Eosinophil peroxidase activates cells by HER2 receptor engagement and ß1-integrin clustering with downstream MAPK cell signaling.

Eosinophils account for 1-3% of peripheral blood leukocytes and accumulate at sites of allergic inflammation, where they play a pathogenic role. Studies have shown that treatment with mepolizumab (an anti-IL-5 monoclonal antibody) is beneficial to patients with severe eosinophilic asthma, however, the mechanism of precisely how eosinophils mediate these pathogenic effects is uncertain. Eosinophils contain several cationic granule proteins, including Eosinophil Peroxidase (EPO). The main significance of this work is the discovery of EPO as a novel ligand for the HER2 receptor. Following HER2 activation, EPO induces activation of FAK and subsequent activation of ß1-integrin, via inside-out signaling. This complex results in downstream activation of ERK1/2 and a sustained up regulation of both MUC4 and the HER2 receptor. These data identify a receptor for one of the eosinophil granule proteins and demonstrate a potential explanation of the proliferative effects of eosinophils.

Obesity, diet and lifestyle in 9-year-old children with parentally reported chronic diseases: findings from the Growing Up in Ireland longitudinal child cohort study.

BACKGROUND: The incidence and prevalence of childhood chronic disease is increasing worldwide. Obesity, poor diet and lifestyle may be more prevalent in children with a chronic disease than in their healthier contemporaries. The Growing Up in Ireland (GUI) study is a nationally representative cohort study of children living in the Republic of Ireland. The study has collected information from 8568 9-year-old Irish children on their experiences within their families, childcare settings, schools and communities, and how these impact on all aspects of children's development. AIMS: This study aims to establish the prevalence of parentally reported chronic disease in children in Ireland and to describe their diet and lifestyle. METHODS: This study analyzed data from the Growing Up in Ireland longitudinal child cohort study and compared the diet, lifestyle and prevalence of obesity in children with and without a parentally reported chronic disease. RESULTS: Overall, 954 parents in the sample (11.1%) reported that their child had a chronic illness and 43.4% of these children are hampered by it in their daily activities. Respiratory disorders were the commonest type of chronic disease (46%) reported. Children with a chronic illness were more likely to be overweight or obese (32.9% compared to 25.0% of those without a chronic illness, p < 0.001). Children with chronic illness were also found to have a poorer diet, take less exercise and experienced significantly more social isolation than their peers (all p < 0.05). CONCLUSIONS: Public health measures to address diet and lifestyle choices need to be cognisant of the needs of children with chronic diseases and tailor activities offered to be inclusive of all children. Medical professionals having contact with children with chronic conditions need to remember to reinforce the importance of diet and lifestyle whenever possible and to explore with families solutions to barriers to making healthy diet and lifestyle choices.

A pilot study to monitor changes in spirometry and lung volume, following an exacerbation of Chronic Obstructive Pulmonary Disease (COPD), as part of a supported discharge program.

BACKGROUND: One-third of patients with an exacerbation of Chronic Obstructive Pulmonary Disease(COPD) are re-hospitalised at 90 days. Exacerbation recovery is associated with reductions in lung hyperinflation and improvements in symptoms and physical activity. We assessed the feasibility of monitoring these clinical parameters in the home. We hypothesised that the degree of change in spirometry and lung volumes differs between those who had an uneventful recovery and those who experienced a further exacerbation. METHODS: Hospitalised patients with an acute exacerbation of COPD referred for a supported discharge program participated in the study. Spirometry and Inspiratory Vital Capacity(IVC) were measured in the home at Days 1, 14 and 42 post-discharge. Patients also completed Medical Research Council(MRC), Borg and COPD Assessment Test(CAT) scores and were provided with a tri-axial accelerometer. Any new exacerbation events were recorded. RESULTS: Sixty-five patients with 72 exacerbation episodes were recruited. Fifty percent experienced a second exacerbation. Adequate IVC measurements were achieved by 90%, while only 70% completed spirometry. Uneventful recovery was accompanied by significant improvements in physiological measurements at day14, improved symptom scores and step count, p < 0.05. Failure of MRC to improve was predictive of re-exacerbation(Area Under Receiver Operating Curve(AUROC) 0.6713) with improvements in FEV1≥100 ml(AUROC 0.6613) and mean daily step count ≥396 steps(AUROC 0.6381) predictive of recovery. CONCLUSION: Monitoring the pattern of improvement in spirometry, lung volumes, symptoms and step count following a COPD exacerbation may help to identify patients at risk of re-exacerbation. It is feasible to carry out these assessments in the home as part of a supported discharge programme.

A phase Ia study to assess the safety and immunogenicity of new malaria vaccine candidates ChAd63 CS administered alone and with MVA CS.

BACKGROUND: Plasmodium falciparum (P. falciparum) malaria remains a significant cause of mortality and morbidity throughout the world. Development of an effective vaccine would be a key intervention to reduce the considerable social and economic impact of malaria. METHODOLOGY: We conducted a Phase Ia, non-randomized, clinical trial in 24 healthy, malaria-naïve adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines encoding the circumsporozoite protein (CS) of P. falciparum. RESULTS: ChAd63-MVA CS administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to CS. With a priming ChAd63 CS dose of 5×109 vp responses peaked at a mean of 1947 SFC/million PBMC (median 1524) measured by ELIspot 7 days after the MVA boost and showed a mixed CD4+/CD8+ phenotype. With a higher priming dose of ChAd63 CS dose 5×1010 vp T cell responses did not increase (mean 1659 SFC/million PBMC, median 1049). Serum IgG responses to CS were modest and peaked at day 14 post ChAd63 CS (median antibody concentration for all groups at day 14 of 1.3 µg/ml (range 0-11.9), but persisted throughout late follow-up (day 140 median antibody concentration groups 1B & 2B 0.9 µg/ml (range 0-4.7). CONCLUSIONS: ChAd63-MVA is a safe and highly immunogenic delivery platform for the CS antigen in humans which warrants efficacy testing. TRIAL REGISTRATION: ClinicalTrials.gov NCT01450280.