Post-Translational Inhibition of IP-10 Secretion in IEC by Probiotic Bacteria: Impact on Chronic Inflammation

Background: Clinical and experimental studies suggest that the probiotic mixture VSL#3 has protective activities in the context of inflammatory bowel disease (IBD). The aim of the study was to reveal bacterial strain-specific molecular mechanisms underlying the anti-inflammatory potential of VSL#3 in intestinal epithelial cells (IEC).

Methodology/Principal Findings: VSL#3 inhibited TNF-induced secretion of the T-cell chemokine interferon-inducible protein (IP-10) in Mode-K cells. Lactobacillus casei (L. casei) cell surface proteins were identified as active anti-inflammatory components of VSL#3. Interestingly, L. casei failed to block TNF-induced IP-10 promoter activity or IP-10 gene transcription at the mRNA expression level but completely inhibited IP-10 protein secretion as well as IP-10-mediated T-cell transmigration. Kinetic studies, pulse-chase experiments and the use of a pharmacological inhibitor for the export machinery (brefeldin A) showed that L. casei did not impair initial IP-10 production but decreased intracellular IP-10 protein stability as a result of blocked IP-10 secretion. Although L. casei induced IP-10 ubiquitination, the inhibition of proteasomal or lysosomal degradation did not prevent the loss of intracellular IP-10. Most important for the mechanistic understanding, the inhibition of vesicular trafficking by 3-methyladenine (3-MA) inhibited IP-10 but not IL-6 expression, mimicking the inhibitory effects of L. casei. These findings suggest that L. casei impairs vesicular pathways important for the secretion of IP-10, followed by subsequent degradation of the proinflammatory chemokine. Feeding studies in TNF Delta ARE and IL-10(-/-) mice revealed a compartimentalized protection of VSL#3 on the development of cecal but not on ileal or colonic inflammation. Consistent with reduced tissue pathology in IL-10(-/-) mice, IP-10 protein expression was reduced in primary epithelial cells.

Conclusions/Significance: We demonstrate segment specific effects of probiotic intervention that correlate with reduced IP-10 protein expression in the native epithelium. Furthermore, we revealed post-translational degradation of IP-10 protein in IEC to be the molecular mechanism underlying the anti-inflammatory effect.

Interventions to improve the appropriate use of polypharmacy for older people

Background
Inappropriate polypharmacy is a particular concern in older people and is associated with negative health outcomes. Choosing the best interventions to improve appropriate polypharmacy is a priority, hence interest in appropriate polypharmacy, where many medicines may be used to achieve better clinical outcomes for patients, is growing.

Objectives
This review sought to determine which interventions, alone or in combination, are effective in improving the appropriate use of polypharmacy and reducing medication-related problems in older people.

Search methods
In November 2013, for this first update, a range of literature databases including MEDLINE and EMBASE were searched, and handsearching of reference lists was performed. Search terms included 'polypharmacy', 'medication appropriateness' and 'inappropriate prescribing'.

Selection criteria
A range of study designs were eligible. Eligible studies described interventions affecting prescribing aimed at improving appropriate polypharmacy in people 65 years of age and older in which a validated measure of appropriateness was used (e.g. Beers criteria, Medication Appropriateness Index (MAI)).

Data collection and analysis
Two review authors independently reviewed abstracts of eligible studies, extracted data and assessed risk of bias of included studies. Study-specific estimates were pooled, and a random-effects model was used to yield summary estimates of effect and 95% confidence intervals (CIs). The GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach was used to assess the overall quality of evidence for each pooled outcome.

Main results
Two studies were added to this review to bring the total number of included studies to 12. One intervention consisted of computerised decision support; 11 complex, multi-faceted pharmaceutical approaches to interventions were provided in a variety of settings. Interventions were delivered by healthcare professionals, such as prescribers and pharmacists. Appropriateness of prescribing was measured using validated tools, including the MAI score post intervention (eight studies), Beers criteria (four studies), STOPP criteria (two studies) and START criteria (one study). Interventions included in this review resulted in a reduction in inappropriate medication usage. Based on the GRADE approach, the overall quality of evidence for all pooled outcomes ranged from very low to low. A greater reduction in MAI scores between baseline and follow-up was seen in the intervention group when compared with the control group (four studies; mean difference -6.78, 95% CI -12.34 to -1.22). Postintervention pooled data showed a lower summated MAI score (five studies; mean difference -3.88, 95% CI -5.40 to -2.35) and fewer Beers drugs per participant (two studies; mean difference -0.1, 95% CI -0.28 to 0.09) in the intervention group compared with the control group. Evidence of the effects of interventions on hospital admissions (five studies) and of medication-related problems (six studies) was conflicting.

Authors' conclusions
It is unclear whether interventions to improve appropriate polypharmacy, such as pharmaceutical care, resulted in clinically significant improvement; however, they appear beneficial in terms of reducing inappropriate prescribing.

How well do midwives use skills and knowledge in examining newborns?

Physical examination of the newborn (PEN) was established as part of postnatal care in the late 1960s. The role of discharging babies within the first 72 hours of birth was traditionally undertaken by junior doctors. Currently midwives, nurses, advanced nurse practitioners, and health visitors are being trained to undertake the PEN (NHS Screening Programmes, 2010). However, only a fraction of midwives utilize their acquired skills in clinical practice. A survey by Townsend et al (2004) showed that 2% of babies in England were examined by midwives while 83% were examined by junior doctors.This study aimed to evaluate how well midwives who undertook the PEN course between 2002 and 2005 (n = 40) at a large London University utilized the skills acquired on the course. Questionnaires with a series of open and closed questions were sent out by post followed by phone and email reminders. The eight that responded were midwives. All respondents said they were appropriately trained and felt well prepared for their role to examine babies. However, they felt they were not provided with opportunities to use the skills. Guidelines based on this extended role are available in the workplace but only a few midwives seemed to have negotiated time to implement these and may need greater managerial support for the role.

From Frank Miller to Zack Snyder, and Return: Contemporary Superhero Comics and Post-Classical Hollywood

Film adaptations of superhero comic-books offer a particularly rich case study to analyse narrative strategies of contemporary Hollywood cinema. The serial structures adopted by the comics they are based on, as well as their use of the spectacular potential of the image, provide a successful model for current audiovisual productions. Without completely abandoning classical techniques, these adaptations try to find a new balance between narrative and digital phantasmagoria. This paper discusses some significant examples of this genre, including adaptations of classical DC and Marvel franchises and more recent series, as well as other comic-book influenced films such as The Matrix and Unbreakable.

Counter-Revolution by Ideology? Law and development's vision(s) for post-revolutionary Egypt

Law and development, as both movement and practice, has led a tumultuous life: a hurried zenith cut short by a fatal critique followed by an opportunistic resurrection. The name alone is su?cient to trigger a range of reactions, extending from the complimentary to the condemnatory. In this article I track law and development’s evolution via an examination of its role in the remodelling of Egyptian society in the post-Nasser era. While the 2011 revolution has encouraged institutions such as USAID to hasten their legal reform e?orts, I argue that these are more akin to counter-revolution by ideology than genuine revolution by law. Nevertheless, rather than relegate the movement to the annals of imperial intrigue, I conclude by proposing the use of legal pluralism to revive, and possibly ignite, law and development’s emancipatory potential.

A leadership framework to support the use of e-learning resources

Aim
This inquiry aims to apply the NHS leadership framework to nurse education for the implementation of e-learning.
Background
Recognition needs to be given to the emerging postgraduate nursing students new status of consumer and the challenge now for nurse education is how to remain relevant and competitive in this consumer led market. The move towards an e-learning paradigm has been suggested as a competitive and contemporary way forward for the student consumer. The successful introduction of e-learning in nurse education will require leadership and a strong organisational management system.
Discussion
Each element of the NHS leadership framework is described and interpreted for application in a higher education setting for the implementation of e-learning.
Conclusions
Change in the delivery of post graduate nurse education is necessary to ensure it remains current and reflective of consumer need in a competitive marketplace. By applying a leadership framework that acknowledges the skills and abilities of staff and encourages the formation of collaborative partnerships from within the wider university community, educators can begin to develop skills and confidence in teaching using e-learning resources.

Non-apologies and prolonged silences in post-conflict settings: The case of post-colonial Cyprus

Despite the growing use of apologies in post-conflict settings, cases of non-apology remain unaddressed and continue to puzzle scholars. This article focuses on the absence of apology by non-state and anti-state actors by examining the case of the Cypriot armed group EOKA, which has refused to offer an apology to the civilian victims of its ‘anti-colonial’ struggle (1955–1959). Using field data and parliamentary debates, and drawing on comparisons, this article analyses the factors that contributed to a lack of apology. It is argued that the inherited timelessness of Greek nationalism, and the impression of a perpetual need for defence, set up textbook conditions for the development of a hegemonic discourse and prevented an apology for human rights violations.

Post mastectomy radiotherapy in breast cancer: a survey of current United Kingdom practice

Purpose: Radiotherapy (RT) is increasingly used following mastectomy for breast cancer While indications for post-mastectomy radiotherapy (PMRT) are clear in patient groups at high risk of local recurrence, guidelines are less clear in intermediate-risk patients and patients with ductal carcinoma in situ (DCIS). This study aimed to determine variations in the use of PMRT in the United Kingdom (UK).

Methods: A postal survey of all consultant breast surgeon members of the Association of Breast Surgery in the UK.

Results: Tumour size and nodal status were confirmed as the most important indications for PMRT There was significant variation in the influence of other factors such as tumour grade, lymphovascular invasion and margin status. Nineteen per cent of respondents stated that they would consider the use of PMRT in cases of DCIS alone.

Conclusions: There is significant variation in practice across the UK with regard to the use of PMRT in intermediate risk breast cancer and patients with DCIS. Further work is required to determine which patients in these groups are likely to benefit from the use of PMRT.

Post-diagnostic prescriptions for low-dose aspirin and breast cancer-specific survival: a nested case-control study in a breast cancer cohort from the UK Clinical Practice Research Datalink

INTRODUCTION: Recent observational studies indicate that post-diagnostic use of aspirin in breast cancer patients may protect against cancer progression perhaps by inhibiting cyclooxygenase-2 dependent mechanisms. Evidence also supports a crucial role for interactions between tumour cells and circulating platelets in cancer growth and dissemination, therefore, use of low-dose aspirin may reduce the risk of death from cancer in breast cancer patients.

METHODS: A cohort of newly diagnosed breast cancer patients (1998 to 2006) were identified in the UK Clinical Practice Research Datalink (and confirmed by cancer registry linkage). Cancer-specific deaths were identified up to 2011 from Office for National Statistics mortality data. A nested case-control analysis was conducted using conditional logistic regression to compare post-diagnostic aspirin exposure using General Practice prescription data in 1,435 cases (breast cancer deaths) with 5,697 controls (matched by age and year of diagnosis).

RESULTS: After breast cancer diagnosis, 18.3% of cancer-specific deaths and 18.5% of matched controls received at least one prescription for low-dose aspirin, corresponding to an odds ratio (OR) of 0.98 (95% CI 0.83, 1.15). Adjustment for potential confounders (including stage and grade) had little impact on this estimate. No dose response relationship was observed when the number of tablets was investigated and no associations were seen when analyses were stratified by receipt of prescriptions for aspirin in the pre-diagnostic period, by stage at diagnosis or by receipt of prescriptions for hormone therapy.

CONCLUSIONS: Overall, in this large population-based cohort of breast cancer patients, there was little evidence of an association between receipt of post-diagnostic prescriptions for low-dose aspirin and breast cancer-specific death. However, information was not available on medication compliance or over-the-counter use of aspirin, which may have contributed to the null findings.

A systematic review of midwife led interventions to address post traumatic stress syndrome

Objective
to systematically identify interventions that midwives could introduce to address post-traumatic stress in women following childbirth.

Methods
a search strategy was developed and relevant papers were identified from databases including Cinahl, Cochrane Library, EMBASE, Maternity and Infant Care, MEDLINE, PsycINFO, and Web of Science. Key search terms used were post-traumatic stress, post partum, intervention, controlled trial and review. Papers eligible for inclusion were primary studies and reviews of research published from 2002–2012, focusing on interventions which could be implemented by midwives for the prevention and/or management of PTSD. For primary studies, RCTs, controlled clinical trials, and cohort studies with a control group were eligible. Eligible reviews were those with a specified search strategy and inclusion/exclusion criteria. Methodological quality was assessed using recognised frameworks.

Findings
six primary studies and eight reviews were eligible for inclusion. The majority of included studies or reviews focused on debriefing and/or counselling interventions; however the results were not consistent due to significant variation in methodological quality and use of dissimilar interventions. Two of the reviews considered the general management of post partum PTSD and one broadly covered anxiety during pregnancy and the post partum, incorporating a section on PTSD. The majority of women reported that the opportunity to discuss their childbirth experience was subjectively beneficial.

Conclusions and implications for practice
no evidence-based midwifery interventions were identified from this systematic review that can be recommended for introduction into practice to address PTSD. It is recommended that future research in this area should incorporate standardised interventions with similar outcome measures to facilitate synthesis of results. Further research on interventions used in non-maternity populations is needed in order to confirm their usefulness in addressing post partum PTSD.

Impact of electric vehicles on a carbon constrained power system—a post 2020 case study

Electric vehicles (EVs) offer great potential to move from fossil fuel dependency in transport once some of the technical barriers related to battery reliability and grid integration are resolved. The European Union has set a target to achieve a 10% reduction in greenhouse gas emissions by 2020 relative to 2005 levels. This target is binding in all the European Union member states. If electric vehicle issues are overcome then the challenge is to use as much renewable energy as possible to achieve this target. In this paper, the impacts of electric vehicle charged in the all-Ireland single wholesale electricity market after the 2020 deadline passes is investigated using a power system dispatch model. For the purpose of this work it is assumed that a 10% electric vehicle target in the Republic of Ireland is not achieved, but instead 8% is reached by 2025 considering the slow market uptake of electric vehicles. Our experimental study shows that the increasing penetration of EVs could contribute to approach the target of the EU and Ireland government on emissions reduction, regardless of different charging scenarios. Furthermore, among various charging scenarios, the off-peak charging is the best approach, contributing 2.07% to the target of 10% reduction of Greenhouse gas emissions by 2025.

Digoxin use after diagnosis of breast cancer and survival: a population-based cohort study

Digoxin has been shown to have an estrogenic effect and is associated with increased risk of gynecomastia and estrogen-sensitive cancers such as breast and uterus cancer. These findings, particularly recent observations of increased breast cancer risk, raise questions about the safety of digoxin use in breast cancer patients. Therefore, we investigated whether digoxin use after breast cancer diagnosis increased the risk of breast cancer-specific mortality in breast cancer patients. A cohort of 17,842 breast cancer patients newly diagnosed from 1998 to 2009 was identified from English cancer registries (from the National Cancer Data Repository). This cohort was linked to the UK Clinical Practice Research Datalink (to provide digoxin and other prescription records) and to the Office of National Statistics mortality data (to identify breast cancer-specific deaths). Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95 % confidence intervals (CIs) were calculated for the association between post-diagnostic exposure to digoxin and breast cancer-specific and all-cause mortality. In 17,842 breast cancer patients, there were 2219 breast cancer-specific deaths. Digoxin users appeared to have increased breast cancer-specific mortality compared with non-users (HR 1.73; 95 % CI 1.39–2.15) but this association was entirely attenuated after adjustment for potential confounders (adjusted HR 0.91; 95 % CI 0.72–1.14). In this large population-based breast cancer cohort study, there was little evidence of an increase in breast cancer-specific mortality with digoxin use after diagnosis. These results provide some reassurance that digoxin use is safe in breast cancer patients.

Effects of peer network interactions on adolescent cannabis use

Purpose
This study capitalises on three waves of longitudinal data from a cohort of 4351 secondary school pupils to examine the effects on individuals’ cannabis use uptake of both peer cannabis use and position within a peer network.

Design/methodology/approach
Both cross-sectional and individual fixed effects models are used to estimate the effect on cannabis use of nominated friends’ cannabis use, of reciprocity and transitivity of nominations across the friendship cluster, and of interactions between these nominated friends. Post hoc analyses parsed the behaviour of reciprocating and non-reciprocating friends.

Findings
Cannabis use varied depending on the stability of friendship network and the degree of reciprocity and interconnectedness within the group. Behavioural influence was strong, but interaction effects were observed between the prevalence of cannabis use among friends, the structure of the friendship group and ego’s proximity to group members. These interactions demonstrate that behavioural influence is more salient in more cohesive groups. When reciprocating and non-reciprocating friends’ mean cannabis use were separated, influence from reciprocating friends was estimated at twice the magnitude of other friends.

Originality/value
While preventing any one individual from using cannabis is likely to have a multiplier effect on classmates, the bonds and interactions between classmates will determine which classmates are affected by this multiplier and the salience of that effect.

Impact of average household income and damage exposure on post-earthquake distress and functioning: A community study following the February 2011 Christchurch earthquake.

Post-traumatic stress, depression and anxiety symptoms are common outcomes following earthquakes, and may persist for months and years. This study systematically examined the impact of neighbourhood damage exposure and average household income on psychological distress and functioning in 600 residents of Christchurch, New Zealand, 4–6 months after the fatal February, 2011 earthquake. Participants were from highly affected and relatively unaffected suburbs in low, medium and high average household income areas. The assessment battery included the Acute Stress Disorder Scale, the depression module of the Patient Health Questionnaire (PHQ-9), and the Generalized Anxiety Disorder Scale (GAD-7), along with single item measures of substance use, earthquake damage and impact, and disruptions in daily life and relationship functioning. Controlling for age, gender and social isolation, participants from low income areas were more likely to meet diagnostic cut-offs for depression and anxiety, and have more severe anxiety symptoms. Higher probabilities of acute stress, depression and anxiety diagnoses were evident in affected versus unaffected areas, and those in affected areas had more severe acute stress, depression and anxiety symptoms. An interaction between income and earthquake effect was found for depression, with those from the low and medium income affected suburbs more depressed. Those from low income areas were more likely, post-earthquake, to start psychiatric medication and increase smoking. There was a uniform increase in alcohol use across participants. Those from the low income affected suburb had greater general and relationship disruption post-quake. Average household income and damage exposure made unique contributions to earthquake-related distress and dysfunction.

Modulating mythology in a post-traumatic era: Murals and re-imaging in Northern Ireland.

Arguably the most ancient of the social media, wall paintings have been a persistent vehicle of cultural meaning management. The dynamics of myth markets are reflected in the sectarian murals of Northern Ireland. In this paper, we draw from consumer research literature on mythology and street art to explore the continuous revision of these wallscapes that seeks to address the enduring contradictions of civic ideology in contested political space. In particular, we focus on the use of classical, historical and pop-cultural mythologies to transform private space into public place. We examine the decommissioning of murals occurring in the wake of the Peace Accords, and speculate on the implications of the creation of a shared mythology for the future of mural painting and the state.