DREAM represses distinct targets by cooperating with different THAP domain proteins.

The DREAM (dimerization partner [DP], retinoblastoma [Rb]-like, E2F, and MuvB) complex controls cellular quiescence by repressing cell-cycle and other genes, but its mechanism of action is unclear. Here, we demonstrate that two C. elegans THAP domain proteins, LIN-15B and LIN-36, co-localize with DREAM and function by different mechanisms for repression of distinct sets of targets. LIN-36 represses classical cell-cycle targets by promoting DREAM binding and gene body enrichment of H2A.Z, and we find that DREAM subunit EFL-1/E2F is specific for LIN-36 targets. In contrast, LIN-15B represses germline-specific targets in the soma by facilitating H3K9me2 promoter marking. We further find that LIN-36 and LIN-15B differently regulate DREAM binding. In humans, THAP proteins have been implicated in cell-cycle regulation by poorly understood mechanisms. We propose that THAP domain proteins are key mediators of Rb/DREAM function.

Burnout in European family doctors: the EGPRN study.

INTRODUCTION: The aim of this study was to determine the prevalence of burnout, and of associated factors, amongst family doctors (FDs) in European countries. Methodology. A cross-sectional survey of FDs was conducted using a custom-designed and validated questionnaire which incorporated the Maslach Burnout Inventory Human Services Survey (MBI-HSS) as well as questions about demographic factors, working experience, health, lifestyle and job satisfaction. MBI-HSS scores were analysed in the three dimensions of emotional exhaustion (EE), depersonalization (DP) and personal accomplishment (PA). RESULTS: Almost 3500 questionnaires were distributed in 12 European countries, and 1393 were returned to give a response rate of 41%. In terms of burnout, 43% of respondents scored high for EE burnout, 35% for DP and 32% for PA, with 12% scoring high burnout in all three dimensions. Just over one-third of doctors did not score high for burnout in any dimension. High burnout was found to be strongly associated with several of the variables under study, especially those relative to respondents' country of residence and European region, job satisfaction, intention to change job, sick leave utilization, the (ab)use of alcohol, tobacco and psychotropic medication, younger age and male sex. CONCLUSIONS: Burnout seems to be a common problem in FDs across Europe and is associated with personal and workload indicators, and especially job satisfaction, intention to change job and the (ab)use of alcohol, tobacco and medication. The study questionnaire appears to be a valid tool to measure burnout in FDs. Recommendations for employment conditions of FDs and future research are made, and suggestions for improving the instrument are listed.

Treatment of Wilson's disease with zinc from the time of diagnosis in pediatric patients: a single-hospital, 10-year follow-up study.

Wilson's disease (WD) is an inherited disorder of copper metabolism characterized by a failure of the liver to excrete copper, leading to its accumulation in the liver, brain, cornea, and kidney, with resulting chronic degenerative changes. It is generally accepted that "presymptomatic" patients--in whom WD is diagnosed in childhood and who are defined as those who, although still asymptomatic, do have liver disease, as indicated by increased serum concentrations of transaminases--should be treated prophylactically. Here we report our results in 22 children treated with continuous oral zinc therapy for 10 years. Zinc sulfate was administered at a dosage of 25 mg elemental zinc twice a day until the age of 6 years, 25 mg three times a day between the ages of 7 and 16 years or until the child attained a body weight of 125 lb, and 50 mg three times a day thereafter. Five years after the start of zinc treatment, we noted highly significant decreases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and urinary copper excretion, but white blood cell counts did not vary significantly. Six of 22 patients continued to demonstrate greater-than-normal ALT concentrations and only 1 patient demonstrated an ALT concentration more than 1.5 times the upper normal limit. Further decreases in ALT, AST, and urinary copper excretion were observed at the end of the 10-year follow-up, but these decreases were not statistically significant. Only 1 patient continued to demonstrate abnormal ALT levels. Again, white blood cells showed no significant variations. All histologic scores (steatosis, inflammation, and fibrosis) were significantly decreased after treatment. Hepatic copper content was also significantly decreased, although it remained higher than normal in all patients. The removal of toxic copper was confirmed by disappearance of Kayser-Fleischer rings in 3 patients. Zinc did not have adverse effects on growth. The efficacy of zinc in WD in presymptomatic pediatric patients has been established in previous studies, and our study adds considerably to the earlier findings because it includes a large number of very young children, as many as 11 younger than 6 years and 20 younger than 10. The excellent clinical results in all patients, coupled with the improvement in hepatic histologic findings in the vast majority, indicate convincingly that zinc treatment can control the disease effectively and safely, preventing its progression over the course of 10 years. Histologic findings reportedly improved in 3 patients treated in an earlier study, but our data are numerically much more relevant. Notably, histologic study of the liver revealed that copper concentration was reduced by treatment, suggesting that oral zinc was able not only to prevent further accumulation of copper but also to promote, at least in part, the depletion of its stores. The lack of adverse effects of zinc on growth suggests that our patients received enough anticopper therapy to prevent damage resulting from copper toxicity but an adequate amount of copper for proper growth and development. In conclusion, our findings indicate that zinc is the treatment of choice in presymptomatic pediatric patients with WD.