Adiponectin in health and disease

The incidence of diseases associated with the metabolic syndrome has rapidly increased in recent years. The most common of these diseases is Type 2 Diabetes. Research into ways of alleviating the pathogenicity of Diabetes is ongoing, and the increase in diagnosis in recent years has motivated scientists to investigate novel risk markers to help predict and prevent Type 2 Diabetes Mellitus and the diseases associated with it. Adiponectin has become an important molecule in this search. Despite being released from adipose tissue, adiponectin correlates inversely with body fat in humans and animals. It also exhibits important metabolic regulatory functions such as glucose regulation and fatty acid catabolism and has been suggested to have anti-inflammatory properties. This thesis reviews literature on the adiponectin molecule and aims to explore the complex functioning of this adipokine and its relationship to Cardiovascular Disease (CVD) and Diabetes. The methodological considerations chapters focus on pre-analytical and analytical variables that may affect the collection of blood and the measurement of the molecule. We observed the molecule to be very stable. The measurement of both the high molecular weight (HMW) and total adiponectin species were not affected by up to 7 freeze thaw cycles. Furthermore, blood processing times and temperatures did not significantly alter results. Although the R&D systems adiponectin kits do not advise the use of citrated plasma, we validated its use in these kits and although absolute concentrations were lower than with EDTA plasma, they were consistently lower throughout the measured sample set. Two other commercial kits (Mercodia and ALPCO diagnostics) were tested for performance against the R&D systems Enzyme-Linked Immunosorbent Assay (ELISA) kit. Although there were differences between absolute values in each kit, the overall performance of the kits were satisfactory as judged by Bland-Altman plots. In the first of the two clinical associations chapters, we report, from a prospective study of older British women, no evidence of any association of HMW adiponectin (or its ratio to total adiponectin) with incident vascular events and suggest that circulating concentrations of adiponectin (and its fractions) may be more strongly aligned to the risk for Diabetes than to vascular events. The final study investigates the relationship between B-type natriuretic peptide (BNP) and adiponectin in Acute Coronary Syndrome (ACS) patients. Adiponectin and BNP are both known to be positively associated with risk of poor outcome, and with each other, in cross-sectional studies. However, serial changes in these parameters, following ACS, have not previously been measured. In this study, adiponectin and BNP positively correlated at baseline, 7 weeks, and importantly, change over 7 weeks in both parameters was significantly correlated. We reported that increases in plasma adiponectin (rather than absolute levels) after ACS are related to risk of adverse outcome, but that this relationship is not independent of BNP levels. Our results allude to a potential direct or indirect effect of BNP on adiponectin levels, post-ACS; an observation that requires further investigation. In summary, this thesis has shown adiponectin to be a very stable and robust analyte in plasma or serum, with good reproducibility within persons and broadly between differing assays. Whilst there are clear data linking low adiponectin with incident diabetes, our clinical studies show adiponectin has more complex associations with vascular disease, perhaps mediated in part by a complex interaction with BNP. Further genetic studies are needed to elaborate causal association for this complex molecule

Methodological development of an exploratory randomised controlled trial of an early years' nutrition intervention: the CHERRY programme (choosing healthy eating when really young)

Good nutrition in the early years of life is vitally important for a child's development, growth and health. Children's diets in the United Kingdom are known to be poor, particularly among socially disadvantaged groups, and there is a need for timely and appropriate interventions that support parents to improve the diets of young children. The Medical Research Council has highlighted the importance of conducting developmental and exploratory research prior to undertaking full-scale trials to evaluate complex interventions, but have provided very limited detailed guidance on the conduct of these initial phases of research. This paper describes the initial developmental stage and the conduct of an exploratory randomised controlled trial undertaken to determine the feasibility and acceptability of a family-centred early years' nutrition intervention. Choosing Healthy Eating when Really Young (CHERRY) is a programme for families with children aged 18 months to 5 years, delivered in children's centres in one urban (Islington) and one rural (Cornwall) location in the United Kingdom. In the development stage, a mixed-methods approach was used to investigate the nature of the problem and options for support. A detailed review of the evidence informed the theoretical basis of the study and the creation of a logic model. In the feasibility and pilot testing stage of the exploratory trial, 16 children's centres, with a sample of 394 families were recruited onto the study. We hope that the methodology, which we present in this paper, will inform and assist other researchers in conducting community-based, exploratory nutrition research in early years settings

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42·4% vs 44·2%; absolute difference -1·69 [-9·58 to 6·11] p=0·67; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5-8] vs 6 [5-8] cm H2O; p=0·0011). ICU mortality was higher in MICs than in HICs (30·5% vs 19·9%; p=0·0004; adjusted effect 16·41% [95% CI 9·52-23·52]; p<0·0001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0·80 [95% CI 0·75-0·86]; p<0·0001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status