The PIKfyve complex regulates the early melanosome homeostasis required for physiological amyloid formation

International audienceThe metabolism of PI(3,5)P2 is regulated by the PIKfyve, VAC14 and FIG4 complex,whose mutations are associated with hypopigmentation in mice. These pigmentationdefects indicate a key but yet unexplored physiological relevance of this complex inthe biogenesis of melanosomes. Here we show that PIKfyve activity regulatesformation of amyloid matrix composed of PMEL protein within early endosomes,called stage I melanosomes. PIKfyve activity controls the membrane remodeling ofstage I melanosomes that increases PMEL abundance and impairs its sorting andprocessing. PIKfyve activity also affects stage I melanosome kiss-and-runinteractions with lysosomes that is required for PMEL amyloidogenesis andestablishment of melanosome identity. Mechanistically, PIKfyve activity promotes theformation and membrane tubules from stage I melanosomes and their release bymodulating endosomal actin branching. Together our data indicate that PIKfyveactivity is a key regulator of the melanosomal import-export machinery that fine tunesthe formation of functional amyloid fibrils in melanosomes and the maintenance ofmelanosome identity

Long-term Death Rates, West Nile Virus Epidemic, Israel, 2000

We studied the 2-year death rate of 246 adults discharged from hospital after experiencing acute West Nile Virus infection in Israel during 2000. The age- and sex-adjusted death rates were significantly higher than in the general population. This excess was greater for men. Significant adverse prognostic factors were age, male sex, diabetes mellitus, and dementia

Organizational factors associated with readiness to implement and translate a primary care based telemedicine behavioral program to improve blood pressure control: the HTN-IMPROVE study

Abstract Background Hypertension is prevalent and often sub-optimally controlled; however, interventions to improve blood pressure control have had limited success. Objectives Through implementation of an evidence-based nurse-delivered self-management phone intervention to facilitate hypertension management within large complex health systems, we sought to answer the following questions: What is the level of organizational readiness to implement the intervention? What are the specific facilitators, barriers, and contextual factors that may affect organizational readiness to change? Study design Each intervention site from three separate Veterans Integrated Service Networks (VISNs), which represent 21 geographic regions across the US, agreed to enroll 500 participants over a year with at least 0.5 full time equivalent employees of nursing time. Our mixed methods approach used a priori semi-structured interviews conducted with stakeholders (n = 27) including nurses, physicians, administrators, and information technology (IT) professionals between 2010 and 2011. Researchers iteratively identified facilitators and barriers of organizational readiness to change (ORC) and implementation. Additionally, an ORC survey was conducted with the stakeholders who were (n = 102) preparing for program implementation. Results Key ORC facilitators included stakeholder buy-in and improving hypertension. Positive organizational characteristics likely to impact ORC included: other similar programs that support buy-in, adequate staff, and alignment with the existing site environment; improved patient outcomes; is positive for the professional nurse role, and is evidence-based; understanding of the intervention; IT infrastructure and support, and utilization of existing equipment and space. The primary ORC barrier was unclear long-term commitment of nursing. Negative organizational characteristics likely to impact ORC included: added workload, competition with existing programs, implementation length, and limited available nurse staff time; buy-in is temporary until evidence shows improved outcomes; contacting patients and the logistics of integration into existing workflow is a challenge; and inadequate staffing is problematic. Findings were complementary across quantitative and qualitative analyses. Conclusions The model of organizational change identified key facilitators and barriers of organizational readiness to change and successful implementation. This study allows us to understand the needs and challenges of intervention implementation. Furthermore, examination of organizational facilitators and barriers to implementation of evidence-based interventions may inform dissemination in other chronic diseases.http://deepblue.lib.umich.edu/bitstream/2027.42/112820/1/13012_2013_Article_683.pd

Patients' knowledge and perception on optic neuritis management before and after an information session

<p>Abstract</p> <p>Background</p> <p>Patients' understanding of their condition affect the choice of treatment. The aim of this study is to evaluate patients' understanding and treatment preferences before and after an information session on the treatment of acute optic neuritis.</p> <p>Methods</p> <p>Participants were asked to complete a questionnaire consisting of 14 questions before and after an information session presented by a neuro-ophthalmologist. The information session highlighted the treatment options and the treatment effects based on the Optic Neuritis Treatment Trial in plain patient language. The information session stressed the finding that high dose intravenous steroid therapy accelerated visual recovery but does not change final vision and that treatment with oral prednisone alone resulted in a higher incidence of recurrent optic neuritis.</p> <p>Results</p> <p>Before the information session, 23 (85%) participants knew that there was treatment available for ON and this increased to 27 (100%) after the information session. There were no significantly change in patients knowledge of symptoms of ON and purpose of treatment before and after the information session. Before the information session, 4 (14%) respondents reported they would like to be treated by oral steroid alone in the event of an optic neuritis and 5 (19%) did not respond. After the education session, only 1 patient (4%) indicated they would undergo treatment with oral steroid alone but 25 (92%) indicated they would undergo treatment with intravenous steroid treatment, alone or in combination with oral treatment. Results indicated that there were significant differences in the numbers of participants selecting that they would undergo treatment with a steroid injection (n = 22, p = 0.016).</p> <p>Conclusions</p> <p>In this study, patients have shown good understanding of the symptoms and signs of optic neuritis. The finding that significant increases in the likelihood of patients engaging in best practice can be achieved with an information session is very important. This suggests that patient knowledge of available treatments and outcomes can play an important role in implementing and adopting guideline recommendations.</p

Organizational factors associated with readiness to implement and translate a primary care based telemedicine behavioral program to improve blood pressure control: the HTN-IMPROVE study

Abstract Background Hypertension is prevalent and often sub-optimally controlled; however, interventions to improve blood pressure control have had limited success. Objectives Through implementation of an evidence-based nurse-delivered self-management phone intervention to facilitate hypertension management within large complex health systems, we sought to answer the following questions: What is the level of organizational readiness to implement the intervention? What are the specific facilitators, barriers, and contextual factors that may affect organizational readiness to change? Study design Each intervention site from three separate Veterans Integrated Service Networks (VISNs), which represent 21 geographic regions across the US, agreed to enroll 500 participants over a year with at least 0.5 full time equivalent employees of nursing time. Our mixed methods approach used a priori semi-structured interviews conducted with stakeholders (n = 27) including nurses, physicians, administrators, and information technology (IT) professionals between 2010 and 2011. Researchers iteratively identified facilitators and barriers of organizational readiness to change (ORC) and implementation. Additionally, an ORC survey was conducted with the stakeholders who were (n = 102) preparing for program implementation. Results Key ORC facilitators included stakeholder buy-in and improving hypertension. Positive organizational characteristics likely to impact ORC included: other similar programs that support buy-in, adequate staff, and alignment with the existing site environment; improved patient outcomes; is positive for the professional nurse role, and is evidence-based; understanding of the intervention; IT infrastructure and support, and utilization of existing equipment and space. The primary ORC barrier was unclear long-term commitment of nursing. Negative organizational characteristics likely to impact ORC included: added workload, competition with existing programs, implementation length, and limited available nurse staff time; buy-in is temporary until evidence shows improved outcomes; contacting patients and the logistics of integration into existing workflow is a challenge; and inadequate staffing is problematic. Findings were complementary across quantitative and qualitative analyses. Conclusions The model of organizational change identified key facilitators and barriers of organizational readiness to change and successful implementation. This study allows us to understand the needs and challenges of intervention implementation. Furthermore, examination of organizational facilitators and barriers to implementation of evidence-based interventions may inform dissemination in other chronic diseases

Geobiology of the late Paleoproterozoic Duck Creek Formation, Western Australia

The ca. 1.8 Ga Duck Creek Formation, Western Australia, preserves 1000 m of carbonates and minor iron formation that accumulated along a late Paleoproterozoic ocean margin. Two upward-deepening stratigraphic packages are preserved, each characterized by peritidal precipitates at the base and iron formation and carbonate turbidites in its upper part. Consistent with recent studies of Neoarchean basins, carbon isotope ratios of Duck Creek carbonates show no evidence for a strong isotopic depth gradient, but carbonate minerals in iron formations can be markedly depleted in C-13. In contrast, oxygen isotopes covary strongly with depth; delta O-18 values as positive as 2%. VPDB in peritidal facies systematically decline to values of 6 to 16% in basinal rocks, reflecting, we posit, the timing of diagenetic closure. The Duck Creek Formation contains microfossils similar to those of the Gunflint Formation, Canada; they are restricted to early diagenetic cherts developed in basinal facies, strengthening the hypothesis that such fossils capture communities driven by iron metabolism. Indeed, X-ray diffraction data indicate that the Duck Creek basin was ferruginous throughout its history. The persistence of ferruginous waters and iron formation deposition in Western Australia for at least several tens of millions of years after the transition to sulfidic conditions in Laurentia suggests that the late Paleoproterozoic expansion of sulfidic subsurface waters was globally asynchronous

Genetic Interaction between MTMR2 and FIG4 Phospholipid Phosphatases Involved in Charcot-Marie-Tooth Neuropathies

We previously reported that autosomal recessive demyelinating Charcot-Marie-Tooth (CMT) type 4B1 neuropathy with myelin outfoldings is caused by loss of MTMR2 (Myotubularin-related 2) in humans, and we created a faithful mouse model of the disease. MTMR2 dephosphorylates both PtdIns3P and PtdIns(3,5)P2, thereby regulating membrane trafficking. However, the function of MTMR2 and the role of the MTMR2 phospholipid phosphatase activity in vivo in the nerve still remain to be assessed. Mutations in FIG4 are associated with CMT4J neuropathy characterized by both axonal and myelin damage in peripheral nerve. Loss of Fig4 function in the plt (pale tremor) mouse produces spongiform degeneration of the brain and peripheral neuropathy. Since FIG4 has a role in generation of PtdIns(3,5)P2 and MTMR2 catalyzes its dephosphorylation, these two phosphatases might be expected to have opposite effects in the control of PtdIns(3,5)P2 homeostasis and their mutations might have compensatory effects in vivo. To explore the role of the MTMR2 phospholipid phosphatase activity in vivo, we generated and characterized the Mtmr2/Fig4 double null mutant mice. Here we provide strong evidence that Mtmr2 and Fig4 functionally interact in both Schwann cells and neurons, and we reveal for the first time a role of Mtmr2 in neurons in vivo. Our results also suggest that imbalance of PtdIns(3,5)P2 is at the basis of altered longitudinal myelin growth and of myelin outfolding formation. Reduction of Fig4 by null heterozygosity and downregulation of PIKfyve both rescue Mtmr2-null myelin outfoldings in vivo and in vitro

The implementation of a translational study involving a primary care based behavioral program to improve blood pressure control: The HTN-IMPROVE study protocol (01295)

<p>Abstract</p> <p>Background</p> <p>Despite the impact of hypertension and widely accepted target values for blood pressure (BP), interventions to improve BP control have had limited success.</p> <p>Objectives</p> <p>We describe the design of a 'translational' study that examines the implementation, impact, sustainability, and cost of an evidence-based nurse-delivered tailored behavioral self-management intervention to improve BP control as it moves from a research context to healthcare delivery. The study addresses four specific aims: assess the implementation of an evidence-based behavioral self-management intervention to improve BP levels; evaluate the clinical impact of the intervention as it is implemented; assess organizational factors associated with the sustainability of the intervention; and assess the cost of implementing and sustaining the intervention.</p> <p>Methods</p> <p>The project involves three geographically diverse VA intervention facilities and nine control sites. We first conduct an evaluation of barriers and facilitators for implementing the intervention at intervention sites. We examine the impact of the intervention by comparing 12-month pre/post changes in BP control between patients in intervention sites versus patients in the matched control sites. Next, we examine the sustainability of the intervention and organizational factors facilitating or hindering the sustained implementation. Finally, we examine the costs of intervention implementation. Key outcomes are acceptability and costs of the program, as well as changes in BP. Outcomes will be assessed using mixed methods (<it>e.g</it>., qualitative analyses--pattern matching; quantitative methods--linear mixed models).</p> <p>Discussion</p> <p>The study results will provide information about the challenges and costs to implement and sustain the intervention, and what clinical impact can be expected.</p