204 research outputs found

    Descriptive epidemiology of limb reduction deformities in Hawaii, 1986-2000.

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    The relationship between limb reduction deformities and clinical and demographic factors in Hawaii during 1986-2000 were examined using population-based birth defects program data. The limb defect rate was highest with maternal age less than 20 years, and the defect was more common among males. Among racial/ethnic groups, Pacific Islanders and Filipinos had higher rates than whites and Far East Asians

    Aryl hydrocarbon receptor activation in primary human keratinocytes and epidermal equivalents

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    The Aryl hydrocarbon Receptor (AhR) mediates the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulting in the human specific toxicity, chloracne. To test whether the chloracnegenic potential of AhR-agonists depends upon binding affinity for the AhR, residency and/or down-regulation of the AhR, we investigated the effects of different AhR agonists in primary human keratinocytes and epidermal equivalents. The AhR agonists used were high-affinity, high-residency and high-potency TCDD, and two agonists not known to induce chloracne; low-affinity, low-residency and low-potency β-naphthoflavone (β-NF) and the low-affinity, low-residency and high-potency physiological agonist 2-(1‟H-indole-3‟-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). -NF, a partial agonist was used to test AhR dependency. The effects of these agonists on AhR activation, terminal differentiation, autophagy and expression of cathepsin D (CTSD) in primary human keratinocytes and epidermal equivalents were determined. All three agonists induced AhR activation by XRE-luciferase assay, which was inhibited by α-NF, demonstrating AhR dependence of the ligands. AhR degradation was induced by all ligands and CYP1A1 was induced strongly by TCDD but weakly by β-NF and ITE. CYP1A1 and XRE-luciferase induction correlated with ligand binding affinity; ranking levels of binding affinity as TCDD>β-NF>ITE. TCDD treatment induced a chloracne-like phenotype in epidermal equivalents, with a decrease in viable cell layer thickness and compacted stratum corneum. This was not induced by β-NF or ITE. To investigate the differential effects of AhR-ligands on epidermal equivalent phenotype, we studied differentiation markers filaggrin, involucrin and TGM-1. TGM-1 expression was induced specifically by TCDD while aberrant expression of involucrin and filaggrin were induced by TCDD, β-NF and ITE. AhR activation was not associated with increased apoptosis. Caspase-3 independent cell death has been implicated as a mechanism of decreased thickness of the viable cell layer, so we studied the effects of AhR-agonists on autophagy. Autophagy in keratinocytes and epidermal equivalents was characterised by induction of LC3 II, p62 degradation and transmission electron microscopy. TCDD robustly induced active autophagy, while ITE induced lower levels and β-NF blocked autophagy. TCDD- and ITE-induced autophagy in epidermal equivalents appeared to result in decreased numbers of lamellar bodies, which may account at least in part for the compacted stratum corneum phenotype shown by the TCDD-induced phenotype in epidermal equivalents and chloracne. As CTSD has been implicated in keratinocyte differentiation and an XRE domain has been identified upstream of CTSD, we studied the effects of ligand-dependent AhR activation on lysosomal aspartic protease CTSD expression. CTSD was increased by AhR activity in epidermal equivalents. Induction of CYP1A1 did not appear to be a specific biomarker of chloracnegenic potential of AhR agonists. The data presented have shown differential effects by TCDD, β-NF and ITE on autophagy that we hypothesise contributes to the chloracne phenotype. In this thesis, potential biomarkers specific to chloracne were identified in keratinocytes, TGM-1, CTSD, autophagy and decreased lamellar bodies, although further validation is required.EThOS - Electronic Theses Online ServiceBBSRCAstraZenecaGBUnited Kingdo

    Stoke-on-Trent Opportunity Area Programme Improving Outcomes for Early Years ‘Understanding the World – Area of Learning’

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    This is a Stoke-on-Trent Opportunity Area funded project. The Opportunity Area Programme seeks to improve social mobility for children and young people, to break the link between social background and destination. Stoke-on-Trent is one of 12 areas selected for additional support from the DfE, working through a partnership of local leaders. The project relates to improving outcomes in the Early Years Foundation Stage (EYFS) to give children the best possible start in life and learning. Data shows that only 71% of pupils achieve or exceed the expected standard against the Understanding the World Area of Learning which incorporates three Early Learning Goals (ELGs). Children in the most deprived wards are least likely to achieve the standard

    “Understanding the World”: a pilot study of effective practice and provision in early years settings

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    This small-scale study explored effective practice and provision in early years settings to support children’s learning. The research was funded by an Opportunity Area programme, a government policy for dealing with social mobility through education. The research investigated the experiences and perceptions of early years practitioners in relation to the Understanding the World area of learning which incorporates three of the seventeen Early Learning Goals contained within the Early Years Foundation Stage. These Early Learning Goals are; ‘People and Communities’, ‘The World’ and ‘Technology’. The study was conducted within the city of Stoke-on-Trent in England where official published data reveals only 71% of pupils achieve or exceed the expected standard against the Understanding the World area of learning where the national average is 83%. The research adopted a mixed methods approach comprising an online survey and semi-structured interviews with practitioners working with children in private and maintained day nurseries and primary school reception classes where good and outstanding results are achieved for the city’s disadvantaged children. The findings of the study include the identification of best practice examples along with features of effective provision. Barriers to children’s progression and attainment of these specific Early Learning Goals were also ascertained. The implications for practice and further research are presented

    Evaluation of the Sector Hub Action Research Project. Funded by the Community Renewal Fund Promoting care as a career – a pilot project devised and led by Acacia Training in Stoke on Trent

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    The Sector Hub Action Research Project (SHARP) is a pilot project designed to inform how providers can work collaboratively to address skills shortages in the adult, child, and domiciliary care sectors. The project was funded by the Government Skills for Growth Plan; a national programme, which seeks to promote the Levelling Up Agenda by improving skills, infrastructure, and innovation. The project had three strands, first was to promote care as a career, including care-focused outreach targeting under-represented groups delivered by Acacia Training and Acorn Training. Secondly, Acacia Training provided care-focused information, advice, and guidance on careers in care, job opportunities, transferrable skills, salary, and progression. Finally, Acacia Training developed a portfolio of care provider resources and actions which support job retention and career progression in the health and social care sector. The evaluation led by Staffordshire University monitored and tracked the outreach, training, and support as well as navigation to employment in the target sector using an Appreciative Inquiry (AI) model. AI provided a rich tapestry of experiences of staff and trainees or potential care staff. The report includes findings from the surveys and interviews illustrating a direct correlation between support provided and outcomes. Six key themes are highlighted in the report, reiterating the impact Covid-19 had on employment relations which are particularly important in the health and social care system. The evaluation emphasised how lack of orientation opportunities influenced workflow and team management procedures during the pandemic. Other barriers identified have been cited in literature, such as the policies around enforced vaccination, the emotional labour of work in the care sector and unwillingness to engage with pride in jobs which involve personal care. The report also stresses the need for holistic support, with reference to enhancing digital access for potential trainees who may be motivated but do not have the technical resources and know how to engage with digital employment routes or systems. The recommendations are linked to the holistic needs highlighted in the pilot and its evaluation, suggesting wrap-around support which enhances appreciation of the range of roles in the sector, the need for localised opportunities and established, attractive progression routes. Comprehensive training and development programmes that support skills, confidence and care as a career are also important
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