Epidermal Growth Factor Removal or Tyrphostin AG1478 Treatment Reduces Goblet Cells & Mucus Secretion of Epithelial Cells from Asthmatic Children Using the Air-Liquid Interface Model

<p>RATIONALE: Epithelial remodelling in asthma is characterised by goblet cell hyperplasia and mucus hypersecretion for which no therapies exist. Differentiated bronchial air-liquid interface cultures from asthmatic children display high goblet cell numbers. Epidermal growth factor and its receptor have been implicated in goblet cell hyperplasia.</p><p>OBJECTIVES: We hypothesised that EGF removal or tyrphostin AG1478 treatment of differentiating air-liquid interface cultures from asthmatic children would result in a reduction of epithelial goblet cells and mucus secretion.</p><p>METHODS: In Aim 1 primary bronchial epithelial cells from non-asthmatic (n = 5) and asthmatic (n = 5) children were differentiated under EGF-positive (10ng/ml EGF) and EGF-negative culture conditions for 28 days. In Aim 2, cultures from a further group of asthmatic children (n = 5) were grown under tyrphostin AG1478, a tyrosine kinase inhibitor, conditions. All cultures were analysed for epithelial resistance, markers of differentiation using immunocytochemistry, ELISA for MUC5AC mucin secretion and qPCR for MUC5AC mRNA.</p><p>RESULTS: In cultures from asthmatic children the goblet cell number was reduced in the EGF negative group (p = 0.01). Tyrphostin AG1478 treatment of cultures from asthmatic children had significant reductions in goblet cells at 0.2��g/ml (p = 0.03) and 2��g/ml (p = 0.003) as well as mucus secretion at 2��g/ml (p = 0.04).</p><p>CONCLUSIONS: We have shown in this preliminary study that through EGF removal and tyrphostin AG1478 treatment the goblet cell number and mucus hypersecretion in differentiating air-liquid interface cultures from asthmatic children is significantly reduced. This further highlights the epidermal growth factor receptor as a potential therapeutic target to inhibit goblet cell hyperplasia and mucus hypersecretion in asthma.</p>

Oscar Wilde at Home

Oscar, Constance, Speranza (and Bosie) are ���at home��� in the exquisitely beautiful Florence Court House this Mayday weekend. House guests will include Jack, Algy, Gwendolen and Cecily from the Importance of Being Earnest, (not to mention the redoubtable Lady Bracknell), Lord and Lady Windermere, the impetuous Lord Darlington, and the precocious Dorian Gray. Visitors will be conducted throughout the house where a range of short scenes from Wilde���s most popular works will be performed live by actors in each of the principal rooms. Is it life or is it art? Come and decide for yourself as we welcome you to the witty, complex and contradictory world of Oscar Wilde. Conceived and directed by David Grant.<br/><br/>Dramatis Personae<br/>Oscar Wilde (and Lord Henry Wotton) ��� Donal Morgan<br/>Constance Wilde (Lady Wotton, and Cecily Cardew) ��� Julie Lamberton<br/>Lady Speranza Wilde (Lady Bracknell and Mrs Erlynne) ��� Antoinette Morelli<br/>Lord Alfred Douglas (and Dorian Gray) ��� Sydney Bull<br/>Lord Darlington and Basil Hallward ��� Richard Croxford<br/>Lady Windermere and Gwendolen Fairfax ��� Stephanie Dale<br/>Jack Worthing ��� Patrick McBrearty<br/>Algernon Moncrieff and Lord Windermere ��� Stefan Dunbar<br/>Lane and Parker ��� Curtis Reed and tbc<br/><br/>Production Team<br/>Costume Design ��� Enda Kenny<br/>Sound Design ��� Sydney Bull<br/>Sound Operator ��� Seth Taylor<br/>Stage Manager ��� Bronagh McFeely<br/>Company Manager ��� Eamon Quinn<br/>Director ��� David Grant<br/>

Double ionization in R-matrix theory using a two-electron outer region

We have developed a two-electron outer region for use within R-matrix theory to describe double ionisation processes. The capability of this method is demonstrated for single-photon double ionisation of He in the photon energy region between 80 eV to 180 eV. The cross sections are in agreement with established data. The extended RMT method also provides information on higher-order processes, as demonstrated by the identification of signatures for sequential double ionisation processes involving an intermediate He⁺ state with n=2.

Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial

<p>BACKGROUND: Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range ��-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases.</p><p>METHODS: In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751.</p><p>FINDINGS: Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15��6 months [95% CI 13��5-18��0] vs 9��8 months [7��3-23��7]; hazard ratio [HR]=0��66, 95% CI 0��52-0��83; p=0��00037). The risks of external beam radiation therapy for bone pain (HR 0��67, 95% CI 0��53-0��85) and spinal cord compression (HR=0��52, 95% CI 0��29-0��93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0��62, 95% CI 0��35-1��09), or the need for tumour-related orthopaedic surgical intervention (HR 0��72, 95% CI 0��28-1��82).</p><p>INTERPRETATION: Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases.</p><p>FUNDING: Algeta and Bayer HealthCare Pharmaceuticals.</p>

Utopia Incomplete: British New Towns and Craigavon

The New towns initiative in the UK and Northern Ireland, enshrined in the Act of 1946, was derived out of a stream of philosophical thought that was a reaction to modernity, paritcularly Victorian industrialisation. This was developed through the writings of Ruskin and Morris and crystalised by Ebenezer Howard in his book Garden Cities of Tomorrow, which culminated with the design of Letchworth by Parker and Unwin (completed 1914). Letchworth however, was a more than just a physical and spatial entity: it was actually a policyscape, a novel economic and social policy landscape that regulated development in a modern and scientific way. <br/><br/>These themes of the scientification of urban design, and the regulation of urban development through policy, run through the whole New Town movement, right up to the development of the eco-towns of today. New Towns, in fact, can be seen as an embodiment of modernity, as well as a reaction to it . <br/>

Effectiveness of a biomarker-based exclusion of ventilator-acquired pneumonia to reduce antibiotic use: protocol for a randomised controlled trial (VAPrapid-2):Study protocol for a randomised controlled trial

Background Ventilator-acquired pneumonia (VAP) is a common reason for antimicrobial therapy in the intensive care unit (ICU). Biomarker-based diagnostics could improve antimicrobial stewardship through rapid exclusion of VAP. Bronchoalveloar lavage (BAL) fluid biomarkers have previously been shown to allow the exclusion of VAP with high confidence. Methods/Design This is a prospective, multi-centre, randomised, controlled trial to determine whether a rapid biomarker-based exclusion of VAP results in fewer antibiotics and improved antimicrobial management. Patients with clinically suspected VAP undergo BAL, and VAP is confirmed by growth of a potential pathogen at���&gt;���104 colony-forming units per millilitre (CFU/ml). Patients are randomised 1:1, to either a ���biomarker-guided recommendation on antibiotics��� in which BAL fluid is tested for IL-1�� and IL-8 in addition to routine microbiology testing, or to ���routine use of antibiotics��� in which BAL undergoes routine microbiology testing only. Clinical teams are blinded to intervention until 6 hours after randomisation, when biomarker results are reported to the clinician. The primary outcome is a change in the frequency distribution of antibiotic-free days (AFD) in the 7 days following BAL. Secondary outcome measures include antibiotic use at 14 and 28 days; ventilator-free days; 28-day mortality and ICU mortality; sequential organ failure assessment (SOFA) at days 3, 7 and 14; duration of stay in critical care and the hospital; antibiotic-associated infections; and antibiotic-resistant pathogen cultures up to hospital discharge, death or 56 days. A healthcare-resource-utilisation analysis will be calculated from the duration of critical care and hospital stay. In addition, safety data will be collected with respect to performing BAL. A sample size of 210 will be required to detect a clinically significant shift in the distribution of AFD towards more patients having fewer antibiotics and therefore more AFD. Discussion This trial will test whether a rapid biomarker-based exclusion of VAP results in rapid discontinuation of antibiotics and therefore improves antibiotic management in patients with suspected VAP.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

<p>BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.</p><p>METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC���+���ZA), standard of care plus docetaxel (SOC���+���Doc), or standard of care with both zoledronic acid and docetaxel (SOC���+���ZA���+���Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2��5% one-sided �� for hazard ratio (HR) 0��75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).</p><p>FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC���+���ZA (HR 0��94, 95% CI 0��79-1��11; p=0��450), 81 months (41 to not reached) for SOC���+���Doc (0��78, 0��66-0��93; p=0��006), and 76 months (39 to not reached) for SOC���+���ZA���+���Doc (0��82, 0��69-0��97; p=0��022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC���+���ZA, 288 (52%) receiving SOC���+���Doc, and 269 (52%) receiving SOC���+���ZA���+���Doc.</p><p>INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.</p><p>FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.</p>

Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient-reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

<p>BACKGROUND: Patient-reported outcomes (PROs) might detect more toxic effects of radiotherapy than do clinician-reported outcomes. We did a quality of life (QoL) substudy to assess PROs up to 24 months after conventionally fractionated or hypofractionated radiotherapy in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial.</p><p>METHODS: The CHHiP trial is a randomised, non-inferiority phase 3 trial done in 71 centres, of which 57 UK hospitals took part in the QoL substudy. Men with localised prostate cancer who were undergoing radiotherapy were eligible for trial entry if they had histologically confirmed T1b-T3aN0M0 prostate cancer, an estimated risk of seminal vesicle involvement less than 30%, prostate-specific antigen concentration less than 30 ng/mL, and a WHO performance status of 0 or 1. Participants were randomly assigned (1:1:1) to receive a standard fractionation schedule of 74 Gy in 37 fractions or one of two hypofractionated schedules: 60 Gy in 20 fractions or 57 Gy in 19 fractions. Randomisation was done with computer-generated permuted block sizes of six and nine, stratified by centre and National Comprehensive Cancer Network (NCCN) risk group. Treatment allocation was not masked. UCLA Prostate Cancer Index (UCLA-PCI), including Short Form (SF)-36 and Functional Assessment of Cancer Therapy-Prostate (FACT-P), or Expanded Prostate Cancer Index Composite (EPIC) and SF-12 quality-of-life questionnaires were completed at baseline, pre-radiotherapy, 10 weeks post-radiotherapy, and 6, 12, 18, and 24 months post-radiotherapy. The CHHiP trial completed accrual on June 16, 2011, and the QoL substudy was closed to further recruitment on Nov 1, 2009. Analysis was on an intention-to-treat basis. The primary endpoint of the QoL substudy was overall bowel bother and comparisons between fractionation groups were done at 24 months post-radiotherapy. The CHHiP trial is registered with ISRCTN registry, number ISRCTN97182923.</p><p>FINDINGS: 2100 participants in the CHHiP trial consented to be included in the QoL substudy: 696 assigned to the 74 Gy schedule, 698 assigned to the 60 Gy schedule, and 706 assigned to the 57 Gy schedule. Of these individuals, 1659 (79%) provided data pre-radiotherapy and 1444 (69%) provided data at 24 months after radiotherapy. Median follow-up was 50��0 months (IQR 38��4-64��2) on April 9, 2014, which was the most recent follow-up measurement of all data collected before the QoL data were analysed in September, 2014. Comparison of 74 Gy in 37 fractions, 60 Gy in 20 fractions, and 57 Gy in 19 fractions groups at 2 years showed no overall bowel bother in 269 (66%), 266 (65%), and 282 (65%) men; very small bother in 92 (22%), 91 (22%), and 93 (21%) men; small bother in 26 (6%), 28 (7%), and 38 (9%) men; moderate bother in 19 (5%), 23 (6%), and 21 (5%) men, and severe bother in four (&lt;1%), three (&lt;1%) and three (&lt;1%) men respectively (74 Gy vs 60 Gy, ptrend=0.64, 74 Gy vs 57 Gy, ptrend=0��59). We saw no differences between treatment groups in change of bowel bother score from baseline or pre-radiotherapy to 24 months.</p><p>INTERPRETATION: The incidence of patient-reported bowel symptoms was low and similar between patients in the 74 Gy control group and the hypofractionated groups up to 24 months after radiotherapy. If efficacy outcomes from CHHiP show non-inferiority for hypofractionated treatments, these findings will add to the growing evidence for moderately hypofractionated radiotherapy schedules becoming the standard treatment for localised prostate cancer.</p><p>FUNDING: Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.</p>

Failure-Free Survival and Radiotherapy in Patients With Newly Diagnosed Nonmetastatic Prostate Cancer: Data From Patients in the Control Arm of the STAMPEDE Trial

<p>Importance: The natural history of patients with newly diagnosed high-risk nonmetastatic (M0) prostate cancer receiving hormone therapy (HT) either alone or with standard-of-care radiotherapy (RT) is not well documented. Furthermore, no clinical trial has assessed the role of RT in patients with node-positive (N+) M0 disease. The STAMPEDE Trial includes such individuals, allowing an exploratory multivariate analysis of the impact of radical RT.</p><p>Objective: To describe survival and the impact on failure-free survival of RT by nodal involvement in these patients.</p><p>Design, Setting, and Participants: Cohort study using data collected for patients allocated to the control arm (standard-of-care only) of the STAMPEDE Trial between October 5, 2005, and May 1, 2014. Outcomes are presented as hazard ratios (HRs) with 95% CIs derived from adjusted Cox models; survival estimates are reported at 2 and 5 years. Participants were high-risk, hormone-naive patients with newly diagnosed M0 prostate cancer starting long-term HT for the first time. Radiotherapy is encouraged in this group, but mandated for patients with node-negative (N0) M0 disease only since November 2011.</p><p>Exposures: Long-term HT either alone or with RT, as per local standard. Planned RT use was recorded at entry.</p><p>Main Outcomes and Measures: Failure-free survival (FFS) and overall survival.</p><p>Results: A total of 721 men with newly diagnosed M0 disease were included: median age at entry, 66 (interquartile range [IQR], 61-72) years, median (IQR) prostate-specific antigen level of 43 (18-88) ng/mL. There were 40 deaths (31 owing to prostate cancer) with 17 months' median follow-up. Two-year survival was 96% (95% CI, 93%-97%) and 2-year FFS, 77% (95% CI, 73%-81%). Median (IQR) FFS was 63 (26 to not reached) months. Time to FFS was worse in patients with N+ disease (HR, 2.02 [95% CI, 1.46-2.81]) than in those with N0 disease. Failure-free survival outcomes favored planned use of RT for patients with both N0M0 (HR, 0.33 [95% CI, 0.18-0.61]) and N+M0 disease (HR, 0.48 [95% CI, 0.29-0.79]).</p><p>Conclusions and Relevance: Survival for men entering the cohort with high-risk M0 disease was higher than anticipated at study inception. These nonrandomized data were consistent with previous trials that support routine use of RT with HT in patients with N0M0 disease. Additionally, the data suggest that the benefits of RT extend to men with N+M0 disease.</p><p>Trial Registration: clinicaltrials.gov Identifier: NCT00268476; ISRCTN78818544.</p>

Prospects and Problems for Religious Education in England, 1967-1970: Curriculum Reform in Political Context

This article provides an historical case study of an abortive attempt to revise policy and legislation relating to Religious Education (RE) in English schools in the late 1960s and early 1970s. Drawing upon published sources, including parliamentary debates, as well as previously unutilised national archival sources from the Department of Education and Science, it comments upon events which have hitherto been omitted from the historiography of RE, but which help to contextualise significant changes in RE theory and practice at that time. Moreover, it demonstrates that the current parlous state of RE in schools is in part the result of latent and longstanding issues and problems, rather than a consequence of present-day government policy alone. Therefore, in reviewing and developing RE policies and practices, all stakeholders are urged to look more closely at both changes and continuities in the subject���s past and the contexts in which they occurred.

Conceptualizing and Researching the Professionalization of Religious Education Teachers: Historical and International Perspectives

Current discussions on Religious Education (RE), both in Germany and England, focus on the quality of teaching and the professionality of teachers, but neglect the historical and institutional process of professionalization upon which conceptions of teaching quality and teacher professionality hinge. This article seeks to provide definitional clarity by differentiating between individual and collective professionalization; exploring teacher professionalization in general and in the special case of RE; and operationalizing the concept of RE teacher professionalization for the purposes of planned historical and international comparative research. A three-fold conceptualization of professionalization is proposed, consisting of the following inter-related levels: (1) initial and continuing professional development; (2) professional self-organization and professional politics; and (3) professional knowledge. The breadth, complexity and significance of the historical and institutional processes associated with the professionalization of RE teachers at each of these levels is described and discussed. It is argued that further historical and international comparative research on these lines would contribute a broader and deeper understanding of the presuppositions of RE teacher professionality beyond current debates.