Noradrenaline acting at β-adrenoceptors induces expression of IL-1β and its negative regulators IL-1ra and IL-1RII, and drives an overall anti-inflammatory phenotype in rat cortex

Evidence indicates that noradrenaline elicits anti-inflammatory actions in the central nervous system (CNS), and plays a neuroprotective role where inflammatory events contribute to pathology. Here we examined the ability of pharmacological enhancement of central noradrenergic tone to impact upon activation of the IL-1 system in rat brain. Treatment with the noradrenaline reuptake inhibitor reboxetine combined with the α2-adrenoceptor antagonist idazoxan induced expression of IL-1β as well as its negative regulators, IL-1 receptor antagonist (IL-1ra) and IL-1 type II receptor (IL-1RII) in rat cortex. The ability of reboxetine/idazoxan treatment to activate the IL-1 system was mediated by β-adrenoceptors, as the aforementioned effects were blocked by the β-adrenoceptor antagonist propranolol. Moreover, administration of the brain penetrant β2-adrenoceptor agonist clenbuterol induced expression of IL-1β, IL-1ra and IL-1RII in rat brain. This action was selective to the IL-1 system, as other inflammatory cytokines including TNF-α, IL-6 or IFN-γ were not induced by clenbuterol. Induction of IL-1β was accompanied by activation of NFκB and of the MAP kinase ERK, and clenbuterol also induced expression of the IL-1β-inducible gene CINC-1. The ability of clenbuterol to activate the IL-1 system was blocked by propranolol, and was mimicked by the highly selective β2-adrenoceptor agonist formoterol. Despite the ability of clenbuterol to activate the central IL-1 system, it largely combated the neuroinflammatory response induced by systemic inflammatory stimulus (bacterial lipopolysaccharide; LPS). Specifically, whilst the ability of clenbuterol to induce expression of IL-1RII and IL-1Ra was maintained following the inflammatory challenge, its ability to induce IL-1β was reduced. In addition, clenbuterol suppressed LPS-induced expression of the inflammatory cytokines TNF-α and IL-6, the inflammatory chemokines RANTES and IP-10, the co-stimulatory molecules CD40 and ICAM-1. Thus overall, clenbuterol suppresses the innate inflammatory response in rat brain

Role of integrated knowledge translation in developing and implementing a multi-component infant feeding intervention: Insights from the CHErIsH study

This article provides an overview and insights from the process of using integrated knowledge translation in developing and implementing the Choosing Healthy Eating for Infant Health (CHErIsH) intervention. Integrated knowledge translation involves collaboration between researchers and research users in the research process, including shaping the research questions, interpreting the results and helping to disseminate the research results (Graham and Tetroe, 2009). The central premise of integrated knowledge translation is that involving knowledge users as equal partners alongside researchers will lead to research that is more relevant to, and more likely to be useful to, the knowledge users (Canadian Institutes of Health Research (CIHR), 2012).peer-reviewe

Role of integrated knowledge translation in developing and implementing a multi-component infant feeding intervention: Insights from the CHErIsH study

This article provides an overview and insights from the process of using integrated knowledge translation in developing and implementing the Choosing Healthy Eating for Infant Health (CHErIsH) intervention. Integrated knowledge translation involves collaboration between researchers and research users in the research process, including shaping the research questions, interpreting the results and helping to disseminate the research results (Graham and Tetroe, 2009). The central premise of integrated knowledge translation is that involving knowledge users as equal partners alongside researchers will lead to research that is more relevant to, and more likely to be useful to, the knowledge users (Canadian Institutes of Health Research (CIHR), 2012)

Exploring healthcare professionals’ views of the acceptability of delivering interventions to promote healthy infant feeding practices within primary care: a qualitative interview study

Objective: Early-life nutrition plays a key role in establishing healthy lifestyles and preventing chronic disease. This study aimed to (1) explore healthcare professionals’ (HCP) opinions on the acceptability of and factors influencing the delivery of interventions to promote healthy infant feeding behaviours within primary care and (2) identify proposed barriers/enablers to delivering such interventions during vaccination visits, to inform the development of a childhood obesity prevention interventio

A collaborative approach to developing sustainable behaviour change interventions for childhood obesity prevention: Development of the Choosing Healthy Eating for Infant Health (CHErIsH) intervention and implementation strategy

Objectives and Design There is growing recognition of the need for effective behaviour change interventions to prevent chronic diseases that are feasible and sustainable and can be implemented within routine health care systems. Focusing on implementation from the outset of intervention development, and incorporating multiple stakeholder perspectives to achieve this, is therefore essential. This study explores the development of the Choosing Healthy Eating for Infant Health (CHErIsH) childhood obesity prevention intervention and implementation strategy to improve infant feeding behaviours. Methods Five qualitative and quantitative evidence syntheses, two primary qualitative studies, and formal/informal consultations were conducted with practice, policy, research, and parent stakeholders. The Behaviour Change Wheel was used to guide the integration of findings. Results The CHErIsH intervention targets parent‐level behaviour change and comprises (1) brief verbal messages and (2) trustworthy resources, to be delivered by health care professionals (HCPs) during routine infant vaccination visits. The implementation strategy targets HCP‐level behaviour change and comprises (1) a local opinion leader, (2) incentivized training, (3) HCP resources and educational materials, (4) electronic delivery prompts, (5) awareness‐raising across all primary care HCPs, and (6) local technical support. Conclusions This study provides a rigorous example of the development of an evidence‐based intervention aimed at improving parental infant feeding behaviours, alongside an evidence‐based behaviour change strategy to facilitate implementation and sustainability in primary care. This approach demonstrates how to systematically incorporate multiple stakeholder perspectives with existing literature and move from multiple evidence sources to clearly specified intervention components for both the intervention and implementation strategy

Choosing healthy eating for infant health (CHErIsH) study: protocol for a feasibility study

Introduction Childhood obesity is a public health challenge. There is evidence for associations between parents’ feeding behaviours and childhood obesity risk. Primary care provides a unique opportunity for delivery of infant feeding interventions for childhood obesity prevention. Implementation strategies are needed to support infant feeding intervention delivery. The Choosing Healthy Eating for Infant Health (CHErIsH) intervention is a complex infant feeding intervention delivered at infant vaccination visits, alongside a healthcare professional (HCP)-level implementation strategy to support delivery. Methods and analysis This protocol provides a description of a non-randomised feasibility study of an infant feeding intervention and implementation strategy, with an embedded process evaluation and economic evaluation. Intervention participants will be parents of infants aged ≤6 weeks at recruitment, attending a participating HCP in a primary care practice. The intervention will be delivered at the infant’s 2, 4, 6, 12 and 13month vaccination visits and involves brief verbal infant feeding messages and additional resources, including a leaflet, magnet, infant bib and sign-posting to an information website. The implementation strategy encompasses a local opinion leader, HCP training delivered prior to intervention delivery, electronic delivery prompts and additional resources, including a training manual, poster and support from the research team. An embedded mixed-methods process evaluation will examine the acceptability and feasibility of the intervention, the implementation strategy and study processes including data collection. Qualitative interviews will explore parent and HCP experiences and perspectives of delivery and receipt of the intervention and implementation strategy. Self-report surveys will examine fidelity of delivery and receipt, and acceptability, suitability and comprehensiveness of the intervention, implementation strategy and study processes. Data from electronic delivery prompts will also be collected to examine implementation of the intervention. A cost–outcome description will be conducted to measure costs of the intervention and the implementation strategy. Ethics and dissemination This study received approval from the Clinical Research Ethics Committee of the Cork Teaching Hospitals. Study findings will be disseminated via peer-reviewed publications and conference presentations

Prediction of Prostate Cancer Biochemical and Clinical Recurrence Is Improved by IHC-Assisted Grading Using Appl1, Sortilin and Syndecan-1

Gleason scoring is used within a five-tier risk stratification system to guide therapeutic decisions for patients with prostate cancer. This study aimed to compare the predictive performance of routine H&E or biomarker-assisted ISUP (International Society of Urological Pathology) grade grouping for assessing the risk of biochemical recurrence (BCR) and clinical recurrence (CR) in patients with prostate cancer. This retrospective study was an assessment of 114 men with prostate cancer who provided radical prostatectomy samples to the Australian Prostate Cancer Bioresource between 2006 and 2014. The prediction of CR was the primary outcome (median time to CR 79.8 months), and BCR was assessed as a secondary outcome (median time to BCR 41.7 months). The associations of (1) H&E ISUP grade groups and (2) modified ISUP grade groups informed by the Appl1, Sortilin and Syndecan-1 immunohistochemistry (IHC) labelling were modelled with BCR and CR using Cox proportional hazard approaches. IHC-assisted grading was more predictive than H&E for BCR (C-statistic 0.63 vs. 0.59) and CR (C-statistic 0.71 vs. 0.66). On adjusted analysis, IHC-assisted ISUP grading was independently associated with both outcome measures. IHC-assisted ISUP grading using the biomarker panel was an independent predictor of individual BCR and CR. Prospective studies are needed to further validate this biomarker technology and to define BCR and CR associations in real-world cohorts

Clenbuterol activates the central IL-1 system via the β2-adrenoceptor without provoking inflammatory response related behaviours in rats

The long-acting, highly lipophilic, β2-adrenoceptor agonist clenbuterol may represent a suitable therapeutic agent for the treatment of neuroinflammation as it drives an anti-inflammatory response within the CNS. However, clenbuterol is also known to increase the expression of IL-1β in the brain, a potent neuromodulator that plays a role in provoking sickness related symptoms including anxiety and depression-related behaviours. Here we demonstrate that, compared to the immunological stimulus lipopolysaccharide (LPS, 250 μg/kg), clenbuterol (0.5 mg/kg) selectively up-regulates expression of the central IL-1 system resulting in a mild stress-like response which is accompanied by a reduction in locomotor activity and food consumption in rats. We provide further evidence that clenbuterol-induced activation of the central IL-1 system occurs in a controlled and selective manner in tandem with its negative regulators IL-1ra and IL-1RII. Furthermore, we demonstrate that peripheral β2-adrenoceptors mediate the suppression of locomotor activity and food consumption induced by clenbuterol and that these effects are not linked to the central induction of IL-1β. Moreover, despite increasing central IL-1β expression, chronic administration of clenbuterol (0.03 mg/kg; twice daily for 21 days) fails to induce anxiety or depressive-like behaviour in rats in contrast to reports of the ability of exogenously administered IL-1 to induce these symptoms in rodents. Overall, our findings suggest that clenbuterol or other selective β2-adrenoceptor agonists could have the potential to combat neuroinflammatory or neurodegenerative disorders without inducing unwanted symptoms of depression and anxiety