Synergistic effects of proteasome inhibitor carfilzomib in combination with tyrosine kinase inhibitors in imatinib-sensitive and -resistant chronic myeloid leukemia models

The tyrosine kinase inhibitor (TKI) imatinib has transformed the treatment and outlook of chronic myeloid leukemia (CML); however, the development of drug resistance and the persistence of TKI-resistant stem cells remain obstacles to eradicating the disease. Inhibition of proteasome activity with bortezomib has been shown to effectively induce apoptosis in TKI-resistant cells. In this study, we show that exposure to the next generation proteasome inhibitor carfilzomib is associated with a decrease in ERK signaling and increased expression of Abelson interactor proteins 1 and 2 (ABI-1/2). We also investigate the effect of carfilzomib in models of imatinib-sensitive and -resistant CML and demonstrate a potent reduction in proliferation and induction of apoptosis in a variety of models of imatinib-resistant CML, including primitive CML stem cells. Carfilzomib acts synergistically with the TKIs imatinib and nilotinib, even in imatinib-resistant cell lines. In addition, we found that the presence of immunoproteasome subunits is associated with an increased sensitivity to carfilzomib. The present findings provide a rational basis to examine the potential of carfilzomib in combination with TKIs as a potential therapy for CML, particularly in imatinib-resistant disease.

The effect of multiple micronutrient supplementation on left ventricular ejection fraction in patients with chronic stable heart failure: a randomized, placebo-controlled trial:A randomized, placebo-controlled trial

Objectives: This study sought to investigate the effect of a multiple micronutrient supplement on left ventricular ejection fraction (LVEF) in patients with heart failure. Background: Observational studies suggest that patients with heart failure have reduced intake and lower concentrations of a number of micronutrients. However, there have been very few intervention studies investigating the effect of micronutrient supplementation in patients with heart failure. Methods: This was a randomized, double-blind, placebo-controlled, parallel-group study involving 74 patients with chronic stable heart failure that compared multiple micronutrient supplementation taken once daily versus placebo for 12 months. The primary endpoint was LVEF assessed by cardiovascular magnetic resonance imaging or 3-dimensional echocardiography. Secondary endpoints were Minnesota Living With Heart Failure Questionnaire score, 6-min walk test distance, blood concentrations of N-terminal prohormone of brain natriuretic peptide, C-reactive protein, tumor necrosis factor alpha, interleukin-6, interleukin-10, and urinary levels of 8-iso-prostaglandin F2 alpha. Results: Blood concentrations of a number of micronutrients increased significantly in the micronutrient supplement group, indicating excellent compliance with the intervention. There was no significant difference in mean LVEF at 12 months between treatment groups after adjusting for baseline (mean difference: 1.6%, 95% confidence interval: -2.6 to 5.8, p = 0.441). There was also no significant difference in any of the secondary endpoints at 12 months between treatment groups. Conclusions: This study provides no evidence to support the routine treatment of patients with chronic stable heart failure with a multiple micronutrient supplement. (Micronutrient Supplementation in Patients With Heart Failure [MINT-HF]; NCT01005303).

The effect of multiple chronic conditions on self-rated health, disability and quality of life among the older populations of Northern Ireland and the Republic of Ireland: a comparison of two nationally representative cross-sectional surveys

Objectives: Multimorbidity is common in the older population, but the impact of combinations of chronic conditions on disability and quality of life (QoL) is not well known. This analysis explores the effect of specific combinations of chronic diseases on disability, QoL and self-rated health (SRH).

Design: We used data from two population representative cross-sectional studies, the Northern Ireland Health and Social Wellbeing Survey (NIHSWS) 2005 and the Survey of Lifestyle, Attitudes and Nutrition (SLAN) 2007 (conducted in the Republic of Ireland).

Setting: Randomly selected community-living participants were interviewed at home.

Participants: A total of 6159 participants aged 50 years and older were included in the analysis.

Outcome measures: Chronic conditions were classified as cardiovascular disease, chronic pain,diabetes or respiratory disease. Interaction terms estimated by logistic regression were used to examine the effects of multiple chronic conditions on disability, SRH and QoL.

Results: Each chronic condition group was correlated with each of the others after adjusting for sociodemographic factors. Those from Northern Ireland were more likely to report a limitation in daily activities (45%) compared to those from the Republic of Ireland (21%). Each condition had an independent effect on disability, SRH and QoL, and those with multiple chronic conditions reported the worst outcomes. However, there were no statistically significant positive interactions between chronic condition groups with respect to any outcome.

Conclusions: Chronic conditions affect individuals largely independent of each other with respect to their effect on disability, SRH and QoL. However, a significant proportion of the population aged 50 years and over across the island of Ireland lives with multimorbidity,and this group is at the highest risk of disability, poor SRH and poor QoL.

A systematic review of interventions aimed at increasing physical activity in adults with chronic musculoskeletal pain-protocol

Background: Chronic musculoskeletal pain is highly prevalent, affecting around one in five people across Europe. Osteoarthritis, low back pain, neck pain and other musculoskeletal disorders are leading causes of disability
worldwide and the most common source of chronic pain. Exercise and/or physical activity interventions have the potential to address not only the pain and disability associated with chronic pain but also the increased risk of morbidity and mortality seen in this population. Although exercise and/or physical activity is widely recommended, there is currently a paucity of research that offers an evidence base upon which the development or optimisation of interventions can be based. This systematic review will investigate the components of interventions associated with changes in physical activity levels in adults with chronic musculoskeletal pain.

Methods/Design: This systematic review will be reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidance. Randomised and quasi-randomised controlled trials of interventions aimed at increasing physical activity in adults with chronic musculoskeletal pain will be included. Articles will be identified through a comprehensive search of the following databases: CENTRAL in the Cochrane Library, the Cochrane Database of Systematic Reviews (CDSR), MEDLINE, Embase, CINAHL, PsycINFO and AMED. Two review authors will independently screen articles retrieved from the search for eligibility, extract relevant data on methodological issues and code interventions according to the behaviour change technique taxonomy (v1) of 93 hierarchically clustered techniques. As complex healthcare interventions can be modified by a wide variety of factors, data will be summarised statistically when the data are available, are sufficiently similar and are of sufficient quality. A narrative synthesis will be completed if there is insufficient data to permit a formal meta-analysis.

Discussion: This review will be of value to clinicians working in chronic pain services and to researchers involved in designing and evaluating interventions.

A worldwide survey of chronic cough: A manifestation of enhanced somatosensory response:A manifestation of enhanced somatosensory response

Reports from individual centres suggest a preponderance of females with chronic cough. Females also have heightened cough reflex sensitivity. Here we have reviewed the age and sex of unselected referrals to 11 cough clinics. To investigate the cause of any observed sex dimorphism, functional magnetic resonance imaging of putative cough centres was analysed in normal volunteers. The demographic profile of consecutive patients presenting with chronic cough was evaluated. Cough challenge with capsaicin was undertaken in normal volunteers to construct a concentration-response curve. Subsequent functional magnetic resonance imaging during repeated inhalation of sub-tussive concentrations of capsaicin observed areas of activation within the brain and differences in the sexes identified. Of the 10 032 patients presenting with chronic cough, two-thirds (6591) were female (mean age 55 years). The patient profile was largely uniform across centres. The most common age for presentation was 60-69 years. The maximum tolerable dose of inhaled capsaicin was lower in females; however, a significantly greater activation of the somatosensory cortex was observed. Patients presenting with chronic cough from diverse racial and geographic backgrounds have a strikingly homogeneous demographic profile, suggesting a distinct clinical entity. The preponderance of females may be explained by sex-related differences in the central processing of cough sensation.