The association between a biomarker score for fruit and vegetable intake and incident type 2 diabetes: the EPIC-Norfolk study.

BACKGROUND/OBJECTIVES: Biomarkers for a mixed fruit and vegetable (FV) diet are needed to provide a better understanding of the association between FV intake and type 2 diabetes. We aimed to examine the prospective association between a composite score comprised of three biomarkers of FV intake in free-living populations and incident diabetes. SUBJECTS/METHODS: A total of 318 incident diabetes cases and 926 controls from the EPIC (European Prospective Investigation of Cancer)-Norfolk study aged 40-79 years at baseline (1993-1997), completed 7-day prospective food diary and had plasma vitamin C and carotenoid measures. A composite biomarker score (CB-score) comprising the sum of plasma vitamin C, beta-carotene and lutein was derived. Odds ratios (ORs) and 95% confidence intervals (CIs) for incident diabetes were estimated using multivariable logistic regression. RESULTS: A strong inverse association was found between the CB-score and incident diabetes. The ORs (95% CI) of diabetes comparing quartiles Q2, Q3 and Q4 of the CB-score with Q1 (reference category) were 0.70 (0.49, 1.00), 0.34 (0.23, 0.52) and 0.19 (0.12, 0.32), respectively, and 0.49 (0.40, 0.58) per s.d. change in CB-score in a model adjusted for demographic and lifestyle factors. The association was marginally attenuated after additionally adjusting for body mass index and waist circumference (0.60 (0.49 and 0.74) per s.d. change in CB-score). CONCLUSIONS: A combination of biomarkers representing the intake of a mixed FV diet was strongly inversely associated with incident diabetes. These findings provide further support for measuring dietary biomarkers in studies of diet-disease associations and highlight the importance of consuming FV for the prevention of diabetes.The EPIC Norfolk study is supported by programme grants from the Medical Research Council UK and Cancer Research UK. The sponsors did not participate in the design or conduct of this study; in the collection, management, analysis, or interpretation of data; in the writing of the manuscript; or in the preparation, review, approval, or decision to submit this manuscript for publication. We acknowledge support from the MRC Epidemiology Unit (MC_UU_12015/5).This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ejcn.2014.24

Bidirectional association between physical activity and muscular strength in older adults: Results from the UK Biobank study.

BACKGROUND: The relationship between physical activity and muscular strength has not been examined in detail among older adults. The objective of this study was to examine the associations between physical activity and hand grip strength among adults aged ≥ 60 years. METHODS: Using data from the UK Biobank study, we included 66 582 men and women with complete baseline data and 6599 with 4.5 years of follow-up data. We used multiple linear regression models to examine the cross-sectional, longitudinal and bidirectional associations between moderate-to-vigorous physical activity (MVPA) and grip strength, adjusting for potential confounding by age, sex, height, weight, health status, education level, smoking status, Townsend deprivation index and retirement status. RESULTS: In cross-sectional analyses, grip strength and MVPA were linearly and positively associated with each other. Longitudinally, baseline MVPA was not associated with grip strength at follow-up {difference between quintile [Q] 5 and Q1 = 0.40 [95% confidence interval (CI): -0.14, 0.94]kg}, whereas baseline grip strength was associated with MVPA at follow-up [Q5 vs Q1 = 7.15 (1.18, 13.12) min/day]. People who maintained/increased time spent in MVPA did not experience any benefit in grip strength [0.08 (-0.20, 0.37) kg] whereas those who increased their grip strength spent 3.69 (0.20, 7.17) min/day extra in MVPA. CONCLUSION: Promotion of strength-training activities may enable and maintain participation in regular physical activity among older adults.This work was supported by the Medical Research Council [Programme number: MC_UU_12015/4] and has been conducted using the UK Biobank Resource.This is the final version of the article. It first appeared from Oxford University Press via https://doi.org/10.1093/ije/dyw05

The descriptive epidemiology of accelerometer-measured physical activity in older adults.

BACKGROUND: Objectively measured physical activity between older individuals and between populations has been poorly described. We aimed to describe and compare the variation in accelerometry data in older UK (EPIC-Norfolk) and American (NHANES) adults. METHODS: Physical activity was measured by uniaxial accelerometry in 4,052 UK (49-91 years) and 3459 US older adults (49-85 years). We summarized physical activity as volume (average counts/minute), its underlying intensity distribution, and as time spent 809 counts/minute is used 18.7% of people reached the 30 min/day threshold. By comparison, 2.5% and 9.5% of American older adults accumulated activity at these levels, respectively. CONCLUSION: As assessed by objectively measured physical activity, the majority of older adults in this UK study did not meet current activity guidelines. Older adults in the UK were more active overall, but also spent more time being sedentary than US adults.This work was supported by programme grants from the Medical Research Council [G9502233; G0401527] and Cancer Research UK [C864/A8257]. A grant from Research into Ageing [262] funded the 3rd health check clinic. KW is supported by a British Heart Foundation Intermediate Basic Science Research Fellowship [FS/12/58/29709], and AJMC, SJG, NJW, and SB are supported by MRC programme grants [MC_UU_12015/3 and MC_UU_12015/4].This is the final version of the article. It was first available from BioMed Central via http://dx.doi.org/10.1186/s12966-015-0316-

Home-HIT improves muscle capillarisation and eNOS/NAD(P)Hoxidase protein ratio in obese individuals with elevated cardiovascular disease risk.

KEY POINTS: Obesity and sedentary behaviour are associated with capillary rarefaction and impaired muscle microvascular vasoreactivity, due to reduced nitric oxide bioavailability. Low-volume high-intensity interval training (HIT) is a time-efficient alternative to traditional moderate-intensity continuous training (MICT), but its effect on the muscle microvasculature has not been studied. The applicability of current lab- and gym-based HIT protocols for obese individuals with low fitness and mobility has been disputed by public health experts, who cite the strenuous nature and complex protocols as major barriers. Therefore, we developed a virtually-supervised HIT protocol targeting this group that can be performed at home without equipment (Home-HIT). This study is the first to show that 12-weeks of virtually-supervised Home-HIT in obese individuals with elevated CVD risk leads to similar increases in capillarisation and eNOS/NAD(P)Hoxidase protein ratio within the muscle microvascular endothelium as virtually-supervised home-based MICT and laboratory-based HIT, while reducing many of the major barriers to exercise. ABSTRACT: This study investigated the effect of a novel virtually-supervised home-based high-intensity interval training (HIT) (Home-HT) intervention in obese individuals with elevated cardiovascular disease (CVD) risk on capillarisation and muscle microvascular eNOS/NAD(P)Hoxidase ratio. Thirty-two adults with elevated CVD risk (age 36 ± 10 years; BMI 34.3 ± 5 kg∙m-2 ; V̇O2peak 24.6 ± 5.7 ml∙kg∙min-1 ), completed one of three 12-week training programmes: Home-HIT (n = 9); laboratory-based supervised HIT (Lab-HIT; n = 10) or virtually-supervised home-based moderate-intensity continuous training (Home-MICT; n = 13). Muscle biopsies were taken pre- and post-training to assess changes in vascular enzymes, capillarisation, mitochondrial density, intramuscular triglyceride content and GLUT4 protein expression using quantitative immunofluorescence microscopy. Training increased V̇O2peak (P < 0.001), whole-body insulin sensitivity (P = 0.033) and flow-mediated dilation (P<0.001), while aortic pulse wave velocity decreased (P < 0.001) in all 3 groups. Immunofluorescence microscopy revealed comparable increases in total eNOS content in terminal arterioles and capillaries (P < 0.001) in the 3 conditions. There was no change in eNOS ser1177 phosphorylation (arterioles P = 0.802; capillaries P = 0.311), but eNOS ser1177 /eNOS content ratio significantly decreased following training in arterioles and capillaries (P < 0.001). Training decreased NOX2 content (arterioles P < 0.001; capillaries P < 0.001), but there was no change in p47phox content (arterioles P = 0.101; capillaries P = 0.345). All measures of capillarisation increased (P < 0.05). There were no between group differences. Despite having no direct supervision during exercise, virtually-supervised Home-HIT resulted in comparable structural and endothelial enzymatic changes in the skeletal muscle microvessels to the traditional training methods. We provide strong evidence that Home-HIT is an effective novel strategy to remove barriers to exercise and improve health in an obese population at risk of CVD. This article is protected by copyright. All rights reserved

An Arthropod Enzyme, Dfurin 1, and a Vertebrate Furin Homolog Display Distinct Cleavage Site Sequence Preferences for a Shared Viral Proprotein Substrate

Alphaviruses replicate in vertebrate and arthropod cells and utilize a cellular enzyme called furin to process the PE2 glycoprotein precursor during virus replication in both cell types. Furin cleaves PE2 at a site immediately following a highly conserved four residue cleavage signal. Prior studies demonstrated that the amino acid immediately adjacent to the cleavage site influenced PE2 cleavage differently in vertebrate and mosquito cells (HW Heidner et al. 1996. Journal of Virology 70: 2069–2073.). This finding was tentatively attributed to potential differences in the substrate specificities of the vertebrate and arthropod furin enzymes or to differences in the carbohydrate processing phenotypes of arthropod and vertebrate cells. To further address this issue, we evaluated Sindbis virus replication and PE2 cleavage in the Chinese hamster, Cricetulus griseus Milne-Edwards (Rodentia: Cricetidae) ovary cells (CHO-K1) and in a CHO-K1-derived furin-negative cell line (RPE.40) engineered to stably express the Dfurin1 enzyme of Drosophila melanogaster Meigen (Diptera: Drosophilidae). Expression of Dfurin1 enhanced Sindbis virus titers in RPE.40 cells by a factor of 102 – 103, and this increase correlated with efficient cleavage of PE2. The PE2-cleavage phenotypes of viruses containing different amino acid substitutions adjacent to the furin cleavage site were compared in mosquito (C6/36), CHO-K1, and Dfurin1-expressing RPE.40 cells. This analysis confirmed that the substrate specificities of Dfurin1 and the putative mosquito furin homolog present in C6/36 cells are similar and suggested that the alternative PE2 cleavage phenotypes observed in vertebrate and arthropod cells were due to differences in substrate specificity between the arthropod and vertebrate furin enzymes and not to differences in host cell glycoprotein processing pathways

Atherosclerotic renal artery stenosis is prevalent in cardiorenal patients but not associated with left ventricular function and myocardial fibrosis as assessed by cardiac magnetic resonance imaging

<p>Abstract</p> <p>Background</p> <p>Atherosclerotic renal artery stenosis (ARAS) is common in cardiovascular diseases and associated with hypertension, renal dysfunction and/or heart failure. There is a paucity of data about the prevalence and the role of ARAS in the pathophysiology of combined chronic heart failure (CHF) and chronic kidney disease (CKD). We investigated the prevalence in patients with combined CHF/CKD and its association with renal function, cardiac dysfunction and the presence and extent of myocardial fibrosis.</p> <p>Methods</p> <p>The EPOCARES study (ClinTrialsNCT00356733) investigates the role of erythropoietin in anaemic patients with combined CHF/CKD. Eligible subjects underwent combined cardiac magnetic resonance imaging (cMRI), including late gadolinium enhancement, with magnetic resonance angiography of the renal arteries (MRA).</p> <p>Results</p> <p>MR study was performed in 37 patients (median age 74 years, eGFR 37.4 ± 15.6 ml/min, left ventricular ejection fraction (LVEF) 43.3 ± 11.2%), of which 21 (56.8%) had ARAS (defined as stenosis >50%). Of these 21 subjects, 8 (21.6%) had more severe ARAS >70% and 8 (21.6%) had a bilateral ARAS >50% (or previous bilateral PTA). There were no differences in age, NT-proBNP levels and medication profile between patients with ARAS versus those without. Renal function declined with the severity of ARAS (p = 0.03), although this was not significantly different between patients with ARAS versus those without. Diabetes mellitus was more prevalent in patients without ARAS (56.3%) against those with ARAS (23.8%) (p = 0.04). The presence and extent of late gadolinium enhancement, depicting myocardial fibrosis, did not differ (p = 0.80), nor did end diastolic volume (p = 0.60), left ventricular mass index (p = 0.11) or LVEF (p = 0.15). Neither was there a difference in the presence of an ischemic pattern of late enhancement in patients with ARAS versus those without.</p> <p>Conclusions</p> <p>ARAS is prevalent in combined CHF/CKD and its severity is associated with a decline in renal function. However, its presence does not correlate with a worse LVEF, a higher left ventricular mass or with the presence and extent of myocardial fibrosis. Further research is required for the role of ARAS in the pathophysiology of combined chronic heart and renal failure.</p

Physical activity, sedentary time and physical capability in early old age: British birth cohort study.

PURPOSE: To investigate the associations of time spent sedentary, in moderate-to-vigorous-intensity physical activity (MVPA) and physical activity energy expenditure (PAEE) with physical capability measures at age 60-64 years. METHODS: Time spent sedentary and in MVPA and, PAEE were assessed using individually calibrated combined heart rate and movement sensing among 1727 participants from the MRC National Survey of Health and Development in England, Scotland and Wales as part of a detailed clinical assessment undertaken in 2006-2010. Multivariable linear regression models were used to examine the cross-sectional associations between standardised measures of each of these behavioural variables with grip strength, chair rise and timed up-&-go (TUG) speed and standing balance time. RESULTS: Greater time spent in MVPA was associated with higher levels of physical capability; adjusted mean differences in each capability measure per 1 standard deviation increase in MVPA time were: grip strength (0.477 kg, 95% confidence interval (CI): 0.015 to 0.939), chair rise speed (0.429 stands/min, 95% CI: 0.093 to 0.764), standing balance time (0.028 s, 95% CI: 0.003 to 0.053) and TUG speed (0.019 m/s, 95% CI: 0.011 to 0.026). In contrast, time spent sedentary was associated with lower grip strength (-0.540 kg, 95% CI: -1.013 to -0.066) and TUG speed (-0.011 m/s, 95% CI: -0.019 to -0.004). Associations for PAEE were similar to those for MVPA. CONCLUSION: Higher levels of MVPA and overall physical activity (PAEE) are associated with greater levels of physical capability whereas time spent sedentary is associated with lower levels of capability. Future intervention studies in older adults should focus on both the promotion of physical activity and reduction in time spent sedentary.This work was supported by the UK Medical Research Council (U120063239, U123092720, MC_UU_12019/1, MC_UU_12019/4, MC_UU_12015/3, and MC_UU_12015/4).This is the final published version. It first appeared at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126465

Synergistic Antitumor Effects of Novel HDAC Inhibitors and Paclitaxel In Vitro and In Vivo

Preclinical studies support the therapeutic potential of histone deacetylases inhibitors (HDACi) in combination with taxanes. The efficacy of combination has been mainly ascribed to a cooperative effect on microtubule stabilization following tubulin acetylation. In the present study we investigated the effect of paclitaxel in combination with two novel HDACi, ST2782 or ST3595, able to induce p53 and tubulin hyperacetylation. A synergistic effect of the paclitaxel/ST2782 (or ST3595) combination was found in wild-type p53 ovarian carcinoma cells, but not in a p53 mutant subline, in spite of a marked tubulin acetylation. Such a synergistic interaction was confirmed in additional human solid tumor cell lines harboring wild-type p53 but not in those expressing mutant or null p53. In addition, a synergistic cytotoxic effect was found when ST2782 was combined with the depolymerising agent vinorelbine. In contrast to SAHA, which was substantially less effective in sensitizing cells to paclitaxel-induced apoptosis, ST2782 prevented up-regulation of p21WAF1/Cip1 by paclitaxel, which has a protective role in response to taxanes, and caused p53 down-regulation, acetylation and mitochondrial localization of acetylated p53. The synergistic antitumor effects of the paclitaxel/ST3595 combination were confirmed in two tumor xenograft models. Our results support the relevance of p53 modulation as a major determinant of the synergistic interaction observed between paclitaxel and novel HDACi and emphasize the therapeutic interest of this combination

Fruit and vegetable intake and cardiovascular risk factors in people with newly diagnosed type 2 diabetes.

BACKGROUND/OBJECTIVES: The cardiovascular benefit of increasing fruit and vegetable (F&V) intake following diagnosis of diabetes remains unknown. We aimed to describe how quantity and variety of F&V intake, and plasma vitamin C, change after diagnosis of type 2 diabetes and examine whether these changes are associated with improvements in cardiovascular risk factors. SUBJECTS/METHODS: A total of 401 individuals with screen-detected diabetes from the ADDITION-Cambridge study were followed up over 5 years. F&V intake was assessed by food frequency questionnaire and plasma vitamin C at baseline, at 1 year and at 5 years. Linear mixed models were used to estimate associations of changes in quantity and variety of F&V intake, and plasma vitamin C, with cardiovascular risk factors and a clustered cardiometabolic risk score (CCMR), where a higher score indicates higher risk. RESULTS: F&V intake increased in year 1 but decreased by year 5, whereas variety remained unchanged. Plasma vitamin C increased at 1 year and at 5 years. Each s.d. increase (250g between baseline and 1 year and 270g between 1 and 5 years) in F&V intake was associated with lower waist circumference (-0.92 (95% CI: -1.57, -0.27) cm), HbA1c (-0.11 (-0.20, -0.03) %) and CCMR (-0.04 (-0.08, -0.01)) at 1 year and higher high-density lipoprotein (HDL)-cholesterol (0.04 (0.01, 0.06) mmol/l) at 5 years. Increased plasma vitamin C (per s.d., 22.5 μmol/l) was associated with higher HDL-cholesterol (0.04 (0.01, 0.06) mmol/l) and lower CCMR (-0.07 (-0.12, -0.03)) between 1 and 5 years. CONCLUSIONS: Increases in F&V quantity following diagnosis of diabetes are associated with lower cardiovascular risk factors. Health promotion interventions might highlight the importance of increasing, and maintaining increases in, F&V intake for improved cardiometabolic health in patients with diabetes.The ADDITION-Cambridge study was supported by the Wellcome Trust (grant G061895), the Medical Research Council (grant G0001164), the National Institute for Health Research (NIHR) Health Technology Assessment Programme (grant 08/116/300), National Health Service R&D support funding (including the Primary Care Research and Diabetes Research Networks). SJG received support from the Department of Health NIHR Programme Grant funding scheme (grant RP-PG-0606-1259). Bio-Rad provided equipment for HbA1c testing during the screening phase

Managing sedentary behavior to reduce the risk of diabetes and cardiovascular disease

Modern human environments are vastly different from those of our forebears. Rapidly advancing technology in transportation, communications, workplaces, and home entertainment confer a wealth of benefits, but increasingly come with costs to human health. Sedentary behavior—too much sitting as distinct from too little physical activity—contributes adversely to cardiometabolic health outcomes and premature mortality. Findings from observational epidemiology have been synthesized in meta-analyses, and evidence is now shifting into the realm of experimental trials with the aim of identifying novel mechanisms and potential causal relationships. We discuss recent observational and experimental evidence that makes a compelling case for reducing and breaking up prolonged sitting time in both the primary prevention and disease management contexts. We also highlight future research needs, the opportunities for developing targeted interventions, and the potential of population-wide initiatives designed to address too much sitting as a health risk