[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: The glycoform profile of a glycoprotein is non-templated, i.e., is not encoded within the genome or otherwise predetermined; however, it is estimated that ~50% of human genes having an open reading frame encode a -N-X-S/T- amino acid sequence, where X represents any amino acid other than proline, that comprises a potential site (sequon) for N-linked glycosylation of the translated protein. N-linked glycosylation is both a co- and post-translational modification. The complex oligosaccharide GlcNAc2Man9Glu3 may be added at a -N-X-S/T- sequon as the polypeptide chain emerges from the ribosome tunnel. Local secondary structure determines whether oligosaccharide is added and the extent of addition. Higher occupancy is observed for -N-X-T- sequons than at -N-X-S- sequins, and the efficiency of addition can be further influenced by adjacent amino acid residues.
[Show abstract][Hide abstract] ABSTRACT: The protein tyrosine phosphatase CD45 is critical in regulating the earliest steps in T cell receptor signalling but, like all PTPs, is susceptible to oxidative inactivation. Given the widely reported effects of oxidant damage associated with rheumatoid arthritis (RA) we examined whether CD45 phosphatase activity was altered in CD4+ T cells from RA patients and related this to CD4+ T cell function and redox status. CD45 phosphatase specific activity in T cells from RA peripheral blood (PB) and synovial fluid (SF) was 56% and 59% lower than in healthy control (HC) PB respectively. In contrast CD45 activity in T cells from disease controls (DSC) was not significantly different to HC. Reduced glutathione (GSH) (p<0.001) and oxidised glutathione (GSSG) (p<0.05), were both significantly lower in RA PB T cells compared with HC PB T cells. Treatment of RA PB T cells with the glutathione precursor N-acetyl cysteine increased CD45 phosphatase activity and proliferation, while decreasing Lck kinase phosphorylation which is regulated by CD45. Our observations lead to the hypothesis that the largely reversible oxidative inactivation of the CD45 phosphatase may underlie the decreased signalling efficiency and functional responsiveness characteristic of RA PB CD4+ T cells.
[Show abstract][Hide abstract] ABSTRACT: Low-income countries typically lag behind industrialised nations, where the introduction of new vaccines is commonly tailored to the pressures of the commercial market. Happily in recent years this paradigm has started to change with the introduction of a univalent meningococcal A conjugate vaccine that is specifically targeted for the prevention of epidemic meningitis in Africa. The declaration of the 2010s as a New Decade of Vaccines, together with Millennium Development Goals 4 and 5, provide a strong mandate for a new approach to the development of vaccines for low-income countries, so that there has never been a more exciting time to work in this field. This review considers the opportunities and challenges of developing these new vaccines in the context of innovations in vaccinology, the need to induce protective immunity in the populations at risk and the requirement for strong partnership between the countries that will use these vaccines and different elements of the vaccine industry.
[Show abstract][Hide abstract] ABSTRACT: Forming the first line of defence against virally-infected and malignant cells, natural killer (NK) cells are critical effector cells of the innate immune system. With age, significant impairments have been reported in the two main mechanisms by which NK cells confer host protection: direct cytotoxicity and the secretion of immunoregulatory cytokines and chemokines. In elderly subjects, decreased NK cell activity has been shown to be associated with an increased incidence and severity of viral infection, highlighting the clinical implications that age-associated changes in NK cell biology have on the health of older adults. However, is an increased susceptibility to viral infection the only consequence of these age-related changes in NK cell function? Recently, evidence has emerged that has shown that in addition to eliminating transformed cells, NK cells are involved in many other biological processes such as immune regulation, anti-microbial immune responses and the recognition and elimination of senescent cells, novel functions that involve NK-mediated cytotoxicity and/or cytokine production. Thus, the decrease in NK cell function that accompanies physiological ageing is likely to have wider implications for the health of older adults than originally thought. Here, we give a detailed description of the changes in NK cell biology that accompany human ageing and propose that certain features of the ageing process such as: (i) the increased reactivation rates of latent Mycobacterium tuberculosis, (ii) the slower resolution of inflammatory responses and (iii) the increased incidence of bacterial and fungal infection are attributable in part to an age-associated decline in NK cell function.
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