Role of microRNAs in the age-associated decline of pancreatic beta cell function in rat islets

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.AIMS/HYPOTHESIS: Ageing can lead to reduced insulin sensitivity and loss of pancreatic beta cell function, predisposing individuals to the development of diabetes. The aim of this study was to assess the contribution of microRNAs (miRNAs) to age-associated beta cell dysfunction. METHODS: The global mRNA and miRNA profiles of 3- and 12-month-old rat islets were collected by microarray. The functional impact of age-associated differences in miRNA expression was investigated by mimicking the observed changes in primary beta cells from young animals. RESULTS: Beta cells from 12-month-old rats retained normal insulin content and secretion, but failed to proliferate in response to mitotic stimuli. The islets of these animals displayed modifications at the level of several miRNAs, including upregulation of miR-34a, miR-124a and miR-383, and downregulation of miR-130b and miR-181a. Computational analysis of the transcriptomic modifications observed in the islets of 12-month-old rats revealed that the differentially expressed genes were enriched for miR-34a and miR-181a targets. Indeed, the induction of miR-34a and reduction of miR-181a in the islets of young animals mimicked the impaired beta cell proliferation observed in old animals. mRNA coding for alpha-type platelet-derived growth factor receptor, which is critical for compensatory beta cell mass expansion, is directly inhibited by miR34a and is likely to be at least partly responsible for the effects of this miRNA. CONCLUSIONS/INTERPRETATION: Changes in the level of specific miRNAs that occur during ageing affect the proliferative capacity of beta cells. This might reduce their ability to expand under conditions of increased insulin demand, favouring the development of type 2 diabetes.Swiss National Science FoundationFondation Francophone pour la Recherche sur le DiabèteWellcome Trust Senior Investigator AwardMRC Programme GrantRoyal Society Wolfson Research Merit AwardWellcome Trust project gran

Radiative Transfer in Star Formation: Testing FLD and Hybrid Methods

We perform a comparison between two radiative transfer algorithms commonly employed in hydrodynamical calculations of star formation: grey flux limited diffusion and the hybrid scheme, in addition we compare these algorithms to results from the Monte-Carlo radiative transfer code MOCASSIN. In disc like density structures the hybrid scheme performs significantly better than the FLD method in the optically thin regions, with comparable results in optically thick regions. In the case of a forming high mass star we find the FLD method significantly underestimates the radiation pressure by a factor of ~100.Comment: 4 Pages; to appear in the proceedings of 'The Labyrinth of Star Formation', Crete, 18-22 June 201

The timing of death in patients with tuberculosis who die during anti-tuberculosis treatment in Andhra Pradesh, South India

Background: India has 2.0 million estimated tuberculosis (TB) cases per annum with an estimated 280,000 TBrelated deaths per year. Understanding when in the course of TB treatment patients die is important for determining the type of intervention to be offered and crucially when this intervention should be given. The objectives of the current study were to determine in a large cohort of TB patients in India:- i) treatment outcomes including the number who died while on treatment, ii) the month of death and iii) characteristics associated with “early” death, occurring in the initial 8 weeks of treatment. Methods: This was a retrospective study in 16 selected Designated Microscopy Centres (DMCs) in Hyderabad, Krishna and Adilabad districts of Andhra Pradesh, South India. A review was performed of treatment cards and medical records of all TB patients (adults and children) registered and placed on standardized anti-tuberculosis treatment from January 2005 to September 2009. Results: There were 8,240 TB patients (5183 males) of whom 492 (6%) were known to have died during treatment. Case-fatality was higher in those previously treated (12%) and lower in those with extra-pulmonary TB (2%). There was an even distribution of deaths during anti-tuberculosis treatment, with 28% of all patients dying in the first 8 weeks of treatment. Increasing age and new as compared to recurrent TB disease were significantly associated with “early death”. Conclusion: In this large cohort of TB patients, deaths occurred with an even frequency throughout anti-TB treatment. Reasons may relate to i) the treatment of the disease itself, raising concerns about drug adherence, quality of anti-tuberculosis drugs or the presence of undetected drug resistance and ii) co-morbidities, such as HIV/ AIDS and diabetes mellitus, which are known to influence mortality. More research in this area from prospective and retrospective studies is needed

Operational research in Malawi: making a difference with cotrimoxazole preventive therapy in patients with tuberculosis and HIV.

BACKGROUND: In Malawi, high case fatality rates in patients with tuberculosis, who were also co-infected with HIV, and high early death rates in people living with HIV during the initiation of antiretroviral treatment (ART) adversely impacted on treatment outcomes for the national tuberculosis and ART programmes respectively. This article i) discusses the operational research that was conducted in the country on cotrimoxazole preventive therapy, ii) outlines the steps that were taken to translate these findings into national policy and practice, iii) shows how the implementation of cotrimoxazole preventive therapy for both TB patients and HIV-infected patients starting ART was associated with reduced death rates, and iv) highlights lessons that can be learnt for other settings and interventions. DISCUSSION: District and facility-based operational research was undertaken between 1999 and 2005 to assess the effectiveness of cotrimoxazole preventive therapy in reducing death rates in TB patients and subsequently in patients starting ART under routine programme conditions. Studies demonstrated significant reductions in case fatality in HIV-infected TB patients receiving cotrimoxazole and in HIV-infected patients about to start ART. Following the completion of research, the findings were rapidly disseminated nationally at stakeholder meetings convened by the Ministry of Health and internationally through conferences and peer-reviewed scientific publications. The Ministry of Health made policy changes based on the available evidence, following which there was countrywide distribution of the updated policy and guidelines. Policy was rapidly moved to practice with the development of monitoring tools, drug procurement and training packages. National programme performance improved which showed a significant decrease in case fatality rates in TB patients as well as a reduction in early death in people with HIV starting ART. SUMMARY: Key lessons for moving this research endeavour through to policy and practice were the importance of placing operational research within the programme, defining relevant questions, obtaining "buy-in" from national programme staff at the beginning of projects and having key actors or "policy entrepreneurs" to push forward the policy-making process. Ultimately, any change in policy and practice has to benefit patients, and the ultimate judge of success is whether treatment outcomes improve or not

Voluntary Counselling, HIV Testing and Adjunctive Cotrimoxazole Reduces Mortality in Tuberculosis Patients in Thyolo, Malawi.

OBJECTIVES: To assess the feasibility and effectiveness of voluntary counselling, HIV testing and adjunctive cotrimoxazole in reducing mortality in a cohort of tuberculosis (TB) patients registered under routine programme conditions in a rural district of Malawi. DESIGN: 'Before' and 'after' cohort study using historical controls. METHODS: Between 1 July 1999 and 30 June 2000 all TB patients were started on standardized anti-TB treatment, and offered voluntary counselling and HIV testing (VCT). Those found to be HIV-positive were offered cotrimoxazole at a dose of 480 mg twice daily, provided there were no contraindications. Side-effects were monitored clinically. End-of-treatment outcomes in this cohort (intervention group) were compared with a cohort registered between 1 July 1998 and 30 June 1999 in whom VCT and cotrimoxazole was not offered (control group). FINDINGS: A total of 1986 patients was registered in the study: 1061 in the intervention group and 925 in the control cohort. In the intervention group, 1019 (96%) patients were counselled pre-test, 964 (91%) underwent HIV testing and 938 (88%) were counselled post-test. The overall HIV-seroprevalence rate was 77%. A total of 693 patients were given cotrimoxazole of whom 14 (2%) manifested minor dermatological reactions. The adjusted relative risk of death in the intervention group compared with the control group was 0.81 (P < 0.001). The number needed to treat with VCT and adjunctive cotrimoxazole to prevent one death during anti-TB treatment was 12.5. INTERPRETATION: This study shows that VCT and adjunctive cotrimoxazole is feasible, safe and reduces mortality rates in TB patients under routine programme conditions

Three-dimensional simulations of rotationally-induced line variability from a Classical T Tauri star with a misaligned magnetic dipole

We present three-dimensional (3-D) simulations of rotationally induced line variability arising from complex circumstellar environment of classical T Tauri stars (CTTS) using the results of the 3-D magnetohydrodynamic (MHD) simulations of Romanova et al., who considered accretion onto a CTTS with a misaligned dipole magnetic axis with respect to the rotational axis. The density, velocity and temperature structures of the MHD simulations are mapped on to the radiative transfer grid, and corresponding line source function and the observed profiles of neutral hydrogen lines (H-beta, Pa-beta and Br-gamma) are computed using the Sobolev escape probability method. We study the dependency of line variability on inclination angles (i) and magnetic axis misalignment angles (Theta). By comparing our models with the Pa-beta profiles of 42 CTTS observed by Folha & Emerson, we find that models with a smaller misaligngment angle (Theta<~15 deg.) are more consistent with the observations which show that majority of Pa-beta are rather symmetric around the line centre. For a high inclination system with a small dipole misalignment angle (Theta ~ 15 deg.), only one accretion funnel (on the upper hemisphere) is visible to an observer at any given rotational phase. This can cause an anti-correlation of the line equivalent width in the blue wing (v0) over a half of a rotational period, and a positive correlation over other half. We find a good overall agreement of the line variability behaviour predicted by our model and those from observations. (Abridged)Comment: 15 pages, 13 figures. Accepted for publication in MNRAS. A version with full resolution figures can be downloaded from http://www.physics.unlv.edu/~rk/preprint/inclined_dipole.pd

Outcomes and safety of concomitant nevirapine and rifampicin treatment under programme conditions in Malawi.

SETTING: Thyolo District Hospital, rural Malawi. OBJECTIVES: To report on 1) clinical, immunological and virological outcomes and 2) safety among human immunodeficiency virus (HIV) infected patients with tuberculosis (TB) who received concurrent nevirapine (NVP) and rifampicin (RMP) based treatment. DESIGN: Retrospective cohort study. METHODS: Analysis of programme data, June-December 2007. RESULTS: Of a total of 156 HIV-infected TB patients who started NVP-based antiretroviral treatment, 136 (87%) completed TB treatment successfully, 16 (10%) died and 5 (4%) were transferred out. Mean body weight and CD4 gain (adults) were respectively 4.4 kg (95%CI 3.3-5.4) and 140 cells/mm(3) (95%CI 117-162). Seventy-four per cent of patients who completed TB treatment and had a viral load performed (n = 74) had undetectable levels (<50 copies/ml), while 17 (22%) had a viral load of 50-1000 copies/ml. Hepatotoxicity was present in 2 (1.3%) patients at baseline. Two patients developed Grade 2 and one developed Grade 3 alanine transaminase enzyme elevations during TB treatment (incidence rate per 10 years of follow-up 4.2, 95%CI 1.4-13.1). There were no reported deaths linked to hepatotoxicity. CONCLUSIONS: In a rural district in Malawi, concomitant NVP and RMP treatment is associated with good TB treatment outcomes and appears safe. Further follow-up of patients would be useful to ascertain the longer-term effects of this concurrent treatment

Educating novice practitioners to detect elder financial abuse: A randomised controlled trial

© 2014 Harries et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.This article has been made available through the Brunel Open Access Publishing Fund.Background - Health and social care professionals are well positioned to identify and intervene in cases of elder financial abuse. An evidence-based educational intervention was developed to advance practitioners’ decision-making in this domain. The objective was to test the effectiveness of a decision-training educational intervention on novices’ ability to detect elder financial abuse. The research was funded by an E.S.R.C. grant reference RES-189-25-0334. Methods - A parallel-group, randomised controlled trial was conducted using a judgement analysis approach. Each participant used the World Wide Web to judge case sets at pre-test and post-test. The intervention group was provided with training after pre-test testing, whereas the control group were purely given instructions to continue with the task. 154 pre-registration health and social care practitioners were randomly allocated to intervention (n78) or control (n76). The intervention comprised of written and graphical descriptions of an expert consensus standard explaining how case information should be used to identify elder financial abuse. Participants’ ratings of certainty of abuse occurring (detection) were correlated with the experts’ ratings of the same cases at both stages of testing. Results - At pre-test, no differences were found between control and intervention on rating capacity. Comparison of mean scores for the control and intervention group at pre-test compared to immediate post-test, showed a statistically significant result. The intervention was shown to have had a positive moderate effect; at immediate post-test, the intervention group’s ratings had become more similar to those of the experts, whereas the control’s capacity did not improve. The results of this study indicate that the decision-training intervention had a positive effect on detection ability. Conclusions - This freely available, web-based decision-training aid is an effective evidence-based educational resource. Health and social care professionals can use the resource to enhance their ability to detect elder financial abuse. It has been embedded in a web resource at http://www.elderfinancialabuse.co.uk.ESR