Nuclear phosphatase PPM1G in cellular survival and neural development.

BACKGROUND: PPM1G is a nuclear localized serine/threonine phosphatase implicated to be a regulator of chromatin remodeling, mRNA splicing, and DNA damage. However, its in vivo function is unknown. RESULTS: Here we show that ppm1g expression is highly enriched in the central nervous system during mouse and zebrafish development. ppm1g(-/-) mice were embryonic lethal with incomplete penetrance after E12.5. Rostral defects, including neural tube and craniofacial defects were observed in ppm1g(-/-) embryos associated with increased cell death in the neural epithelium. In zebrafish, loss of ppm1g also led to neural defects with aberrant neural marker gene expression. Primary fibroblasts from ppm1g(-/-) embryos failed to grow without immortalization while immortalized ppm1g(-/-) fibroblasts had increased cell death upon oxidative and genotoxic stress when compared to wild type fibroblasts. CONCLUSIONS: Our in vivo and in vitro studies revealed a critical role for PPM1G in normal development and cell survival.

p38γ activity is required for maintenance of slow skeletal muscle size.

INTRODUCTION: p38γ kinase is highly enriched in skeletal muscle and is implicated in myotube formation. However, the activation status of p38γ in muscle is unclear. METHODS: p38γ activity in slow and fast adult mouse skeletal muscle tissue was examined, as was the impact of p38γ deficiency on muscle development and gene expression. RESULTS: p38γ is preferentially activated in slow muscle, but it is inactive in fast muscle types. Furthermore, the loss of p38γ in mice led to decreased muscle mass associated with a smaller myofiber diameter in slow muscle, but there was no impact on fast muscle in either mass or myofiber diameter. Finally, p38γ-deficient muscle showed selective changes in genes related to muscle growth in slow muscle fibers. CONCLUSION: This study provides evidence that p38γ is selectively activated in slow skeletal muscle and is involved in the normal growth and development of a subset of skeletal muscle.

Estimate of the commercial value of underage drinking and adult abusive and dependent drinking to the alcohol industry.

OBJECTIVES: To document quantity and cash value of underage and adult Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-defined abusive and dependent drinking as well as underage drinking and adult DSM-IV-defined abusive and dependent drinking combined to the alcohol industry. DESIGN: Analysis of multiple cross-sectional national data sets. SETTING: The 2001 National Household Survey on Drug Abuse, the 2001 Youth Risk Behavior Survey, the 2001 Behavioral Risk Factor Surveillance Survey, the 2000 US Census, the 2000 to 2001 National Epidemiological Survey on Alcohol and Related Conditions, and the 2001 Adams Business Research. PARTICIPANTS: A total of 260,580 persons aged 12 years and older across 4 data sources. MAIN EXPOSURE: Underage drinking or pathological drinking defined as meeting the DSM-IV criteria for abusive or dependent drinking. MAIN OUTCOME MEASURES: Total amount of alcohol consumed and the cash value for alcohol consumed among underage and adult drinkers with DSM-IV-defined alcohol abuse and dependence as well as all underage drinkers combined with adult drinkers with DSM-IV-defined alcohol abuse and dependence. RESULTS: The short-term cash value of underage drinking to the alcohol industry was 22.5 billion dollars in 2001-17.5% of total consumer expenditures for alcohol. The long-term commercial value of underage drinking is the contribution of underage drinking to maintaining consumption among adult drinkers with alcohol abuse and dependence, which was equal to at least 25.8 billion dollars in 2001. CONCLUSIONS: The combined value of illegal underage drinking and adult pathological drinking to the industry was at least 48.3 billion dollars, or 37.5% of consumer expenditures for alcohol, in 2001. Alternative estimates suggest that these costs may be closer to 62.9 billion dollars, or 48.8% of consumer expenditures for alcohol.

Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation.

Sclerostin (Sost) is a negative regulator of bone formation that acts upon the Wnt signaling pathway. Sost is mechanically regulated at both mRNA and protein level such that loading represses and unloading enhances Sost expression, in osteocytes and in circulation. The non-coding evolutionarily conserved enhancer ECR5 has been previously reported as a transcriptional regulatory element required for modulating Sost expression in osteocytes. Here we explored the mechanisms by which ECR5, or several other putative transcriptional enhancers regulate Sost expression, in response to mechanical stimulation. We found that in vivo ulna loading is equally osteoanabolic in wildtype and Sost-/- mice, although Sost is required for proper distribution of load-induced bone formation to regions of high strain. Using Luciferase reporters carrying the ECR5 non-coding enhancer and heterologous or homologous hSOST promoters, we found that ECR5 is mechanosensitive in vitro and that ECR5-driven Luciferase activity decreases in osteoblasts exposed to oscillatory fluid flow. Yet, ECR5-/- mice showed similar magnitude of load-induced bone formation and similar periosteal distribution of bone formation to high-strain regions compared to wildtype mice. Further, we found that in contrast to Sost-/- mice, which are resistant to disuse-induced bone loss, ECR5-/- mice lose bone upon unloading to a degree similar to wildtype control mice. ECR5 deletion did not abrogate positive effects of unloading on Sost, suggesting that additional transcriptional regulators and regulatory elements contribute to load-induced regulation of Sost.

Absenteeism and business costs: does substance abuse matter?

We conducted an empirical test of the assertion that absenteeism related to substance abuse and dependence among workers is an important contributor to the cost of doing business among American companies, a cost sufficient to motivate firms to aggressively intervene to eliminate abuse and dependence among their employees. The results of this analysis, based on relevant national data sets, suggest that such abuse-based absenteeism is, at best, an incidental cost to business and is insufficient to justify significant prophylactic or therapeutic investments of scarce human resource dollars to achieve an abuse and dependence free workplace. These findings force both public and private sector policymakers to turn to a "hazardous use"/"critical incident" rational as the basis of their argument that American business should invest human resource dollars in specific programs and technologies designed to achieve a drug-free workplace.

Alcohol consumption and expenditures for underage drinking and adult excessive drinking.

CONTEXT: Although estimates of the amount and proportion of alcohol consumed by underage and adult drinkers have been reported, more accurate estimates are possible and the economic impact has not been explored. OBJECTIVES: To provide accurate estimates of underage and adult excessive drinking and to describe consumer expenditures linked to underage and adult excessive drinking. DESIGN AND SETTING: Information was obtained from national data sets, including 1999 versions of the National Household Survey of Drug Abuse, the Youth Risk Behavior Survey (YRBS), the Behavior Risk Factor Surveillance System (BRFSS), 2000 US Census, and national data on consumption and consumer expenditures for alcohol, published by Adams Business Research. PARTICIPANTS: A total of 217 192 persons aged 12 years or older across 3 data sources. MAIN OUTCOME MEASURES: Amount as a proportion of total alcohol consumed and proportion of consumer expenditures on alcohol among underage (12-20 years) and adult excessive (> or =21 years) drinkers. RESULTS: The proportion of 12- to 20-year-olds who drink was estimated to be 50.0% using data from the YRBS; the proportion of adults aged 21 or older who drink was estimated to be 52.8% using data from the BRFSS. The estimated total number of drinks consumed per month was 4.21 billion; underage drinkers consumed 19.7% of this total. The amount of adult drinking that was excessive (>2 drinks per day) was 30.4%. Consumer expenditure on alcohol in the United States in 1999 was $116.2 billion; of that, $22.5 billion was attributed to underage drinking and $34.4 billion was attributed to adult excessive drinking. CONCLUSION: These data suggest that underage drinkers and adult excessive drinkers are responsible for 50.1% of alcohol consumption and 48.9% of consumer expenditure.