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    ABSTRACT: PRH/HHex (proline-rich homeodomain protein) is a transcription factor that controls cell proliferation and cell differentiation in a variety of tissues. Aberrant subcellular localisation of PRH is associated with breast cancer and thyroid cancer. Further, in blast crisis chronic myeloid leukaemia, and a subset of acute myeloid leukaemias, PRH is aberrantly localised and its activity is downregulated. Here we show that PRH is involved in the regulation of cell migration and cancer cell invasion. We show for the first time that PRH is expressed in prostate cells and that a decrease in PRH protein levels increases the migration of normal prostate epithelial cells. We show that a decrease in PRH protein levels also increases the migration of normal breast epithelial cells. Conversely, PRH overexpression inhibits cell migration and cell invasion by PC3 and DU145 prostate cancer cells and MDA-MB-231 breast cancer cells. Previous work has shown that the transforming growth factor-β co-receptor Endoglin inhibits the migration of prostate and breast cancer cells. Here we show that PRH can bind to the Endoglin promoter in immortalised prostate and breast cells. PRH overexpression in these cells results in increased Endoglin protein expression, whereas PRH knockdown results in decreased Endoglin protein expression. Moreover, we demonstrate that Endoglin overexpression abrogates the increased migration shown by PRH knockdown cells. Our data suggest that PRH controls the migration of multiple epithelial cell lineages in part at least through the direct transcriptional regulation of Endoglin. We discuss these results in terms of the functions of PRH in normal cells and the mislocalisation of PRH seen in multiple cancer cell types.Oncogene advance online publication, 18 November 2013; doi:10.1038/onc.2013.496.
    Oncogene 11/2013; 33(49). DOI:10.1038/onc.2013.496
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    ABSTRACT: To examine the quality of transitional care in a paediatric and adult hospital by investigating (i) adherence to national transition guidance and (ii) whether implementation is associated with better patient/carer experiences. A cross-sectional study was conducted in a UK paediatric hospital (PH) and neighbouring adult hospital. Clinics completed a questionnaire to determine characteristics of their transitional care provision and invited patients aged 11-21 years and parents/carers to complete a questionnaire ('Mind the Gap') to assess their satisfaction. Twenty-three clinics participated. Fourteen (70%) reported delivering a transition programme, but only 5 (25%) indicated this was holistic (addressing medical, psychosocial and vocational issues). Participants included 457 young people and 330 parents, 71% and 88% respectively attending the PH. Ratings of current care were significantly lower than ratings of best care. These 'gap' scores were not excessive, although some participants were very dissatisfied. Better satisfaction was associated with attending clinics that provided transitional care, especially when defined as 'holistic' and youth-friendly. Transition programmes that adhere to current guidance are associated with better satisfaction, but variations in provision suggest barriers to implementation. Attention is required to how youth-friendly transitional care is defined with particular reference to the specific clinic model.
    Child Care Health and Development 10/2013; 40(5). DOI:10.1111/cch.12110
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    ABSTRACT: Dementia is common and often undiagnosed. Improving rates of diagnosis has become a key part of current dementia guidelines. Older people admitted to hospital are a potential target population for screening for dementia. The objective was to report whether instruments advocated in screening for dementia had been validated in hospital inpatients and to make recommendations on evidence-based screening for dementia in this population. a systematic review was performed by an initial electronic database search using three key search criteria. Studies were then selected in a systematic fashion using specific predetermined criteria. Pooled meta-analysis was performed. Inclusion criteria were studies where the study group were inpatients in general hospitals, including a clearly defined group of older people (60 or older), they used a recognised screening instrument compared with a reference standard, and included at least 10 cases of dementia. Demographic data as well as sensitivity and specificity were recorded from the selected studies. in total nine studies describing validation of six discreet instruments satisfied all our criteria and we were able to perform meta-analysis with one instrument, the Abbreviated Mental Test Score (AMTS). With a cut-off of <7, pooled analysis of the AMTS showed a sensitivity of 81%, a specificity of 84% and an area under the curve (AUC) of 0.88. a small number of instruments have been validated for screening for dementia in general hospital. Understanding strengths and weaknesses of currently available instruments allows informed decisions about screening in this setting.
    Age and Ageing 10/2013; 42(6). DOI:10.1093/ageing/aft145
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    ABSTRACT: Pulmonary hypertension (PH) can occur at any time during the course of systemic lupus erythematosus (SLE), and can be independent of lupus disease activity in other systems. The pathogenesis of PH in SLE can be multifactorial, but pulmonary arterial hypertension (PAH) is the commonest cause of PH in SLE. The international PH registries have published that approximately 15% of connective tissue disease-associated PH is lupus related in their cohorts. As the symptoms of PH in SLE can be mild and non-specific in early stages, an increasing awareness of this devastating complication is essential for early diagnosis. Echocardiographic evaluation of several right heart variables in addition to systolic pulmonary artery pressure estimation reduces false positive rates for PH detection. Antiphospholipid antibodies may predict SLE-PAH. Prompt treatment of PAH with newer PAH therapy as well as immunosuppression can reduce morbidity and prolong survival. The survival in SLE-associated PAH is better compared with systemic sclerosis-associated PH but worse than idiopathic PAH. Pregnancy in SLE-PAH can result in a fatal outcome, especially in severe and poorly controlled PH at onset.
    Lupus 10/2013; 22(12):1274-1285. DOI:10.1177/0961203313505010
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    ABSTRACT: Although the inhibitory effects of therapeutic glucocorticoids (GC) upon dendritic cells (DC) are well established, the roles of endogenous GC upon DC homeostasis are less clear. A critical element regulating endogenous GC concentrations involves local conversion of inactive substrates to active 11-hydroxyglucocorticoids, a reduction reaction catalyzed within the endoplasmic reticulum by an enzyme complex containing 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and hexose-6-phosphate dehydrogenase (H6PDH). In this study, we find that this GC amplification pathway operates both constitutively and maximally in steady state murine DC populations and is unaffected by additional inflammatory stimuli. Under physiological conditions, 11βHSD1-H6PDH increases the sensitivity of plasmacytoid DC (pDC) to GC-induced apoptosis and restricts the survival of this population through a cell-intrinsic mechanism. Upon CpG activation, the effects of enzyme activity are overridden, with pDC becoming resistant to GC and fully competent to release type I interferon. CD8α+ DC are also highly proficient in amplifying GC levels, leading to impaired maturation following TLR-mediated signaling. Indeed, pharmacological inhibition of 11βHSD1 synergized with CpG to enhance specific T cell responses following vaccination targeted to CD8α+ DC. In conclusion, amplification of endogenous GC is a critical cell-autonomous mechanism for regulating the survival and functions of DC in vivo.
    Blood 09/2013; 122(19). DOI:10.1182/blood-2013-03-489138
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    ABSTRACT: From their interesting data Becker et al (Br J Dermatol 2013;168:362-6) induce that … 'AD seems to be a priming precondition for the development of LS in boys' … consistent with … a permissive effect of atopy facilitating the development of LS' …. Not unreasonably, they continue … 'genetic defects causing a lack of filaggrin have been reported in 50% of all AD cases, underlining the pathogenetic hypothesis that a disturbed atopic skin barrier is more susceptible to infectious and allergic and possibly LS-triggering agents' …, but then take a tendentious wrong-turning to conclude that … 'further studies are needed to illuminate the underlying immunological mechanisms in both entities to clarify the linkage between AD and LS'. This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 08/2013; 169(4). DOI:10.1111/bjd.12553
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    ABSTRACT: The spondyloarthropathies represent highly enigmatic conditions and although their clinical features, anatomical distribution of disease and genetic predisposing factors have been known for some time, a unified concept of the basic pathobiology underlying these illnesses has remained undefined. Recently progress has been made because numerous independent studies have converged upon IL-23 as a central cytokine in spondyloarthropathy and the mechanism and sites of action of this cytokine have now become much clearer. These findings enable the rational design of therapeutic strategies which it is hoped will profoundly modify the progression of these diseases. We will review the anatomical sites affected and the evidence for the importance of IL-23 in these conditions, before drawing these lines of investigation together to propose a model for the unified understanding of spondyloarthropathy.
    Molecular Immunology 08/2013; DOI:10.1016/j.molimm.2013.06.010
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    ABSTRACT: Beta lactams (BL) are the most widely prescribed antibiotics in the UK and the commonest cause of hypersensitivity reactions. There are no UK guidelines for BL testing and the most relevant guidelines were devised by the European Network for Drug Allergy (ENDA) on behalf of the European Academy of Allergy and Clinical Immunology. Delivery of allergy services differs across Europe, so this survey was designed to investigate how closely UK practice adhered to these guidelines. An online survey, using surveymonkey.com software, was sent to all consultants offering an allergy service in the UK and who were members of either BSACI or 'Travellers' (Immunology consultant group). The response rate was 48% (n=81/165) and BL allergy testing was undertaken by 78% of respondents. All responders requested SsIgE, although four responders stated they rarely requested. Skin testing was undertaken by 87% of respondents who perform beta lactam testing with 17% undertaking skin prick testing (SPT) only, 77% SPT followed by intra-dermal testing (IDT) if the former were negative or indeterminate and 6% SPT and IDT in all cases. The drugs, doses and protocols for skin testing varied considerably. Drug provocation testing was undertaken by 87% of respondents who undertake beta lactam testing with significant heterogeneity in protocols. Respondents that investigated ≤ 20 patients per year demonstrated lower adherence to ENDA recommendations compared to those who saw > 20. Following positive testing, 79% advised avoidance of all penicillins only and the remainder advised additional drug avoidance. This survey revealed variation in the investigation and management of BL hypersensitivity in the UK with some centres reporting procedures that could potentially put patients at risk of anaphylaxis if allergy was falsely excluded. This survey highlights an urgent need for evidence based national guidelines and standardisation of practice.
    Clinical & Experimental Allergy 08/2013; 43(8):941-9. DOI:10.1111/cea.12134
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    ABSTRACT: Full length adiponectin is a potent immune modulatory adipokine, impacting upon the actions of several immune cells. Neutrophil oxidative burst has been shown to decrease in response to adiponectin, and we speculated that it could have other effects on neutrophil function. Here we report that adiponectin reduces the phagocytic ability of human neutrophils, decreasing significantly the ingestion of opsonised E. coli by these cells in whole blood (p<0.05) and as isolated neutrophils (p<0.05). We then determined the mechanisms involved. We observed that the activation of Mac-1, the receptor engaged in complement-mediated phagocytosis, was decreased by adiponectin in response to E. coli stimulation. Moreover, treatment of neutrophils with adiponectin prior to incubation with E. coli significantly inhibited signalling through the PI3K/PKB and ERK 1/2 pathways, with a parallel reduction of F-actin content. Studies with pharmacological inhibitors showed that inhibition of PI3K/PKB, but not ERK 1/2 signalling was able to prevent the activation of Mac-1. In conclusion, we propose that adiponectin negatively affects neutrophil phagocytosis, reducing the uptake of E. coli and inhibiting Mac-1 activation, the latter by blockade of the PI3K/PKB signal pathway.
    PLoS ONE 07/2013; 8(7):e69108. DOI:10.1371/journal.pone.0069108
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    ABSTRACT: Hip fracture is a common trauma in older adults with a high incidence of depression, which relates to poorer prognosis including increased risk of infection. Ageing is accompanied by reduced immunity, termed immunesenescence, resulting in increased susceptibility to infection. We examined whether physical trauma (hip fracture) and psychological distress (depressive symptoms) had additive effects upon the aged immune system that might contribute to poor outcomes after injury. Neutrophil function was assessed in 101 hip fracture patients (81 female) 6 weeks and 6 months after injury and 43 healthy age-matched controls (28 female). 38 fracture patients had depressive symptoms at 6 weeks. No difference in neutrophil phagocytosis of E. coli was observed between controls and hip fracture patients, but superoxide production was significantly reduced in hip fracture patients with depressive symptoms compared with patients without symptoms (p = .001) or controls (p = .004) at 6 weeks. Superoxide production improved 6 months following fracture to the level seen in controls. We detected elevated serum cortisol, reduced dehydroepiandrosterone sulphate (DHEAS) and an increased cortisol:DHEAS ratio in fracture patients with depressive symptoms compared with patients without depressive symptoms or controls at 6 weeks and 6 months after injury. Serum IL6, TNFα and IL10 were higher among patients with depressive symptoms at 6 weeks. The cortisol:DHEAS ratio and IL6 levels related to depressive symptom scores but not to neutrophil function. In conclusion, depressive symptoms related to poorer neutrophil function after hip fracture, but this was not driven by changes in stress hormone or cytokine levels.
    Brain Behavior and Immunity 07/2013; 33(100). DOI:10.1016/j.bbi.2013.07.004
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