End-of-life care and dementia

In the UK, research continues to confirm that people with certain chronic illnesses, such as chronic lung disease and cardiac failure, represent the ‘disadvantaged dying’ compared to those with terminal cancer. But what is the situation for people dying with advanced dementia and what is the experience of their carers? Practical guidance for clinicians is scarce. In Standard 7 of the National Service Framework for Older People, which covers mental health, there is mention neither of how care should be provided nor of how patient choice should be ensured for people with dementia at the end of life. In the UK, 5% of the population aged 65 and over and 20% of those aged 80 and over have dementia similar prevalence figures are found in the USA. Current predictions suggest that the number of people with dementia will increase by 40% by 2026 and will double by 2050. The increased demand for end-of-life care for people with dementia will be associated with major social and economic costs, but what is the current standard of such care? How can the quality be improved? And how should future services be configured to cope with this increasing need? In this paper, we review current knowledge around end-of-life care in dementia, discuss the clinical challenges and ethical dilemmas presented to carers, consider the difficulties in delivering such care and suggest practical approaches to improve the quality of such care

Mobile Phones and Contact Arrangements for Children Living in Care

This article reports the findings from the first UK study to examine the use of mobile phones by looked after children. Contact with family and friends is important, but it has sometimes to be carefully managed to avoid unintended consequences such as placement instability. The study examined the ways in which mobile phone technology impacts on contact, drawing on the experiences of children and young people in foster-care and residential care, and of policy makers, social workers, foster parents and residential care staff. No guidance was available that addressed the issue of mobile phone contact arrangements for looked after children and young people. Three years on from the start of the study, this remains the case in the area where the study was conducted, resulting in variation in the way mobile phone use for contact is managed; the issue appears only to be specifically addressed when identified as a problem. The position of mobile phone facilitated contact as a recognised form of contact requires review. The evidence suggests it should routinely form part of children’s care plans, and that residential staff and foster parents need to be adequately prepared and supported for the dynamics of mobile phone facilitated contact

'Country life'? Rurality, folk music and 'Show of Hands'

This paper examines the contribution of folk music to understanding the dynamic, fluid and multi-experiential nature of the countryside. Drawing from literature on the geographies of music, it examines the work of 'Show of Hands', a contemporary folk band from Devon in England. Three areas are studied. First, the paper examines the musical style of Show of Hands in order to explore how hybridised, yet distinctive, styles of music emerge in particular places. Second, it demonstrates how Show of Hands' hybrid musical style has become closely associated with the Southwest of England. Finally, within these spatial and hybrid contexts, attention is given to the ways in which their music represents the 'everyday lives of the rural'. Taken together these themes assess the relevance of music in the understanding of rurality as hybrid space. © 2008 Elsevier Ltd. All rights reserved

The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.

Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma

Spitzer Space Telescope Measurements of Dust Reverberation Lags in the Seyfert 1 Galaxy NGC 6418

We present results from a fifteen-month campaign of high-cadence (~ 3 days) mid-infrared Spitzer and optical (B and V ) monitoring of the Seyfert 1 galaxy NGC 6418, with the objective of determining the characteristic size of the dusty torus in this active galactic nucleus (AGN). We find that the 3.6 $\mu$m and 4.5 $\mu$m flux variations lag behind those of the optical continuum by $37.2^{+2.4}_{-2.2}$ days and $47.1^{+3.1}_{-3.1}$ days, respectively. We report a cross-correlation time lag between the 4.5 $\mu$m and 3.6 $\mu$m flux of $13.9^{+0.5}_{-0.1}$ days. The lags indicate that the dust emitting at 3.6 $\mu$m and 4.5 $\mu$m is located at a distance of approximately 1 light-month (~ 0.03 pc) from the source of the AGN UV-optical continuum. The reverberation radii are consistent with the inferred lower limit to the sublimation radius for pure graphite grains at 1800 K, but smaller by a factor of ~ 2 than the corresponding lower limit for silicate grains; this is similar to what has been found for near-infrared (K-band) lags in other AGN. The 3.6 and 4.5 $\mu$m reverberation radii fall above the K-band $\tau \propto L^{0.5}$ size-luminosity relationship by factors $\lesssim 2.7$ and $\lesssim 3.4$, respectively, while the 4.5 $\mu$m reverberation radius is only 27% larger than the 3.6 $\mu$m radius. This is broadly consistent with clumpy torus models, in which individual optically thick clouds emit strongly over a broad wavelength range.Comment: 13 pages, 9 figure

Allergen Delivery Inhibitors: A Rationale for Targeting Sentinel Innate Immune Signaling of Group 1 House Dust Mite Allergens through Structure-Based Protease Inhibitor Design

Diverse evidence from epidemiologic surveys and investigations into the molecular basis of allergenicity have revealed that a small cadre of “initiator” allergens promote the development of allergic diseases, such as asthma, allergic rhinitis, and atopic dermatitis. Pre-eminent among these initiators are the group 1 allergens from house dust mites (HDM). In mites, group 1 allergens function as cysteine peptidase digestive enzymes to which humans are exposed by inhalation of HDM fecal pellets. Their protease nature confers the ability to activate high gain signaling mechanisms which promote innate immune responses, leading to the persistence of allergic sensitization. An important feature of this process is that the initiator drives responses both to itself and to unrelated allergens lacking these properties through a process of collateral priming. The clinical significance of group 1 HDM allergens in disease, their serodominance as allergens, and their IgE-independent bioactivities in innate immunity make these allergens interesting therapeutic targets in the design of new small-molecule interventions in allergic disease. The attraction of this new approach is that it offers a powerful, root-cause-level intervention from which beneficial effects can be anticipated by interference in a wide range of effector pathways associated with these complex diseases. This review addresses the general background to HDM allergens and the validation of group 1 as putative targets. We then discuss structure-based drug design of the first-in-class representatives of allergen delivery inhibitors aimed at neutralizing the proteolytic effects of HDM group 1 allergens, which are essential to the development and maintenance of allergic diseases

Making progress with the automation of systematic reviews: principles of the International Collaboration for the Automation of Systematic Reviews (ICASR)

Systematic reviews (SR) are vital to health care, but have become complicated and time-consuming, due to the rapid expansion of evidence to be synthesised. Fortunately, many tasks of systematic reviews have the potential to be automated or may be assisted by automation. Recent advances in natural language processing, text mining and machine learning have produced new algorithms that can accurately mimic human endeavour in systematic review activity, faster and more cheaply. Automation tools need to be able to work together, to exchange data and results. Therefore, we initiated the International Collaboration for the Automation of Systematic Reviews (ICASR), to successfully put all the parts of automation of systematic review production together. The first meeting was held in Vienna in October 2015. We established a set of principles to enable tools to be developed and integrated into toolkits. This paper sets out the principles devised at that meeting, which cover the need for improvement in efficiency of SR tasks, automation across the spectrum of SR tasks, continuous improvement, adherence to high quality standards, flexibility of use and combining components, the need for a collaboration and varied skills, the desire for open source, shared code and evaluation, and a requirement for replicability through rigorous and open evaluation. Automation has a great potential to improve the speed of systematic reviews. Considerable work is already being done on many of the steps involved in a review. The ‘Vienna Principles’ set out in this paper aim to guide a more coordinated effort which will allow the integration of work by separate teams and build on the experience, code and evaluations done by the many teams working across the globe

Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease.

Mycobacterium ulcerans infection causes a neglected tropical disease known as Buruli ulcer that is now found in poor rural areas of West Africa in numbers that sometimes exceed those reported for another significant mycobacterial disease, leprosy, caused by M. leprae. Unique among mycobacterial diseases, M. ulcerans produces a plasmid-encoded toxin called mycolactone (ML), which is the principal virulence factor and destroys fat cells in subcutaneous tissue. Disease is typically first manifested by the appearance of a nodule that eventually ulcerates and the lesions may continue to spread over limbs or occasionally the trunk. The current standard treatment is 8 weeks of daily rifampin and injections of streptomycin (RS). The treatment kills bacilli and wounds gradually heal. Whether RS treatment actually stops mycolactone production before killing bacilli has been suggested by histopathological analyses of patient lesions. Using a mouse footpad model of M. ulcerans infection where the time of infection and development of lesions can be followed in a controlled manner before and after antibiotic treatment, we have evaluated the progress of infection by assessing bacterial numbers, mycolactone production, the immune response, and lesion histopathology at regular intervals after infection and after antibiotic therapy. We found that RS treatment rapidly reduced gross lesions, bacterial numbers, and ML production as assessed by cytotoxicity assays and mass spectrometric analysis. Histopathological analysis revealed that RS treatment maintained the association of the bacilli with (or within) host cells where they were destroyed whereas lack of treatment resulted in extracellular infection, destruction of host cells, and ultimately lesion ulceration. We propose that RS treatment promotes healing in the host by blocking mycolactone production, which favors the survival of host cells, and by killing M. ulcerans bacilli

Progesterone receptor modulates ERα action in breast cancer.

Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERα(+) cell line xenografts and primary ERα(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERα(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.We would like to acknowledge the support of the University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited. Research reported in this manuscript was supported by the National Cancer Institute of the National Institutes of Health under award number 5P30CA142543 (to UT Southwestern) and Department of Defense grants W81XWH-12-1-0288-03 (GVR). W.D.T. is supported by grants from the National Health and Medical Research Council of Australia (ID 1008349; ID 1084416) and Cancer Australia (ID 627229) T.E.H held a Fellowship Award from the US Department of Defense Breast Cancer Research Program (BCRP; #W81XWH-11-1-0592) and currently is supported by a Florey Fellowship from the Royal Adelaide Hospital Research Foundation. J.S.C is supported by an ERC starting grant and an EMBO Young investigator award.This is the accepted manuscript. The final version is available at www.nature.com/nature/journal/v523/n7560/full/nature14583.htm