SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy

Dysregulated autophagy is associated with steatosis and non-alcoholic fatty liver disease (NAFLD), however the mechanisms connecting them remain poorly understand. Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomitant with an increase in SREBP-2 driven autophagy in mice fed a high-fat diet (HFD). We further show that the statin mediated increase in SREBP-2 directly activates expression of patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene, and PNPLA8 associates with autophagosomes and is associated with a decrease in cellular triglyceride. Moreover, we show that over-expression of PNPLA8 dramatically decreases hepatic steatosis through increased autophagy in hepatocytes of HFD-fed mice. Live-cell imaging analyses also reveal that PNPLA8 dynamically interacts with LC3 and we suggest that the SREBP-2/PNPLA8 axis represents a novel regulatory mechanism for lipid homeostasis. These data provide a possible mechanism for the reported beneficial effects of statins for decreasing hepatic triglyceride levels in NAFLD patients.ope

LSQ14efd: observations of the cooling of a shock break-out event in a type Ic Supernova

We present the photometric and spectroscopic evolution of the type Ic supernova LSQ14efd, discovered by the La Silla QUEST survey and followed by PESSTO. LSQ14efd was discovered few days after explosion and the observations cover up to ~100 days. The early photometric points show the signature of the cooling of the shock break-out event experienced by the progenitor at the time of the supernova explosion, one of the first for a type Ic supernova. A comparison with type Ic supernova spectra shows that LSQ14efd is quite similar to the type Ic SN 2004aw. These two supernovae have kinetic energies that are intermediate between standard Ic explosions and those which are the most energetic explosions known (e.g. SN 1998bw). We computed an analytical model for the light-curve peak and estimated the mass of the ejecta 6.3 +/- 0.5 Msun, a synthesized nickel mass of 0.25 Msun and a kinetic energy of Ekin = 5.6 +/- 0.5 x 10^51 erg. No connection between LSQ14efd and a GRB event could be established. However we point out that the supernova shows some spectroscopic similarities with the peculiar SN-Ia 1999ac and the SN-Iax SN 2008A. A core-collapse origin is most probable considering the spectroscopic, photometric evolution and the detection of the cooling of the shock break-out

Intent to migrate among nursing students in Uganda: Measures of the brain drain in the next generation of health professionals

Background: There is significant concern about the worldwide migration of nursing professionals from low-income countries to rich ones, as nurses are lured to fill the large number of vacancies in upper-income countries. This study explores the views of nursing students in Uganda to assess their views on practice options and their intentions to migrate. Methods: Anonymous questionnaires were distributed to nursing students at the Makerere Nursing School and Aga Khan University Nursing School in Kampala, Uganda, during July 2006, using convenience sampling methods, with 139 participants. Two focus groups were also conducted at one university. Results: Most (70%) of the participants would like to work outside Uganda, and said it was likely that within five years they would be working in the U.S. (59%) or the U.K. (49%). About a fourth (27%) said they could be working in another African country. Only eight percent of all students reported an unlikelihood to migrate within five years of training completion. Survey respondents were more dissatisfied with financial remuneration than with any other factor pushing them towards emigration. Those wanting to work in the settings of urban, private, or U.K./U.S. practices were less likely to express a sense of professional obligation and/or loyalty to country. Those who have lived in rural areas were less likely to report wanting to emigrate. Students with a desire to work in urban areas or private practice were more likely to report an intent to emigrate for financial reasons or in pursuit of country stability, while students wanting to work in rural areas or public practice were less likely to want to emigrate overall. Conclusion: Improving remuneration for nurses is the top priority policy change sought by nursing students in our study. Nursing schools may want to recruit students desiring work in rural areas or public practice to lead to a more stable workforce in Uganda.University of Washington Department of Global Healt

On Quality Control Measures in Genome-Wide Association Studies: A Test to Assess the Genotyping Quality of Individual Probands in Family-Based Association Studies and an Application to the HapMap Data

Allele transmissions in pedigrees provide a natural way of evaluating the genotyping quality of a particular proband in a family-based, genome-wide association study. We propose a transmission test that is based on this feature and that can be used for quality control filtering of genome-wide genotype data for individual probands. The test has one degree of freedom and assesses the average genotyping error rate of the genotyped SNPs for a particular proband. As we show in simulation studies, the test is sufficiently powerful to identify probands with an unreliable genotyping quality that cannot be detected with standard quality control filters. This feature of the test is further exemplified by an application to the third release of the HapMap data. The test is ideally suited as the final layer of quality control filters in the cleaning process of genome-wide association studies. It identifies probands with insufficient genotyping quality that were not removed by standard quality control filtering

Glutamine Acts as a Neuroprotectant against DNA Damage, Beta-Amyloid and H2O2-Induced Stress

Glutamine is the most abundant free amino acid in the human blood stream and is ‘conditionally essential’ to cells. Its intracellular levels are regulated both by the uptake of extracellular glutamine via specific transport systems and by its intracellular synthesis by glutamine synthetase (GS). Adding to the regulatory complexity, when extracellular glutamine is reduced GS protein levels rise. Unfortunately, this excess GS can be maladaptive. GS overexpression is neurotoxic especially if the cells are in a low-glutamine medium. Similarly, in low glutamine, the levels of multiple stress response proteins are reduced rendering cells hypersensitive to H2O2, zinc salts and DNA damage. These altered responses may have particular relevance to neurodegenerative diseases of aging. GS activity and glutamine levels are lower in the Alzheimer's disease (AD) brain, and a fraction of AD hippocampal neurons have dramatically increased GS levels compared with control subjects. We validated the importance of these observations by showing that raising glutamine levels in the medium protects cultured neuronal cells against the amyloid peptide, Aβ. Further, a 10-day course of dietary glutamine supplementation reduced inflammation-induced neuronal cell cycle activation, tau phosphorylation and ATM-activation in two different mouse models of familial AD while raising the levels of two synaptic proteins, VAMP2 and synaptophysin. Together, our observations suggest that healthy neuronal cells require both intracellular and extracellular glutamine, and that the neuroprotective effects of glutamine supplementation may prove beneficial in the treatment of AD

Financial incentives for return of service in underserved areas: a systematic review

<p>Abstract</p> <p>Background</p> <p>In many geographic regions, both in developing and in developed countries, the number of health workers is insufficient to achieve population health goals. Financial incentives for return of service are intended to alleviate health worker shortages: A (future) health worker enters into a contract to work for a number of years in an underserved area in exchange for a financial pay-off.</p> <p>Methods</p> <p>We carried out systematic literature searches of PubMed, the Excerpta Medica database, the Cumulative Index to Nursing and Allied Health Literature, and the National Health Services Economic Evaluation Database for studies evaluating outcomes of financial-incentive programs published up to February 2009. To identify articles for review, we combined three search themes (health workers or students, underserved areas, and financial incentives). In the initial search, we identified 10,495 unique articles, 10,302 of which were excluded based on their titles or abstracts. We conducted full-text reviews of the remaining 193 articles and of 26 additional articles identified in reference lists or by colleagues. Forty-three articles were included in the final review. We extracted from these articles information on the financial-incentive programs (name, location, period of operation, objectives, target groups, definition of underserved area, financial incentives and obligation) and information on the individual studies (authors, publication dates, types of study outcomes, study design, sample criteria and sample size, data sources, outcome measures and study findings, conclusions, and methodological limitations). We reviewed program results (descriptions of recruitment, retention, and participant satisfaction), program effects (effectiveness in influencing health workers to provide care, to remain, and to be satisfied with work and personal life in underserved areas), and program impacts (effectiveness in influencing health systems and health outcomes).</p> <p>Results</p> <p>Of the 43 reviewed studies 34 investigated financial-incentive programs in the US. The remaining studies evaluated programs in Japan (five studies), Canada (two), New Zealand (one) and South Africa (one). The programs started between 1930 and 1998. We identified five different types of programs (service-requiring scholarships, educational loans with service requirements, service-option educational loans, loan repayment programs, and direct financial incentives). Financial incentives to serve for one year in an underserved area ranged from year-2000 United States dollars 1,358 to 28,470. All reviewed studies were observational. The random-effects estimate of the pooled proportion of all eligible program participants who had either fulfilled their obligation or were fulfilling it at the time of the study was 71% (95% confidence interval 60–80%). Seven studies compared retention in the <it>same </it>(underserved) area between program participants and non-participants. Six studies found that participants were less likely than non-participants to remain in the same area (five studies reported the difference to be statistically significant, while one study did not report a significance level); one study did not find a significant difference in retention in the same area. Thirteen studies compared provision of care or retention in <it>any </it>underserved area between participants and non-participants. Eleven studies found that participants were more likely to (continue to) practice in any underserved area (nine studies reported the difference to be statistically significant, while two studies did not provide the results of a significance test); two studies found that program participants were significantly less likely than non-participants to remain in any underserved area. Seven studies investigated the satisfaction of participants with their work and personal lives in underserved areas.</p> <p>Conclusion</p> <p>Financial-incentive programs for return of service are one of the few health policy interventions intended to improve the distribution of human resources for health on which substantial evidence exists. However, the majority of studies are from the US, and only one study reports findings from a developing country, limiting generalizability. The existing studies show that financial-incentive programs have placed substantial numbers of health workers in underserved areas and that program participants are more likely than non-participants to work in underserved areas in the long run, even though they are less likely to remain at the site of original placement. As none of the existing studies can fully rule out that the observed differences between participants and non-participants are due to selection effects, the evidence to date does not allow the inference that the programs have caused increases in the supply of health workers to underserved areas.</p

Ischemia-Reperfusion Injury Leads to Distinct Temporal Cardiac Remodeling in Normal versus Diabetic Mice

Diabetes is associated with higher incidence of myocardial infarction (MI) and increased propensity for subsequent events post-MI. Here we conducted a temporal analysis of the influence of diabetes on cardiac dysfunction and remodeling after ischemia reperfusion (IR) injury in mice. Diabetes was induced using streptozotocin and IR performed by ligating the left anterior descending coronary artery for 30 min followed by reperfusion for up to 42 days. We first evaluated changes in cardiac function using echocardiography after 24 hours reperfusion and observed IR injury significantly decreased the systolic function, such as ejection fraction, fractional shortening and end systolic left ventricular volume (LVESV) in both control and diabetic mice. The longitudinal systolic and diastolic strain rate were altered after IR, but there were no significant differences between diabetic mice and controls. However, a reduced ability to metabolize glucose was observed in the diabetic animals as determined by PET-CT scanning using 2-deoxy-2-(18F)fluoro-D-glucose. Interestingly, after 24 hours reperfusion diabetic mice showed a reduced infarct size and less apoptosis indicated by TUNEL analysis in heart sections. This may be explained by increased levels of autophagy detected in diabetic mice hearts. Similar increases in IR-induced macrophage infiltration detected by CD68 staining indicated no change in inflammation between control and diabetic mice. Over time, control mice subjected to IR developed mild left ventricular dilation whereas diabetic mice exhibited a decrease in both end diastolic left ventricular volume and LVESV with a decreased intraventricular space and thicker left ventricular wall, indicating concentric hypertrophy. This was associated with marked increases in fibrosis, indicted by Masson trichrome staining, of heart sections in diabetic IR group. In summary, we demonstrate that diabetes principally influences distinct IR-induced chronic changes in cardiac function and remodeling, while a smaller infarct size and elevated levels of autophagy with similar cardiac function are observed in acute phase

Strategies to overcome physician shortages in northern Ontario: A study of policy implementation over 35 years

<p>Abstract</p> <p>Background</p> <p>Shortages and maldistibution of physicians in northern Ontario, Canada, have been a long-standing issue. This study seeks to document, in a chronological manner, the introduction of programmes intended to help solve the problem by the provincial government over a 35-year period and to examine several aspects of policy implementation, using these programmes as a case study.</p> <p>Methods</p> <p>A programme analysis approach was adopted to examine each of a broad range of programmes to determine its year of introduction, strategic category, complexity, time frame, and expected outcome. A chronology of programme initiation was constructed, on the basis of which an analysis was done to examine changes in strategies used by the provincial government from 1969 to 2004.</p> <p>Results</p> <p>Many programmes were introduced during the study period, which could be grouped into nine strategic categories. The range of policy instruments used became broader in later years. But conspicuous by their absence were programmes of a directive nature. Programmes introduced in more recent years tended to be more complex and were more likely to have a longer time perspective and pay more attention to physician retention. The study also discusses the choice of policy instruments and use of multiple strategies.</p> <p>Conclusion</p> <p>The findings suggest that an examination of a policy is incomplete if implementation has not been taken into consideration. The study has revealed a process of trial-and-error experimentation and an accumulation of past experience. The study sheds light on the intricate relationships between policy, policy implementation and use of policy instruments and programmes.</p

Pan-STARRS and PESSTO search for an optical counterpart to the LIGO gravitational-wave source GW150914

This is the author accepted manuscript. The final version is available from Oxford University Press via http://dx.doi.org/10.1093/mnras/stw1893We searched for an optical counterpart to the first gravitational wave source discovered by LIGO (GW150914), using a combination of the Pan-STARRS1 wide-field telescope and the PESSTO spectroscopic follow-up programme. As the final LIGO sky maps changed during analysis, the total probability of the source being spatially coincident with our fields was finally only 4.2 per cent. Therefore we discuss our results primarily as a demonstration of the survey capability of Pan-STARRS and spectroscopic capability of PESSTO. We mapped out 442 square degrees of the northern sky region of the initial map. We discovered 56 astrophysical transients over a period of 41 days from the discovery of the source. Of these, 19 were spectroscopically classified and a further 13 have host galaxy redshifts. All transients appear to be fairly normal supernovae and AGN variability and none is obviously linked with GW150914. We illustrate the sensitivity of our survey by defining parameterised lightcurves with timescales of 4, 20 and 40 days and use the sensitivity of the Pan-STARRS1 images to set limits on the luminosities of possible sources. The Pan-STARRS1 images reach limiting magnitudes of $\textit{i}$$_{P\rceil}$ = 19.2, 20.0 and 20.8 respectively for the three timescales. For long timescale parameterised lightcurves (with FWHM≃40d) we set upper limits of $\textit{M}$$_{i}$ ≤ −17.2$^{−0.9}_{+1.4}$ if the distance to GW150914 is $\textit{D}_{\lfloor}$ = 400 ± 200 Mpc. The number of type Ia SN we find in the survey is similar to that expected from the cosmic SN rate, indicating a reasonably complete efficiency in recovering supernova like transients out to $\textit{D}_{\lfloor}$ = 400 ± 200 Mpc.Pan-STARRS is supported by the University of Hawaii and the National Aeronautics and Space Administration's Planetary Defense Office under Grant No. NNX14AM74G. The Pan-STARRS-LIGO effort is in collaboration with the LIGO Consortium and supported by Queen's University Belfast. The Pan-STARRS1 Sky Surveys have been made possible through contributions by the Institute for Astronomy, the University of Hawaii, the Pan-STARRS Project Office, the Max Planck Society and its participating institutes, the Max Planck Institute for Astronomy, Heidelberg and the Max Planck Institute for Extraterrestrial Physics, Garching, The Johns Hopkins University, Durham University, the University of Edinburgh, the Queen's University Belfast, the Harvard-Smithsonian Center for Astrophysics, the Las Cumbres Observatory Global Telescope Network Incorporated, the National Central University of Taiwan, the Space Telescope Science Institute, and the National Aeronautics and Space Administration under Grant No. NNX08AR22G issued through the Planetary Science Division of the NASA Science Mission Directorate, the National Science Foundation Grant No. AST-1238877, the University of Maryland, Eotvos Lorand University (ELTE), and the Los Alamos National Laboratory. This work is based (in part) on observations collected at the European Organisation for Astronomical Research in the Southern Hemisphere, Chile as part of PESSTO, (the Public ESO Spectroscopic Survey for Transient Objects Survey) ESO programs 188.D-3003, 191.D-0935. Some of the data presented herein were obtained at the Palomar Observatory, California Institute of Technology. SJS acknowledges funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no [291222] and STFC grants ST/I001123/1 and ST/L000709/1. MF is supported by the European Union FP7 programme through ERC grant number 320360. KM acknowledges support from the STFC through an Ernest Rutherford Fellowship FOE acknowledges support from FONDECYT through postdoctoral grant 3140326. This research has made use of the NASA/IPAC Extragalactic Database (NED) which is operated by the Jet Propulsion Laboratory, California Institute of Technology, under contract with the National Aeronautics and Space Administration and data products from the Two Micron All Sky Survey, which is a joint project of the University of Massachusetts and the Infrared Processing and Analysis Center/California Institute of Technology, funded by the National Aeronautics and Space Administration and the National Science Foundation

Incorporating one health into medical education

One Health is an emerging concept that stresses the linkages between human, animal, and environmental health, as well as the need for interdisciplinary communication and collaboration to address health issues including emerging zoonotic diseases, climate change impacts, and the human-animal bond. It promotes complex problem solving using a systems framework that considers interactions between humans, animals, and their shared environment. While many medical educators may not yet be familiar with the concept, the One Health approach has been endorsed by a number of major medical and public health organizations and is beginning to be implemented in a number of medical schools. In the research setting, One Health opens up new avenues to understand, detect, and prevent emerging infectious diseases, and also to conduct translational studies across species. In the clinical setting, One Health provides practical ways to incorporate environmental and animal contact considerations into patient care. This paper reviews clinical and research aspects of the One Health approach through an illustrative case updating the biopsychosocial model and proposes a basic set of One Health competencies for training and education of human health care providers