Dysregulated apoptosis and NFkappaB expression in COPD subjects.

Background
The abnormal regulation of neutrophil apoptosis may contribute to the ineffective resolution of inflammation in chronic lung diseases. Multiple signalling pathways are implicated in regulating granulocyte apoptosis, in particular, NF?B (nuclear factor-kappa B) signalling which delays constitutive neutrophil apoptosis. Although some studies have suggested a dysregulation in the apoptosis of airway cells in chronic obstructive pulmonary disease (COPD), no studies to date have directly investigated if NF?B is associated with apoptosis of airway neutrophils from COPD patients. The objectives of this study were to examine spontaneous neutrophil apoptosis in stable COPD subjects (n = 13), healthy smoking controls (n = 9) and non-smoking controls (n = 9) and to investigate whether the neutrophil apoptotic process in inflammatory conditions is associated with NF?B activation.

Methods
Analysis of apoptosis in induced sputum was carried out by 3 methods; light microscopy, Annexin V/Propidium iodide and the terminal transferase-mediated dUTP nick end-labeling (TUNEL) method. Activation of NF?B was assessed using a flow cytometric method and the phosphorylation state of I?Ba was carried out using the Bio-Rad Bio-Plex phosphoprotein I?Ba assay.

Results
Flow cytometric analysis showed a significant reduction in the percentage of sputum neutrophils undergoing spontaneous apoptosis in healthy smokers and subjects with COPD compared to non-smokers (p < 0.001). Similar findings were demonstrated using the Tunel assay and in the morphological identification of apoptotic neutrophils. A significant increase was observed in the expression of both the p50 (p = 0.006) and p65 (p = 0.006) subunits of NF?B in neutrophils from COPD subjects compared to non-smokers.

Conclusion
These results demonstrate that apoptosis is reduced in the sputum of COPD subjects and in healthy control smokers and may be regulated by an associated activation of NF?B.

Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques

Objectives: To investigate the pharmacokinetics (PK) of maraviroc, a CCR5-targeted HIV-1 entry inhibitor, in rhesus macaques following vaginal administration of various maraviroc-loaded aqueous hydroxyethylcellulose (HEC) gels, and to correlate the PK data with efficacy in a single high-dose vaginal SHIV-162P3 challenge model.

Methods: Maraviroc concentrations in vaginal fluid (Weck-Cel® sponge), vaginal tissue (punch biopsy) and plasma were assessed over 72 h following single dose vaginal application of various maraviroc-loaded HEC gels. The range of maraviroc gel concentrations was sufficiently broad (0.003 – 3.3% w/w) such that test gels included both fully solubilised and predominantly dispersed formulations. The efficacy of the HEC gels against a single high dose vaginal SHIV-162P3 challenge was also measured, and correlated with the PK concentrations.

Results: Maraviroc concentrations in vaginal fluid (range 104 – 107 ng/mL), vaginal tissue (100-1200 ng/g) and plasma (< 102 ng/mL) were highly dependent on maraviroc gel loading, irrespective of the form of the maraviroc component within the gel (solubilised vs. dispersed). Fluid and plasma concentrations were generally highest 0.5 or 2 h after gel application, before declining steadily out to 72 h. Maraviroc concentrations in the various biological compartments correlated strongly with the extent of protection against vaginal SHIV-162P3 challenge. Complete protection was achieved with a 3.3% w/w maraviroc gel.

Conclusions: A high degree of correlation between PK and efficacy was observed. Based on the data obtained with the 3.3% w/w maraviroc gel, maintenance of vaginal fluid and tissue levels in the order of 107 ng/mL and 103 ng/g, respectively, are required for complete protection with this compound.

Cycle Ergometer Tests in Children With Cystic Fibrosis:Reliability and Feasibility

The aim of this study was to assess the reliability and feasibility of cycle ergometer tests in young children with cystic fibrosis (CF). Children with CF aged 6-11 years and with stable lung disease performed two cycle ergometry tests (intermittent sprint and continuous incremental) on two occasions 1 week apart. Reliability was assessed using repeated-measures ANOVA. Bias was considered to be significant at P?

Quality of life and healthcare utilisation in cystic fibrosis:A multicentre UK study

The aim of our study was to discover the health status and healthcare utilisation associated with pulmonary exacerbations in cystic fibrosis (CF) and chronic Pseudomonas aeruginosa infection.

Patients with CF from five UK CF centres attended two visits, 8–12 weeks apart. They were classified at visit 1 as being in one of the three health states: no current pulmonary exacerbation; “mild” (no hospitalisation) pulmonary exacerbation; and “severe” (hospitalisation) pulmonary exacerbation. All patients completed the Cystic Fibrosis Questionnaire-Revised (CFQ-R) and EuroQol (EQ-5D) and a clinical form, and forced expiratory volume in 1 s (FEV1) was measured at visits 1 and 2. Annual healthcare utilisation data were collected.

94 patients of mean±sd age 28.5±8.2 yrs and FEV1 58.7±26.8% were recruited. 60 patients had no pulmonary exacerbation, 15 had a mild and 19 had a severe pulmonary exacerbation at visit 1. EQ-5D and CFQ-R data showed that the worse the exacerbation, the poorer the health-related quality of life (HRQoL). There were strong relationships between the CFQ-R and EQ-5D domain scores. The mean rate of pulmonary exacerbations per patient per year was 3.6 (1.5 in hospital and 2.2 at home). The mean length of stay per hospital pulmonary exacerbation was 9 days.

As exacerbation status worsens, patients experience worse HRQoL. There is a significant healthcare burden associated with treatment of pulmonary exacerbation and long-term prophylaxis.

Cystic fibrosis research in allied health and nursing professions

This report is the result of the "Allied Health and Nursing Professions Working Group" meeting which took place in Verona, Italy, November 2009, which was organised by the European Cystic Fibrosis Society, and involved 32 experts. The meeting was designed to provide a "roadmap" of high priority research questions that can be addressed by Allied Health Professionals (AHP) and nursing. The other goal was to identify research skills that would be beneficial to AHP and nursing researchers and would ultimately improve the research capacity and capability of these professions. The following tasks were accomplished: 1) a Delphi survey was used to identify high priority research areas and themes, 2) common research designs used in AHP and nursing research were evaluated in terms of their strengths and weaknesses, 3) methods for assessing the clinimetric and psychometric properties, as well as feasibility, of relevant outcome measures were reviewed, and 4) a common skill set for AHPs and nurses undertaking clinical research was agreed on and will guide the planning of future research opportunities. This report has identified important areas and themes for future research which include: adherence; physical activity/exercise; nutritional interventions; interventions for the newborn with CF and evaluation of outcome measures for use in AHP and nursing research. It has highlighted the significant challenges AHPs and nurses experience in conducting clinical research, and proposes strategies to overcome these challenges. It is hoped that this report will encourage research initiatives that assess the efficacy/effectiveness of AHP and nursing interventions in order to improve the evidence base. This should increase the quality of research conducted by these professions, justify services they currently provide, and expand their skills in new areas, with the ultimate goal of improving care for patients with CF.

The Computational Complexity of Dominance and Consistency in CP-Nets

We investigate the computational complexity of testing dominance and consistency in CP-nets. Previously, the complexity of dominance has been determined for restricted classes in which the dependency graph of the CP-net is acyclic. However, there are preferences of interest that define cyclic dependency graphs; these are modeled with general CP-nets. In our main results, we show here that both dominance and consistency for general CP-nets are PSPACE-complete. We then consider the concept of strong dominance, dominance equivalence and dominance incomparability, and several notions of optimality, and identify the complexity of the corresponding decision problems. The reductions used in the proofs are from STRIPS planning, and thus reinforce the earlier established connections between both areas.

The 1863 Melbourne Shakespeare War: Barry Sullivan, Charles and Ellen Kean, and the Play of Cultural Usurpation on the Australian Stage

This essay investigates an intricate drama of cultural identity in performances of Shakespeare on the nineteenth-century Melbourne stage. It considers the rivalry between Charles and Ellen Kean and their competitor, Barry Sullivan, for the two-month period in 1863 during which their Australian tours overlapped. This Melbourne Shakespeare war was anticipated,augmented, and richly documented in Melbourne’s papers: The Age, The Argus and Melbourne Punch. This essay pursues two seams of inquiry. The first is an investigation of the discourses of cultural and aesthetic value laced through the language of reviews of their Shakespearean roles.The essay identifies how reviewers register affective engagement with the performers in these roles, and suggests how the roles themselves reflected, by accident or design, the terms of the dispute. The second is concerned with the national identity of the actors. Kean, although born in Waterford, Ireland, had held the post of Queen Victoria’s Master of the Revels and identified himself as English. Sullivan, although born in Birmingham, was of Cork parentage and was identified as Irish by both his supporters and his detractors. This essay tracks the development of the actors’ national and artistic identities established prior to Melbourne and ask how they played out on in the context of the particularities of Australian reception. It shows that, in this instance, these actors were implicated in complex debates over national authority and cultural ownership.

Mucociliary clearance in cystic fibrosis: Physiology and pharmacological treatments

The understanding of how mutations of the cystic fibrosis gene results in recurrent infection and the development of bronchiectasis is now well established. This review examines aspects of lung pathophysiology specifically, abnormal mucociliary clearance, inflammation and infection which are the basis of the daily symptoms encountered by people with cystic fibrosis. Other components of the lung epithelium and their potential contribution to cystic fibrosis disease are discussed. Therapeutic interventions which aim to target abnormal mucociliary clearance are summarized. © 2011 Elsevier Ltd.

Lung Clearance Index Is a Repeatable and Sensitive Indicator of Radiological Changes in Bronchiectasis

RATIONALE: In bronchiectasis there is a need for improved markers of lung function to determine disease severity and response to therapy.

OBJECTIVES: To assess whether the lung clearance index is a repeatable and more sensitive indicator of computed tomography (CT) scan abnormalities than spirometry in bronchiectasis.

METHODS: Thirty patients with stable bronchiectasis were recruited and lung clearance index, spirometry, and health-related quality of life measures were assessed on two occasions, 2 weeks apart when stable (study 1). A separate group of 60 patients with stable bronchiectasis was studied on a single visit with the same measurements and a CT scan (study 2).

MEASUREMENTS AND MAIN RESULTS: In study 1, the intervisit intraclass correlation coefficient for the lung clearance index was 0.94 (95% confidence interval, 0.89 to 0.97; P < 0.001). In study 2, the mean age was 62 (10) years, FEV1 76.5% predicted (18.9), lung clearance index 9.1 (2.0), and total CT score 14.1 (10.2)%. The lung clearance index was abnormal in 53 of 60 patients (88%) and FEV1 was abnormal in 37 of 60 patients (62%). FEV1 negatively correlated with the lung clearance index (r = -0.51, P < 0.0001). Across CT scores, there was a relationship with the lung clearance index, with little evidence of an effect of FEV1. There were no significant associations between the lung clearance index or FEV1 and health-related quality of life.

CONCLUSIONS: The lung clearance index is repeatable and a more sensitive measure than FEV1 in the detection of abnormalities demonstrated on CT scan. The lung clearance index has the potential to be a useful clinical and research tool in patients with bronchiectasis.

Walking Exercise for Chronic Musculoskeletal Pain: Systematic Review and Meta-Analysis

Objective: To systematically review the evidence examining effects of walking interventions on pain and self-reported function in individuals with chronic musculoskeletal pain.
Data Sources: Six electronic databases (Medline, CINAHL, PsychINFO, PEDro, Sport Discus and the Cochrane Central Register of Controlled Trials) were searched from January 1980 up to March 2014.
Study Selection: Randomized and quasi-randomized controlled trials in adults with chronic low back pain, osteoarthritis or fibromyalgia comparing walking interventions to a non-exercise or non-walking exercise control group.
Data Extraction: Data were independently extracted using a standardized form. Methodological quality was assessed using the United States Preventative Services Task Force (USPSTF) system.
Data Synthesis: Twenty-six studies (2384 participants) were included and suitable data from 17 were pooled for meta-analysis with a random effects model used to calculate between group mean differences and 95% confidence intervals. Data were analyzed according to length of follow-up (short-term: ≤8 weeks post randomization; medium-term: >2 months - 12 months; long-term: > 12 months). Interventions were associated with small to moderate improvements in pain at short (mean difference (MD) -5.31, 95% confidence interval (95% CI) -8.06 to -2.56) and medium-term follow-up (MD -7.92, 95% CI -12.37 to -3.48). Improvements in function were observed at short (MD -6.47, 95% CI -12.00 to -0.95), medium (MD -9.31, 95% CI -14.00 to -4.61) and long-term follow-up (MD -5.22, 95% CI 7.21 to -3.23).
Conclusions: Evidence of fair methodological quality suggests that walking is associated with significant improvements in outcome compared to control interventions but longer-term effectiveness is uncertain. Using the USPSTF system, walking can be recommended as an effective form of exercise or activity for individuals with chronic musculoskeletal pain but should be supplemented with strategies aimed at maintaining participation. Further work is also required examining effects on important health related outcomes in this population in robustly designed studies.