Glucose-induced down regulation of thiamine transporters in the kidney proximal tubular epithelium produces thiamine insufficiency in diabetes

Increased renal clearance of thiamine (vitamin B1) occurs in experimental and clinical diabetes producing thiamine insufficiency mediated by impaired tubular re-uptake and linked to the development of diabetic nephropathy. We studied the mechanism of impaired renal re-uptake of thiamine in diabetes. Expression of thiamine transporter proteins THTR-1 and THTR-2 in normal human kidney sections examined by immunohistochemistry showed intense polarised staining of the apical, luminal membranes in proximal tubules for THTR-1 and THTR-2 of the cortex and uniform, diffuse staining throughout cells of the collecting duct for THTR-1 and THTR-2 of the medulla. Human primary proximal tubule epithelial cells were incubated with low and high glucose concentration, 5 and 26 mmol/l, respectively. In high glucose concentration there was decreased expression of THTR-1 and THTR-2 (transporter mRNA: −76% and −53% respectively, p<0.001; transporter protein −77% and −83% respectively, p<0.05), concomitant with decreased expression of transcription factor specificity protein-1. High glucose concentration also produced a 37% decrease in apical to basolateral transport of thiamine transport across cell monolayers. Intensification of glycemic control corrected increased fractional excretion of thiamine in experimental diabetes. We conclude that glucose-induced decreased expression of thiamine transporters in the tubular epithelium may mediate renal mishandling of thiamine in diabetes. This is a novel mechanism of thiamine insufficiency linked to diabetic nephropathy

Characterisation of feline renal cortical fibroblast cultures and their transcriptional response to transforming growth factor beta 1

Chronic kidney disease (CKD) is common in geriatric cats, and the most prevalent pathology is chronic tubulointerstitial inflammation and fibrosis. The cell type predominantly responsible for the production of extra-cellular matrix in renal fibrosis is the myofibroblast, and fibroblast to myofibroblast differentiation is probably a crucial event. The cytokine TGF-β1 is reportedly the most important regulator of myofibroblastic differentiation in other species. The aim of this study was to isolate and characterise renal fibroblasts from cadaverous kidney tissue of cats with and without CKD, and to investigate the transcriptional response to TGF-β1

Oxygen-regulated transcription factors and their role in pulmonary disease

The transcription factors nuclear factor interleukin-6 (NF-IL6), early growth response-1 (EGR-1) and hypoxia-inducible factor-1 (HIF-1) have important roles in the molecular pathophysiology of hypoxia-associated pulmonary disease. NF-IL6 controls the production of interleukin (IL)-6 in vascular endothelial cells, which may have anti-inflammatory activity by counteracting effects of IL-1 and IL-8. EGR-1 controls the production of tissue factor by macrophages, which triggers fibrin deposition in the pulmonary vasculature. HIF-1 activates the expression of the vasoconstrictor endothelin-1 in vascular endothelial cells. Angiotensin II induces HIF-1 expression and hypertrophy of pulmonary arterial smooth muscle cells. HIF-1 might therefore have multiple roles in the pathogenesis of pulmonary vascular remodeling

A scoping study of interventions to increase the uptake of physical activity (PA) amongst individuals with mild-to-moderate depression (MMD)

Background - Depression is the largest contributor to disease burden globally. The evidence favouring physical activity as a treatment for mild-to-moderate depression is extensive and relatively uncontested. It is unclear, however, how to increase an uptake of physical activity amongst individuals experiencing mild-to-moderate depression. This leaves professionals with no guidance on how to help people experiencing mild-to-moderate depression to take up physical activity. The purpose of this study was to scope the evidence on interventions to increase the uptake of physical activity amongst individuals experiencing mild-to-moderate depression, and to develop a model of the mechanisms by which they are hypothesised to work. Methods - A scoping study was designed to include a review of primary studies, grey literature and six consultation exercises; two with individuals with experience of depression, two pre-project consultations with physical activity, mental health and literature review experts, one with public health experts, and one with community engagement experts. Results - Ten papers met the inclusion criteria and were included in the review. Consultation exercises provided insights into the mechanisms of an uptake of physical activity amongst individuals experiencing mild-to-moderate depression; evidence concerning those mechanisms is (a) fragmented in terms of design and purpose; (b) of varied quality; (c) rarely explicit about the mechanisms through which the interventions are thought to work. Physical, environmental and social factors that may represent mediating variables in the uptake of physical activity amongst people experiencing mild-to-moderate depression are largely absent from studies. Conclusions - An explanatory model was developed. This represents mild-to-moderate depression as interfering with (a) the motivation to take part in physical activity and (b) the volition that it is required to take part in physical activity. Therefore, both motivational and volitional elements are important in any intervention to increase physical activity in people with mild-to-moderate depression. Furthermore, mild-to-moderate depression-specific factors need to be tackled in any physical activity initiative, via psychological treatments such as Cognitive Behavioural Therapy. We argu

Search for Kaluza-Klein Graviton Emission in ppˉp\bar{p} Collisions at s=1.8\sqrt{s}=1.8 TeV using the Missing Energy Signature

We report on a search for direct Kaluza-Klein graviton production in a data sample of 84 ${pb}^{-1}$ of \ppb collisions at $\sqrt{s}$ = 1.8 TeV, recorded by the Collider Detector at Fermilab. We investigate the final state of large missing transverse energy and one or two high energy jets. We compare the data with the predictions from a $3+1+n$-dimensional Kaluza-Klein scenario in which gravity becomes strong at the TeV scale. At 95% confidence level (C.L.) for $n$=2, 4, and 6 we exclude an effective Planck scale below 1.0, 0.77, and 0.71 TeV, respectively.Comment: Submitted to PRL, 7 pages 4 figures/Revision includes 5 figure

Measurement of the average time-integrated mixing probability of b-flavored hadrons produced at the Tevatron

We have measured the number of like-sign (LS) and opposite-sign (OS) lepton pairs arising from double semileptonic decays of $b$ and $\bar{b}$-hadrons, pair-produced at the Fermilab Tevatron collider. The data samples were collected with the Collider Detector at Fermilab (CDF) during the 1992-1995 collider run by triggering on the existence of $\mu \mu$ and $e \mu$ candidates in an event. The observed ratio of LS to OS dileptons leads to a measurement of the average time-integrated mixing probability of all produced $b$-flavored hadrons which decay weakly, $\bar{\chi} = 0.152 \pm 0.007$ (stat.) $\pm 0.011$ (syst.), that is significantly larger than the world average $\bar{\chi} = 0.118 \pm 0.005$.Comment: 47 pages, 10 figures, 15 tables Submitted to Phys. Rev.

Multidimensional individualised Physical ACTivity (Mi-PACT) - a technology-enabled intervention to promote physical activity in primary care: Study protocol for a randomised controlled trial

© 2015 Peacock et al. Background: Low physical activity is a major public health problem. New cost-effective approaches that stimulate meaningful long-term changes in physical activity are required, especially within primary care settings. It is becoming clear that there are various dimensions to physical activity with independent health benefits. Advances in technology mean that it is now possible to generate multidimensional physical activity 'profiles' that provide a more complete representation of physical activity and offer a variety of options that can be tailored to the individual. Mi-PACT is a randomised controlled trial designed to examine whether personalised multidimensional physical activity feedback and self-monitoring alongside trainer-supportive sessions increases physical activity and improves health outcomes in at-risk men and women. Methods/Design: We aim to recruit 216 patients from within primary care aged 40 to 70years and at medium or high risk of cardiovascular disease and/or type II diabetes mellitus. Adopting an unequal allocation ratio (intervention: control) of 2:1, participants will be randomised to one of two groups, usual care or the intervention. The control group will receive usual care from their general practitioner (GP) and standardised messages about physical activity for health. The intervention group will receive physical activity monitors and access to a web-based platform for a 3-month period to enable self-monitoring and the provision of personalised feedback regarding the multidimensional nature of physical activity. In addition, this technology-enabled feedback will be discussed with participants on 5 occasions during supportive one-to-one coaching sessions across the 3-month intervention. The primary outcome measure is physical activity, which will be directly assessed using activity monitors for a 7-day period at baseline, post intervention and at 12months. Secondary measures (at these time-points) include weight loss, fat mass, and markers of metabolic control, motivation and well-being. Discussion: Results from this study will provide insight into the effects of integrated physical activity profiling and self-monitoring combined with in-person support on physical activity and health outcomes in patients at risk of future chronic disease. Trial registration:ISRCTN18008011Trial registration date: 31 July 201

Trial baseline characteristics of a cluster randomised controlled trial of a school-located obesity prevention programme; the Healthy Lifestyles Programme (HeLP) trial

This is the final version of the article. Available from BioMed Central via the DOI in this record.Background We have developed a healthy lifestyles programme (HeLP) for primary school aged children (9–10 years), currently being evaluated in a definitive cluster randomised controlled trial. This paper descriptively presents the baseline characteristics of trial children (BMI, waist circumference, % body fat, diet and physical activity) by gender, cluster level socio-economic status, school size and time of recruitment into the trial. Methods Schools were recruited from across the South West of England and allocated 1:1 to either intervention (HeLP) or control (usual practice) stratified by the proportion of children eligible for free school meals (FSM, 1 Year 5 class). The primary outcome is change in body mass index standard deviation score (BMI sds) at 24 months post-randomisation. Secondary outcomes are BMI sds at 18 months, waist circumference and percentage body fat sds at 18 and 24 months, proportion of children classified as underweight, overweight and obese at 18 and 24 months, physical activity (for a sub-sample) and food intake at 18 months. Results At baseline 11.4% and 13.6% of children were categorised as overweight or obese respectively. A higher percentage of girls than boys (25.3% vs 24.8%) and children from schools in FSM category 2 (28.2% vs 23.2%) were overweight or obese. Children were consuming a mean (range) of 4.15 (0–13) energy dense snacks (EDS) and 3.23 (0–9) healthy snacks (HS) per day with children from schools in FSM category 2 consuming more EDS and negative food markers and less HS and positive food markers. Children spent an average 53.6 min per day (11.9 to 124.8) in MVPA and thirteen hours (779.3 min) per day (11 h to 15 h) doing less than ‘light’ intensity activity. Less than 5% of children achieved the Departments of Health’s recommendation of 60 min of MVPA every day. Conclusion We have excellent completeness of baseline data for all measures and have achieved compliance to accelerometry not seen before in other large scale studies. Our anthropometric baseline data is representative of local and national data for children this age and reflects the gender and socio-economic variations expected of children this age in relation to physical activity and weight status.The definitive trial of HeLP is funded by the UK National Institute for Health Research (NIHR) Public Health Research Programme (10/3010/01) and a full report will be published on the NIHR website. Intervention materials and delivery was funded by the Peninsula College of Medicine and Dentistry. PenCLAHRC provided methodological support during the transition from the exploratory trial to the definitive evaluation

Low-Volume High-Intensity Interval Training in a Gym Setting Improves Cardio-Metabolic and Psychological Health.

BACKGROUND: Within a controlled laboratory environment, high-intensity interval training (HIT) elicits similar cardiovascular and metabolic benefits as traditional moderate-intensity continuous training (MICT). It is currently unclear how HIT can be applied effectively in a real-world environment. PURPOSE: To investigate the hypothesis that 10 weeks of HIT, performed in an instructor-led, group-based gym setting, elicits improvements in aerobic capacity (VO2max), cardio-metabolic risk and psychological health which are comparable to MICT. METHODS: Ninety physically inactive volunteers (42±11 y, 27.7±4.8 kg.m-2) were randomly assigned to HIT or MICT group exercise classes. HIT consisted of repeated sprints (15-60 seconds, >90% HRmax) interspersed with periods of recovery cycling (≤25 min.session-1, 3 sessions.week-1). MICT participants performed continuous cycling (~70% HRmax, 30-45 min.session-1, 5 sessions.week-1). VO2max, markers of cardio-metabolic risk, and psychological health were assessed pre and post-intervention. RESULTS: Mean weekly training time was 55±10 (HIT) and 128±44 min (MICT) (p<0.05), with greater adherence to HIT (83±14% vs. 61±15% prescribed sessions attended, respectively; p<0.05). HIT improved VO2max, insulin sensitivity, reduced abdominal fat mass, and induced favourable changes in blood lipids (p<0.05). HIT also induced beneficial effects on health perceptions, positive and negative affect, and subjective vitality (p<0.05). No difference between HIT and MICT was seen for any of these variables. CONCLUSIONS: HIT performed in a real-world gym setting improves cardio-metabolic risk factors and psychological health in physically inactive adults. With a reduced time commitment and greater adherence than MICT, HIT offers a viable and effective exercise strategy to target the growing incidence of metabolic disease and psychological ill-being associated with physical inactivity