Exact and approximate boundary data interpolation in the finite element method

Matching boundary data exactly in an elliptic problem avoids one of Strang's "variational crimes". (Strang and Fix (1973)). Supporting numerical evidence for this procedure is given by Marshall and Mitchell (1973), who considered the solution of Laplace's equation with Dirichlet boundary data by bilinear elements over squares and measured the errors in the L2 norm. Then Marshall and Mitchell (1978) obtained some surprising results: for certain triangular elements, matching the boundary data exactly produced worse results than the usual procedure of interpolating the boundary data

Suicide and Primary Care Contact in Cumbria

This is a supplementary report to the ‘Avoidable Mortality in Cumbria: A Case File Review of 78 Suicides’ document. The results presented below are based on suicides of Cumbria residents that were registered between 01 Jan 2012 to 31 Dec 2012 and 01 Apr 2013 to 18 Aug 2013. Further information regarding the definition of suicide and methodology used can be obtained from the main report and it is recommended that the two reports be read in conjunction with one another

Acceptability of financial incentives to improve health outcomes in UK and US samples

This study was funded as part of a strategic award from the Wellcome Trust Biomedical Ethics Programme (PI Marteau: 086031/Z/08/Z)

HIV infection in orphanages in South Western Nigeria

Background: As a result of the expanding HIV epidemic, affected children may end up in institutionalized care. Objectives: To determine the prevalence of HIV infection among children into orphanages in South Western Nigeria . Admission policies, knowledge and attitude of caregivers with respect to HIVwere also assessed Design: This was a cross sectional study in which interviewer administered questionnaires were used to collect information on consecutive children, heads of the orphanages and caregivers. Rapid HIV antibody testing was carried out. Results: A total of 190 children were enrolled from 7 homes with males accounting for 89 (46.8%). The main reasons for admission into the orphanages were; orphaned 85 (44.7%), abandoned 79 (41.6%) and mental illness in mother 11(5.8%). Two children were HIV positive, giving a prevalence rate of 1.05%. All the homes (100%) had a policy which excluded admission of HIV positive children but seldom carried out HIV testing at entry. Fear of disease transmission to others was the reason given for not admitting such children. Conclusion: The policy which excluded admission of HIV infected children may have contributed to the low prevalence of the infection in the orphanages. There needs to be a reform on the current policies in order to reduce discr iminat ion against HIV orphans.Keywords: HIV; Prevalence; Children; Orphanages; Admission policies; Caregiver

Identification of genetic interactions in a S. pombe yeast model for juvenile CLN3 disease

Juvenile CLN3 disease is a rare lysosomal storage disease, and the most common cause of neurodegeneration in children. Since the identification of the disease gene (CLN3) in 1995, efforts in various cellular and animal models have led to CLN3 being associated with several cellular pathologies. However, its precise molecular function remains unknown. Furthermore, with only a limited knowledge of disease pathogenesis, there remains a considerable need to identify therapeutic targets in order to accelerate the development of therapies for this prematurely fatal disease. Schizosaccharomyces pombe has proved to be a powerful and accurate model to help elucidate the function of CLN3 by virtue of its evolutionary conserved orthologue, btn1+. To date it has revealed both a new cellular localisation and potential functions for btn1+. The primary aim of this project was therefore to further exploit this fission yeast (btn1∆) model, and use synthetic genetic array analysis (SGAs) to identify genome- wide, genetic interactions of btn1+. It was hypothesised that defining the genetic relationships of btn1+ would provide insight into its molecular role, which in turn could be used to infer CLN3 gene function. It was also hoped that such information could be used to identify therapeutic targets and help refine the focus of future work in higher eukaryotic models. Using such an approach, this thesis provides a considerable step in our understand- ing of the function of btn1+, and by extrapolation CLN3, by suggesting that their function likely converges with various stress response pathways. A comprehensive characterization of the btn1∆ strain revealed numerous phenotypes co-incident with known stress response mutants, suggesting that this strain indeed displays compromised stress signalling which may contribute to disease pathogenesis. This thesis also details a number of therapeutic targets as the genetic manipulation of two highly conserved mitogen activated protein kinase pathways (the cell wall integrity (CWI) pathway and stress associated protein kinase (SAPK) pathway) and the interconnected TOR kinase complexes, are shown to rescue aspects, if not all, of the btn1∆ phenotypes investigated. This is the most successful rescue of disease phenotypes in any model for juvenile CLN3 disease to date

Enteric glia mediate neuron death in colitis through purinergic pathways that require connexin-43 and nitric oxide

The concept of enteric glia as regulators of intestinal homeostasis is slowly gaining acceptance as a central concept in neurogastroenterology. Yet how glia contribute to intestinal disease is still poorly understood. Purines generated during inflammation drive enteric neuron death by activating neuronal P2X7 purine receptors (P2X7R), triggering ATP release via neuronal pannexin-1 channels that subsequently recruits intracellular calcium ([Ca(2+)]i) responses in the surrounding enteric glia. We tested the hypothesis that the activation of enteric glia contributes to neuron death during inflammation.We studied neuroinflammation in vivo using the 2,4-dinitrobenzenesulfonic acid model of colitis and in situ using whole-mount preparations of human and mouse intestine. Transgenic mice with a targeted deletion of glial connexin-43 (Cx43) [GFAP∷Cre (ERT2+/-)/Cx43(f/f) ] were used to specifically disrupt glial signaling pathways. Mice deficient in inducible nitric oxide (NO) synthase (iNOS (-/-)) were used to study NO production. Protein expression and oxidative stress were measured using immunohistochemistry and in situ Ca(2+) and NO imaging were used to monitor glial [Ca(2+)]i and [NO]i.Purinergic activation of enteric glia drove [Ca(2+)]i responses and enteric neuron death through a Cx43-dependent mechanism. Neurotoxic Cx43 activity, driven by NO production from glial iNOS, was required for neuron death. Glial Cx43 opening liberated ATP and Cx43-dependent ATP release was potentiated by NO.Our results show that the activation of glial cells in the context of neuroinflammation kills enteric neurons. Mediators of inflammation that include ATP and NO activate neurotoxic pathways that converge on glial Cx43 hemichannels. The glial response to inflammatory mediators might contribute to the development of motility disorders

Avoidable Mortality in Cumbria: A Case File Review of 78 Suicides

On average, one person dies each week as a result of suicide in Cumbria. Gathering intelligence about suicide enables the identification of high-risk groups, risk factors and risk escalators, which can inform the development and implementation of local suicide prevention efforts. An overview of avoidable mortality in Cumbria based on deaths between 2008 and 2012, it was revealed that the rate of avoidable deaths due to injuries (which include suicide) was significantly higher compared than the England average in 2011. Cumbria’s Director of Public Health then requested that an in-depth review of suicide be undertaken. A total of 78 suicides were reviewed in detail for this report (58 registered in 2012 and 20 registered in 2013), using coroner information, primary care files, and secondary mental health care files (where applicable). A key message from this in-depth review is that the circumstances surrounding suicide are often complex characterised by a myriad of risk factors, risk escalators and precipitating factors present in an individual’s life with often no single attributable factor. Coroner Related Information Hanging was the most common method of male suicide, and drug related poisoning was the most common method of female suicide and this mirrors national findings. Male suicide by hanging has increased considerably over the last 9 years. There were 21 (27%) individuals who were known to have consumed alcohol at the time of death. The proportion of narrative verdicts delivered by Cumbria’s coroners has increased more than two-fold since 2006. These commonly make reference to a mental health illness. The increase in narrative verdicts mirrors an increase seen at a national level. Primary Care History Most individuals who died by suicide in Cumbria consulted with their GP in the year prior to death (81%), and over one fifth consulted in the week prior. Non-attenders were all male and most were under the age of 44 years. Mental illness and self-harm are well-documented risk factors for suicide, and in Cumbria 49 (63%) of individuals had a diagnosis of a current/on-going mental health condition at the time of death, most commonly depression, and 33 (42%) individuals had a history of self-harm. Alcohol and/or drug misuse/dependence was diagnosed in 13 (17%) individuals, over half of whom had a dual diagnosis (depression). The most commonly prescribed psychotropic drugs were selective serotonin reuptake inhibitors. Psychiatric History There were 49 (63%) individuals who had some previous contact with specialist mental health services in their lifetime. Nationally, 33% of individuals who died by suicide in 2011 had contact with mental health services in the 12 months prior to death (patient suicide) and this review found that in Cumbria there were 28 (36%) patient suicides. Of those 49 individuals who had specialist mental health service contact, 17 (35%) had been admitted to a psychiatric in-patient ward in their lifetime. Of the 28 patient suicides, 9 (32%) had been admitted to a psychiatric in-patient ward in the 12 months prior to their death. Emerging Risk Factors Alongside risk factors well documented in the literature, three emergent risk factors were noted in Cumbria. The first relates to welfare reform: in 5 (6%) cases a confirmed or potential change to an individual’s benefits was described to have caused worry, distress or anxiety in the days prior to death. The second relates to chronic pain and long term conditions: 18 (23%) individuals had a pain condition at the time of their death which often coexisted with a number of other suicide risk factors such as alcohol misuse/dependence. Finally, individuals in contact with the criminal justice system were also identified as a particular risk group, with 13 (17%) individuals being in contact in the 2 months prior to death. Suicide Audit Process In Cumbria, it is recognised that although conducting an in-depth review of suicide is a highly resource intensive process, the results are highly valued as a way of informing local suicide prevention strategies and action plans. Whilst carrying out this in-depth review, it became clear that the data collection tool being used could be adapted into a more condensed, practical and time efficient version. The way in which risk and escalating factors are documented for analytical purposes could also be improved. Recommendations To ensure that staff of Citizens Advice Bureau, Housing Associations, Job Centres and GPs that come into contact with individuals in distress as a result of benefit changes and other types of economic loss, know where to signpost individuals to appropriate support services. Healthcare professionals to consider the impact of chronic pain and other long term conditions in connection with other known risk factors and escalators when carrying out individual suicide risk assessments. To disseminate the findings of this report to the mental health and criminal justice steering group in Cumbria for further investigation and action in relation to individuals in recent contact with the criminal justice system. To produce a data collection pro-forma for future suicide audits in Cumbria that allows data to be collected in a more time-efficient manner, but that also does not compromise on the quality of information being produced. The production of agency specific reports in a format which can easily be updated following any successive suicide audits. Recommended agency specific reports include firstly the police (due to those in contact with the CJS identified locally and nationally as a risk group); secondly for specialist mental health services (on patient suicide) and thirdly a report for primary care professionals. The production of local authority specific summary reports, following interest from councillors in Cumbria. In order to make the suicide review process as complete as possible in the future, it is recommended that the primary care file of a deceased patient includes the full electronic GP summary print out

UBE2QL1 is Disrupted by a Constitutional Translocation Associated with Renal Tumor Predisposition and is a Novel Candidate Renal Tumor Suppressor Gene

Investigation of rare familial forms of renal cell carcinoma (RCC) has led to the identification of genes such as VHL and MET that are also implicated in the pathogenesis of sporadic RCC. In order to identify a novel candidate renal tumor suppressor gene, we characterized the breakpoints of a constitutional balanced translocation, t(5;19)(p15.3;q12), associated with familial RCC and found that a previously uncharacterized gene UBE2QL1 was disrupted by the chromosome 5 breakpoint. UBE2QL1 mRNA expression was downregulated in 78.6% of sporadic RCC and, although no intragenic mutations were detected, gene deletions and promoter region hypermethylation were detected in 17.3% and 20.3%, respectively, of sporadic RCC. Reexpression of UBE2QL1 in a deficient RCC cell line suppressed anchorage-independent growth. UBE2QL1 shows homology to the E2 class of ubiquitin conjugating enzymes and we found that (1) UBE2QL1 possesses an active-site cysteine (C88) that is monoubiquitinated in vivo, and (2) UBE2QL1 interacts with FBXW7 (an F box protein providing substrate recognition to the SCF E3 ubiquitin ligase) and facilitates the degradation of the known FBXW7 targets, CCNE1 and mTOR. These findings suggest UBE2QL1 as a novel candidate renal tumor suppressor gen

Avoidable Mortality in Cumbria: A Review of 73 Fatal Road Traffic Collisions

This report presents a retrospective review of 73 fatal road traffic collisions (RTCs) which occurred in Cumbria during 2012 and 2014 that resulted in 78 deaths and 2,120 potential years of life lost (PYLL). The data was compiled from collision investigation reports produced by Cumbria Constabulary’s Collision Investigation Unit. To develop effective prevention programmes in Cumbria, the factors associated with fatal RTCs must be identified and understood. The intelligence within this report is therefore intended to support local decision-making and inform the development of local plans to reduce the risk of death from RTCs in the county. Collision investigators attend each serious and potentially fatal RTC that occurs in the county. The files which are prepared by the collision investigators include photographs of the collision scene, witness statements, maps and diagrams, toxicology results, and their findings which are then compiled into a report. On average, a collision investigator in Cumbria arrives at the scene in 1 hour and 08 minutes following the collision. At the time of writing, 55 inquests had been held in relation to the fatal RTCs included within this report, resulting in a coroner’s verdict. The most common verdict delivered was ‘road traffic collision’ (n.27, 35%) closely followed by ‘accidental death’ (n.15, 31%). There was also 1 verdict of misadventure and 1 narrative verdict delivered and in 2 cases the inquest verdict was unknown. There were 8 cases where the inquest was still pending. The remaining 15 cases had been passed to the Crown Prosecution Service (CPS