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Homeostatic regulation of ionic currents is of paramount importance during periods of synaptic growth or remodeling. Our previous work has identified the translational repressor Pumilio (Pum) as a regulator of sodium current (INa ) and excitability in Drosophila motoneurons. In this current study, we show that Pum is able to bind directly the mRNA encoding the Drosophila voltage-gated sodium channel paralytic ( para). We identify a putative binding site for Pumin the 3' end of the para open reading frame (ORF). Characterization of the mechanism of action of Pum, using whole-cell patch clamp and real-time reverse transcription-PCR, reveals that the full-length protein is required for translational repression of para mRNA. Additionally, the cofactor Nanos is essential for Pum-dependent para repression, whereas the requirement for Brain Tumor (Brat) is cell type specific. Thus, Pum-dependent regulation of INa in motoneurons requires both Nanos and Brat, whereas regulation in other neuronal types seemingly requires only Nanos but not Brat. We also show that Pum is able to reduce the level of nanos mRNA and as such identify a potential negative-feedback mechanism to protect neurons from overactivity of Pum. Finally, we show coupling between INa ( para) and IK (Shal) such that Pum-mediated change in para results in a compensatory change in Shal. The identification of para as a direct target of Pum represents the first ion channel to be translationally regulated by this repressor and the location of the binding motif is the first example in an ORF rather than in the canonical 3'-untranslated region of target transcripts. [ABSTRACT FROM AUTHOR]

Objectives: To determine correlations between excessively long working hours and subjectively experienced somatic health complaints among hospital physicians. Methods: Quantitative data were collected as part of the survey “Working life, Lifestyle and Health of Hospital Physicians in Germany 2006” using self-reporting questionnaires. The individually experienced health was assessed on the basis of Zerssen’s [1] list of somatic complaints. The indicator of excessively long working hours was defined as 10 or more working hours per working day and 6 or more on-call shifts a month among full-time employees. The net sample consisted of 3295 randomly selected physicians from 515 hospitals. Results: The response rate was 58% (n=1917). Physicians with excessively long working hours (19%) had significantly higher sum score of health complaints (p=0.0001) and significantly increased mental and physical fatigue symptoms (feeling faint, languor, uneasiness, heavy legs, excessive need for sleep, trembling; p=0.0001 to 0.047), mood changes (irritability, brooding; p=0.008 to 0.014), gastrointestinal (nausea, loss of weight; p=0.0001 to 0.014) and heart disorders (lumpy sensation in the throat, chest pain; p=0.0001 to 0.042). When the sum score of health complaints was controlled for selected confounders, being female (B=-3.44, p=0.0001) and having excessively long working hours (B=2.76, p=0.0001) were significantly correlated with health complaints. In a separate gender analysis, being exposed to excessively long working hours remained a significant predictor for health complaints among both females (B=3.78, p=0.001) and males (B=2.28, p=0.004). Conclusions: Excessively long working hours are associated with an increased risk of health complaints. Reducing working hours may be the first step to improving physicians' health.