Effect of increased fruit and vegetable consumption on bone turnover in older adults:a randomised controlled trial

Evidence suggests that increased fruit and vegetable (FV) intake may be associated with improved bone health, but there is limited evidence from intervention trials to support this. This 16-week study showed that increased FV consumption (five or more portions per day) does not have any effect on the markers of bone health in older adults. INTRODUCTION: Observational evidence suggests that increased FV consumption may be associated with improved bone health. However, there is lack of evidence from intervention trials to support this. This study examined the effect of increased FV consumption on bone markers among healthy, free-living older adults. METHODS: A randomised controlled trial was undertaken. Eighty-three participants aged 65-85 years, habitually consuming less than or equal to two portions of FV per day, were randomised to continue their normal diet or to consume five or more portions of FV per day for 16 weeks. FV were delivered to all participants each week, free of charge. Compliance was assessed at baseline and at 6, 12 and 16 weeks by diet histories and biomarkers of micronutrient status. Fasting serum bone markers (osteocalcin (OC) and C-terminal telopeptide of type 1 collagen (CTX)) were measured using enzyme-linked immunosorbent assay. RESULTS: Eighty-two participants completed the intervention. The five portions per day group showed a significantly greater change in daily FV consumption compared to the two portions per day group (p?

Apolipoprotein-defined and NMR lipoprotein subclasses in the veterans affairs diabetes trial

The VADT was a randomized clinical trial designed to assess the effect of intensive vs. standard glucose management on cardiovascular events in Type 2 diabetes. At the end of the study, intensive management failed to improve outcomes. We performed plasma lipoprotein subclass analyses to yield new information on the effects of study randomization on cardiovascular risk.

Serum Inflammatory Markers and Preeclampsia in Type 1 Diabetes:A prospective study

OBJECTIVE Inflammation and endothelial dysfunction have been associated with the immunobiology of preeclampsia (PE), a significant cause of adverse pregnancy outcomes. The prevalence of PE is elevated several fold in the presence of maternal type 1 diabetes mellitus (T1DM). Although cross-sectional studies of pregnancies among women without diabetes have shown altered inflammatory markers in the presence of PE, longitudinal studies of diabetic women are lacking. In maternal serum samples, we examined the temporal associations of markers of inflammation with the subsequent development of PE in women with T1DM. RESEARCH DESIGN AND METHODS We conducted longitudinal analyses of serum C-reactive protein (CRP), adhesion molecules, and cytokines during the first (mean ± SD, 12.2 ± 1.9 weeks), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy (visits 1-3, respectively). All study visits took place before the onset of PE. Covariates were BMI, HbA1c, age of onset, duration of diabetes, and mean arterial pressure. RESULTS In women with T1DM who developed PE versus those who remained normotensive, CRP tended to be higher at visits 1 (P = 0.07) and 2 (P = 0.06) and was significantly higher at visit 3 (P <0.05); soluble E-selectin and interferon-?-inducible protein-10 (IP-10) were significantly higher at visit 3; interleukin-1 receptor antagonist (IL-1ra) and eotaxin were higher and lower, respectively, at visit 2 (all P <0.05). These conclusions persisted following adjustment for covariates. CONCLUSIONS In pregnant women with T1DM, elevated CRP, soluble E-selectin, IL-1ra, and IP-10 and lower eotaxin were associated with subsequent PE. The role of inflammatory factors as markers and potential mechanisms of the high prevalence of PE in T1DM merits further investigation.

Plasma Lipoproteins and Preeclampsia in Women with Type 1 Diabetes: A Prospective Study

Context: In nondiabetic pregnancy, cross-sectional studies have shown associations between maternal dyslipidemia and preeclampsia (PE). In type 1 diabetes mellitus (T1DM), the prevalence of PE is increased 4-fold, but prospective associations with plasma lipoproteins are unknown.

Objectives: The aim of this study was to define lipoprotein-related markers and potential mechanisms for PE in T1DM.

Design and Settings: We conducted a multicenter prospective study in T1DM pregnancy.

Patients: We studied 118 T1DM women (26 developed PE, 92 remained normotensive). Subjects were studied at three visits before PE onset [12.2 1.9, 21.6 1.5, and 31.5 1.7 wk gestation (means SD)] and at term (37.6 2.0 wk). Nondiabetic normotensive pregnant women (n 21) were included for reference.

Main Outcome Measures: Conventional lipid profiles, lipoprotein subclasses [defined by size (nuclear magnetic resonance) and by apolipoprotein content], serum apolipoproteins (ApoAI, ApoB, and ApoCIII), and lipolysis (ApoCIII ratio) were measured in T1DM women with and without subsequent PE.

Results: In women with vs. without subsequent PE, at the first and/or second study visits: lowdensity lipoprotein (LDL)-cholesterol, particle concentrations of total LDL and large (but not small) LDL, serum ApoB, and ApoB:ApoAI ratio were all increased (P 0.05); peripheral lipoprotein lipolysis was decreased (P0.01). These early differences remained significant in covariate analysis (glycated hemoglobin, actual prandial status, gravidity, body mass index, and diabetes duration) but were not present at the third study visit. High-density lipoprotein and very low-density lipoprotein subclasses did not differ between groups before PE onset.

Conclusions: Early in pregnancy, increased cholesterol-rich lipoproteins and an index suggesting decreased peripheral lipolysis were associated with subsequent PE in T1DM women. Background maternal lipoprotein characteristics, perhaps masked by effects of late pregnancy, may influence PE risk.

The role of angiogenic and antiangiogenic factors in the second trimester in the prediction of preeclampsia in pregnant women with type 1 diabetes

OBJECTIVE To assess the association between circulating angiogenic and antiangiogenic factors in the second trimester and risk of preeclampsia in women with type 1 diabetes.

RESEARCH DESIGN AND METHODS Maternal plasma concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), and soluble endoglin (sEng) were available at 26 weeks of gestation in 540 women with type 1 diabetes enrolled in the Diabetes and Preeclampsia Intervention Trial.

RESULTS Preeclampsia developed in 17% of pregnancies (n = 94). At 26 weeks of gestation, women in whom preeclampsia developed later had significantly lower PlGF (median [interquartile range]: 231 pg/mL [120–423] vs. 365 pg/mL [237–582]; P < 0.001), higher sFlt-1 (1,522 pg/mL [1,108–3,393] vs. 1,193 pg/mL [844–1,630] P < 0.001), and higher sEng (6.2 ng/mL [4.9–7.9] vs. 5.1 ng/mL[(4.3–6.2]; P < 0.001) compared with women who did not have preeclampsia. In addition, the ratio of PlGF to sEng was significantly lower (40 [17–71] vs. 71 [44–114]; P < 0.001) and the ratio of sFlt-1 to PlGF was significantly higher (6.3 [3.4–15.7] vs. 3.1 [1.8–5.8]; P < 0.001) in women who later developed preeclampsia. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to a logistic model containing established risk factors (area under the curve [AUC], 0.813) significantly improved the predictive value (AUC, 0.850 and 0.846, respectively; P < 0.01) and significantly improved reclassification according to the integrated discrimination improvement index (IDI) (IDI scores 0.086 and 0.065, respectively; P < 0.001).

CONCLUSIONS These data suggest that angiogenic and antiangiogenic factors measured during the second trimester are predictive of preeclampsia in women with type 1 diabetes. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to established clinical risk factors significantly improves the prediction of preeclampsia in women with type 1 diabetes.

Preeclampsia is characterized by the development of hypertension and new-onset proteinuria during the second half of pregnancy (1,2), leading to increased maternal morbidity and mortality (3). Women with type 1 diabetes are at increased risk for development of preeclampsia during pregnancy, with rates being two-times to four-times higher than that of the background maternity population (4,5). Small advances have come from preventive measures, such as low-dose aspirin in women at high risk (6); however, delivery remains the only effective intervention, and preeclampsia is responsible for up to 15% of preterm births and a consequent increase in infant mortality and morbidity (7).

Although the etiology of preeclampsia remains unclear, abnormal placental vascular remodeling and placental ischemia, together with maternal endothelial dysfunction, hemodynamic changes, and renal pathology, contribute to its pathogenesis (8). In addition, over the past decade accumulating evidence has suggested that an imbalance between angiogenic factors, such as placental growth factor (PlGF), and antiangiogenic factors, such as soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), plays a key role in the pathogenesis of preeclampsia (8,9). In women at low risk (10–13) and women at high risk (14,15), concentrations of angiogenic and antiangiogenic factors are significantly different between women who later develop preeclampsia (lower PlGF, higher sFlt-1, and higher sEng levels) compared with women who do not.

Few studies have specifically focused on circulating angiogenic factors and risk of preeclampsia in women with diabetes, and the results have been conflicting. In a small study, higher sFlt-1 and lower PlGF were reported at the time of delivery in women with diabetes who developed preeclampsia (16). In a longitudinal prospective cohort of pregnant women with diabetes, Yu et al. (17) reported increased sFlt-1 and reduced PlGF in the early third trimester as potential predictors of preeclampsia in women with type 1 diabetes, but they did not show any difference in sEng levels in women with preeclampsia compared with women without preeclampsia. By contrast, Powers et al. (18) reported only increased sEng in the second trimester in women with pregestational diabetes who developed preeclampsia.

The aim of this study, which was significantly larger than the previous studies highlighted, was to assess the association between circulating angiogenic (PlGF) and antiangiogenic (sFlt-1 and sEng) factors and the risk of preeclampsia in women with type 1 diabetes. A further aim was to evaluate the added predictive ability and clinical usefulness of angiogenic factors and established risk factors for preeclampsia risk prediction in women with type 1 diabetes.

Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome

Cushing's syndrome (CS) is a disorder associated with significant morbidity and mortality due to prolonged exposure to high cortisol concentrations.

Survival in dialysis patients is different between patients with diabetes as primary renal disease and patients with diabetes as a co-morbid condition.

AIMS/HYPOTHESIS:

A previous study in Dutch dialysis patients showed no survival difference between patients with diabetes as primary renal disease and those with diabetes as a co-morbid condition. As this was not in line with our hypothesis, we aimed to verify these results in a larger international cohort of dialysis patients.

METHODS:

For the present prospective study, we used data from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry. Incident dialysis patients with data on co-morbidities (n?=?15,419) were monitored until kidney transplantation, death or end of the study period (5 years). Cox regression was performed to compare survival for patients with diabetes as primary renal disease, patients with diabetes as a co-morbid condition and non-diabetic patients.

RESULTS:

Of the study population, 3,624 patients (24%) had diabetes as primary renal disease and 1,193 (11%) had diabetes as a co-morbid condition whereas the majority had no diabetes (n?=?10,602). During follow-up, 7,584 (49%) patients died. In both groups of diabetic patients mortality was higher compared with the non-diabetic patients. Mortality was higher in patients with diabetes as primary renal disease than in patients with diabetes as a co-morbid condition, adjusted for age, sex, country and malignancy (HR 1.20, 95% CI 1.10, 1.30). An analysis stratified by dialysis modality yielded similar results.

CONCLUSIONS/INTERPRETATION:

Overall mortality was significantly higher in patients with diabetes as primary renal disease compared with those with diabetes as a co-morbid condition. This suggests that survival in diabetic dialysis patients is affected by the extent to which diabetes has induced organ damage.

The relationship between breastfeeding and postpartum weight change-a systematic review and critical evaluation

Pregnancy and the postpartum period is a time of increased vulnerability for retention of excess body fat in women. Breastfeeding (BF) has been shown to have many health benefits for both mother and baby; however, its role in postpartum weight management is unclear. Our aim was to systematically review and critically appraise the literature published to date in relation to the impact of BF on postpartum weight change, weight retention and maternal body composition. Electronic literature searches were carried out using MEDLINE, EMBASE, PubMed, Web of Science, BIOSIS, CINAHL and British Nursing Index. The search covered publications up to 12 June 2012 and included observational studies (prospective and retrospective) carried out in BF mothers (either exclusively or as a subgroup), who were 2 years postpartum and with a body mass index (BMI) >18.5 kg m(-2), with an outcome measure of change in weight (including weight retention) and/or body composition. Thirty-seven prospective studies and eight retrospective studies were identified that met the selection criteria; studies were stratified according to study design and outcome measure. Overall, studies were heterogeneous, particularly in relation to sample size, measurement time points and in the classification of BF and postpartum weight change. The majority of studies reported little or no association between BF and weight change (n=27, 63%) or change in body composition (n=16, 89%), although this seemed to depend on the measurement time points and BF intensity. However, of the five studies that were considered to be of high methodological quality, four studies demonstrated a positive association between BF and weight change. This systematic review highlights the difficulties of examining the association between BF and weight management in observational research. Although the available evidence challenges the widely held belief that BF promotes weight loss, more robust studies are needed to reliably assess the impact of BF on postpartum weight management.International Journal of Obesity advance online publication, 20 August 2013; doi:10.1038/ijo.2013.132.

Polycythaemia-inducing mutations in the erythropoietin receptor (EPOR):mechanism and function as elucidated by epidermal growth factor receptor-EPOR chimeras

Primary familial and congenital polycythaemia (PFCP) is a disease characterized by increased red blood cell mass, and can be associated with mutations in the intracellular region of the erythropoietin (EPO) receptor (EPOR). Here we explore the mechanisms by which EPOR mutations induce PFCP, using an experimental system based on chimeric receptors between epidermal growth factor receptor (EGFR) and EPOR. The design of the chimeras enabled EPOR signalling to be triggered by EGF binding. Using this system we analysed three novel EPOR mutations discovered in PFCP patients: a deletion mutation (Del1377-1411), a nonsense mutation (C1370A) and a missense mutation (G1445A). Three different chimeras, bearing these mutations in the cytosolic, EPOR region were generated; Hence, the differences in the chimera-related effects are specifically attributed to the mutations. The results show that the different mutations affect various aspects related to the signalling and metabolism of the chimeric receptors. These include slower degradation rate, higher levels of glycan-mature chimeric receptors, increased sensitivity to low levels of EGF (replacing EPO in this system) and extended signalling cascades. This study provides a novel experimental system to study polycythaemia-inducing mutations in the EPOR, and sheds new light on underlying mechanisms of EPOR over-activation in PFCP patients.

Effectiveness of a programme of exercise on physical function in survivors of critical illness following discharge from the ICU: study protocol for a randomised controlled trial (REVIVE)

Background: Following discharge home from the ICU, patients often suffer from reduced physical function, exercise capacity, health-related quality of life and social functioning. There is usually no support to address these longer term problems, and there has been limited research carried out into interventions which could improve patient outcomes. The aim of this study is to investigate the effectiveness and cost-effectiveness of a 6-week programme of exercise on physical function in patients discharged from hospital following critical illness compared to standard care.

Methods/Design: The study design is a multicentre prospective phase II, allocation-concealed, assessor-blinded, randomised controlled clinical trial. Participants randomised to the intervention group will complete three exercise sessions per week (two sessions of supervised exercise and one unsupervised session) for 6 weeks. Supervised sessions will take place in a hospital gymnasium or, if this is not possible, in the participants home and the unsupervised session will take place at home. Blinded outcome assessment will be conducted at baseline after hospital discharge, following the exercise intervention, and at 6 months following baseline assessment (or equivalent time points for the standard care group). The primary outcome measure is physical function as measured by the physical functioning subscale of the Short-Form-36 health survey following the exercise programme. Secondary outcomes are health-related quality of life, exercise capacity, anxiety and depression, self efficacy to exercise and healthcare resource use. In addition, semi-structured interviews will be conducted to explore participants’ perceptions of the exercise programme, and the feasibility (safety, practicality and acceptability) of providing the exercise programme will be assessed. A within-trial cost-utility analysis to assess the cost-effectiveness of the intervention compared to standard care will also be conducted.

Discussion: If the exercise programme is found to be effective, this study will improve outcomes that are meaningful to patients and their families. It will inform the design of a future multicentre phase III clinical trial of exercise following recovery from critical illness. It will provide useful information which will help the development of services for patients after critical illness.

An exploratory study of specialist and generalist teachers: predicting self efficacy in delivering primary physical education.

We aimed to determine whether primary school teachers’ motivational regulations to exercise and self efficacy in delivering a physical education (PE) lesson are different based on prior PE training. Two groups of qualified primary school teachers were recruited; PE specialists and a group of generalist primary school teachers who also teach PE. All teachers completed the Behavioural Regulation in Exercise Questionnaire-2, International Physical Activity Questionnaire and the Teachers’ Sense of Efficacy Scale. PE specialists demonstrated significantly higher levels of intrinsic motivation towards exercise participation and took part in more physical activity in comparison to the generalist teachers. Regression analysis showed that being a PE specialist predicted higher scores in instructional strategies and classroom management in PE. Our findings support the useof Self Determination Theory concepts in understanding teacher’s exercise participation motivations. These findings have implications for the modelling role of teachers in encouraging children to be physically active.

Chaotropic and hydrophobic stress mechanisms of antifungal substances

Growth and metabolism of fungi can be curtailed by chaotropic solutes and hydrophobic substances, both of which can weaken or inhibit non-covalent interactions within and between macromolecular systems. Here we explore the potential to utilize the fungistatic and fungicidal activities of such stressors as the basis for commercial formulations. A method was developed for the quantification of chaotropicity, which can be used for chemically diverse substances, in order elucidate roles of chaotropicity and hydrophobicity in microbial ecology (both of which are sufficiently potent to limit the Earth’s microbial biosphere). A large number of naturally occurring substances act as chaotropic or hydrophobic stressors including aliphatic alcohols, salts such as MgCl2, aromatics such as phenol, and hydrocarbons such as hexane and octene. We suggest that these stress parameters provide the (hitherto unidentified) modes-of-action for some extant antifungal products. The findings are discussed in relation to the development of a new generation of antifungals.