to describe worldwide levels and trends of tobacco control policy by comparing low and middle income countries with other income categories from 2007 to 2014 and to analyze the corresponding relation to recent changes in smoking prevalence. Policy measure data representing years 2007 to 2014 were collected from all available World Health Organization (WHO) reports on the global tobacco epidemic. Corresponding policy percentage scores (PS) were calculated based on MPOWER measures. Age-standardized smoking prevalence data for years 2010 and 2015 were collected from the WHO Global Health Observatory Data Repository. Trends of PS were analysed with respect to WHO region and OECD country income category. Scatter plots and regression analysis were used to depict the relationship between tobacco control policy of 2010 and change in smoking prevalence between 2015 and 2010 by sex and income category. Combined PS for all countries increased significantly from 47% in 2007 to 61% by 2014 (p < 0.001). When grouped by income category and region, policies were strengthened in all categories, albeit with varying progression. By 2014, tobacco control policy legislation had reached 45% in the Least Developed Countries (LDCs), 59% in Low Middle Income Countries (LMICs), 66% in Upper Middle Income Countries (UMICs) and 70% in High Income Countries (HICs). Overall, there was a negative relationship between higher policy scores and change in smoking prevalence. Although policy strengthening had been conducted between 2007 and 2014, room for considerable global improvement remains, particularly in LDCs.