OBJECTIVE: New medical graduates are the front-line staff in many hospital settings and manage patients with diabetes frequently. Prescribing is an area of concern for junior doctors, however, with insulin prescribing reported as a particular weakness. This study aimed to produce an educational intervention which aimed to improve preparedness to manage patients with diabetes and evaluate it using a mixed methods approach. RESEARCH DESIGN AND METHODS: an e-resource (http://www.diabetesscenariosforjuniordoctors.co.uk) was created to contain commonplace and authentic diabetes decision-making scenarios. -32 junior doctors (n=20) and year 5 students (n=12) in South West England worked through the scenarios while 'thinking aloud' and then undertook a semistructured interview. Qualitative data were transcribed verbatim and analyzed thematically. Participant confidence to manage patients with diabetes before, immediately after, and 6â€
weeks after the educational intervention was also measured using a self-rating scale. RESULTS: Participants reported that patients with diabetes were daunting to manage because of the wide array of insulin products, their lack of confidence with chronic disease management and the difficulty of applying theory to practice. The e-resource was described as authentic, practical, and appropriate for the target audience. Junior doctors' self-rated confidence to manage patients with diabetes increased from 4.7 (of 10) before using the e-resource, to 6.4 immediately afterwards, and 6.8 6â€
weeks later. Medical students' confidence increased from 5.1 before, to 6.4 immediately afterwards, and 6.4 6â€
weeks later. CONCLUSIONS: Providing opportunities to work with authentic scenarios in a safe environment can help to ameliorate junior doctors' lack of confidence to manage patients with diabetes.

Childhood spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by mutations in the survival motor neuron (SMN) gene. The severity of the disease is dictated by the copy number of a second copy of the gene, known as SMN2, with higher copy numbers associated with milder forms of SMA. This is because the level of SMN protein produced by patients dictates the severity of the disease. As all patients retain at least one copy of the SMN2 gene, therapeutic strategies are geared towards increasing full-length SMN protein expression from SMN2. One of the identified therapeutic compounds is valproic acid, or valproate (VPA), a histone deacetylase inhibitor (HDACI) that has been used since the 1970s as an anti-convulsant. Here, we discuss VPA's modes of action and potential side effects in the treatment of SMA.

GTPase activating proteins (GAPs) of the centaurin family regulate the actin cytoskeleton and vesicle trafficking through inactivation of the ADP-ribosylation factor (ARF) family of small GTP-binding proteins. We report the functional characterisation of centaurin-alpha(2), which is structurally related to the centaurin-alpha(1) ARF6 GAP. centaurin-alpha(2) contains an N-terminal GAP domain followed by two pleckstrin homology (PH) domains (N-PH and C-PH). In vitro, GFP-centaurin-alpha(2) specifically binds the phosphatidylinositol (PI) 3-kinase lipid products, PI 3,4-P(2) and PI 3,4,5-P(3) (PIP(3)), through its C-terminal PH domain. In agreement with this observation, GFP-centaurin-alpha(2) was recruited to the plasma membrane from the cytosol in EGF-stimulated cells in a PI-3-kinase-dependent manner. Moreover, the C-PH domain is sufficient and necessary for membrane recruitment of centaurin-alpha(2). centaurin-alpha(2) shows sustained kinetics of PI-3-kinase-mediated membrane recruitment in EGF-stimulated cells, owing to its binding to PI 3,4-P(2). centaurin-alpha(2) prevents ARF6 translocation to, and cortical actin formation at, the plasma membrane, which are phenotypic indications for ARF6 activation in EGF-stimulated cells. Moreover, the constitutively active mutant of ARF6 reverses the effect of centaurin-alpha(2) on cortical actin formation. The membrane targeted centaurin-alpha(2) is constitutively active. Together, these studies indicate that centaurin-alpha(2) is recruited in a sustained manner to the plasma membrane through binding to PI 3,4-P(2) and thereby regulates actin reorganisation via ARF6.

The ADP-ribosylation factor (ARF) 6 small GTPase regulates vesicle trafficking and cytoskeletal actin reorganization. The GTPase-activating proteins (GAPs) catalyze the formation of inactive ARF6GDP. Centaurin-alpha1 contains an ARF GAP and two pleckstrin homology (PH) domains, which bind the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3). Here, we show that centaurin-alpha1 specifically inhibits in vivo GTP loading of ARF6 and redistribution of ARF6 from the endosomal compartment to the plasma membrane, which are indicative of its activation. Centaurin-alpha1 also inhibited cortical actin formation in a PIP3-dependent manner. Moreover, the constitutively active mutant of ARF6, but not that of ARF1, reverses the inhibition of cortical actin formation by centaurin-alpha1. An artificially plasma membrane-targeted centaurin-alpha1 bypasses the requirement of PIP3 for its involvement in ARF6 inactivation, suggesting that PIP3 is required for recruitment of centaurin-alpha1 to the plasma membrane but not for its activity. Together, these data suggest that centaurin-alpha1 negatively regulates ARF6 activity by functioning as an in vivo PIP3-dependent ARF6 GAP.