Mouse hypothalamic GT1-7 cells demonstrate AMPK-dependent intrinsic glucose-sensing behaviour.

AIMS/HYPOTHESIS: Hypothalamic glucose-excited (GE) neurons contribute to whole-body glucose homeostasis and participate in the detection of hypoglycaemia. This system appears defective in type 1 diabetes, in which hypoglycaemia commonly occurs. Unfortunately, it is at present unclear which molecular components required for glucose sensing are produced in individual neurons and how these are functionally linked. We used the GT1-7 mouse hypothalamic cell line to address these issues. METHODS: Electrophysiological recordings, coupled with measurements of gene expression and protein levels and activity, were made from unmodified GT1-7 cells and cells in which AMP-activated protein kinase (AMPK) catalytic subunit gene expression and activity were reduced. RESULTS: Hypothalamic GT1-7 neurons express the genes encoding glucokinase and ATP-sensitive K(+) channel (K(ATP)) subunits K ( ir ) 6.2 and Sur1 and exhibit GE-type glucose-sensing behaviour. Lowered extracellular glucose concentration hyperpolarised the cells in a concentration-dependent manner, an outcome that was reversed by tolbutamide. Inhibition of glucose uptake or metabolism hyperpolarised cells, showing that energy metabolism is required to maintain their resting membrane potential. Short hairpin (sh)RNA directed to Ampkα2 (also known as Prkaa2) reduced GT1-7 cell AMPKα2, but not AMPKα1, activity and lowered the threshold for hypoglycaemia-induced hyperpolarisation. shAmpkα1 (also known as Prkaa1) had no effect on glucose-sensing or AMPKα2 activity. Decreased uncoupling protein 2 (Ucp2) mRNA was detected in AMPKα2-reduced cells, suggesting that AMPKα2 regulates UCP2 levels. CONCLUSIONS/INTERPRETATION: We have demonstrated that GT1-7 cells closely mimic GE neuron glucose-sensing behaviour, and reducing AMPKα2 blunts their responsiveness to hypoglycaemic challenge, possibly by altering UCP2 activity. These results show that suppression of AMPKα2 activity inhibits normal glucose-sensing behaviour and may contribute to defective detection of hypoglycaemia.This study was funded by: grants from the Wellcome Trust (grant numbers 068692 and 086989) and Diabetes UK (grant number RD08/0003681) to M.L.J. Ashford; a Juvenile Diabetes Research Foundation (JDRF) Postdoctoral Fellowship to C. Beall (grant number 3-576-2010); grants from JDRF and European Foundation for the study of Diabetes to R.J. McCrimmon, and from the British Heart Foundation to A. Jovanović

Television Viewing and Incident Cardiovascular Disease: Prospective Associations and Mediation Analysis in the EPIC Norfolk Study

Background: Although television viewing time is detrimentally associated with intermediate cardiovascular risk factors, the relationship with incident total (i.e. combined fatal and non-fatal) cardiovascular disease (CVD), non-fatal CVD and coronary heart disease is largely unknown. This study examined whether television viewing time is associated with these three outcomes, independently of physical activity energy expenditure and other confounding variables. Methodology/Principal Findings: A population-based cohort of 12,608 men and women (aged 61.4 +/- 9.0), free from stroke, myocardial infarction and cancer at baseline in 1998-2000 were followed up until 2007 (6.9 +/- 1.9 years). Participants self-reported education, smoking, alcohol use, antihypertensive, lipid lowering and antidepressant medication, disease history, total energy intake, sleep duration, physical activity and television viewing. BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol and glycated haemoglobin (HbA(1c)) were measured by standardized procedures; a clustered metabolic risk score was constructed. Every one hour/day increase in television viewing was associated with an increased hazard for total (HR = 1.06, 95% CI = 1.03-1.08; 2,620 cases), non-fatal CVD (HR = 1.06, 95% CI = 1.03-1.09; 2,134 cases), and coronary heart disease (HR = 1.08, 95% CI = 1.03-1.13; 940 cases), independent of gender, age, education, smoking, alcohol, medication, diabetes status, CVD family history, sleep duration and physical activity energy expenditure. Energy intake, BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol, HbA(1c) and the clustered metabolic risk score only partially mediated these associations. Conclusions: These results indicate that the most prevalent leisure time (sedentary) behaviour, television viewing, independently contributes to increased CVD risk. Recommendations on reducing television viewing time should be considered

Objective vs. Self-Reported Physical Activity and Sedentary Time: Effects of Measurement Method on Relationships with Risk Biomarkers

<p><b>Purpose:</b> Imprecise measurement of physical activity variables might attenuate estimates of the beneficial effects of activity on health-related outcomes. We aimed to compare the cardiometabolic risk factor dose-response relationships for physical activity and sedentary behaviour between accelerometer- and questionnaire-based activity measures.</p> <p><b>Methods:</b> Physical activity and sedentary behaviour were assessed in 317 adults by 7-day accelerometry and International Physical Activity Questionnaire (IPAQ). Fasting blood was taken to determine insulin, glucose, triglyceride and total, LDL and HDL cholesterol concentrations and homeostasis model-estimated insulin resistance (HOMAIR). Waist circumference, BMI, body fat percentage and blood pressure were also measured.</p> <p><b>Results:</b> For both accelerometer-derived sedentary time (<100 counts.min−1) and IPAQ-reported sitting time significant positive (negative for HDL cholesterol) relationships were observed with all measured risk factors – i.e. increased sedentary behaviour was associated with increased risk (all p≤0.01). However, for HOMAIR and insulin the regression coefficients were >50% lower for the IPAQ-reported compared to the accelerometer-derived measure (p<0.0001 for both interactions). The relationships for moderate-to-vigorous physical activity (MVPA) and risk factors were less strong than those observed for sedentary behaviours, but significant negative relationships were observed for both accelerometer and IPAQ MVPA measures with glucose, and insulin and HOMAIR values (all p<0.05). For accelerometer-derived MVPA only, additional negative relationships were seen with triglyceride, total cholesterol and LDL cholesterol concentrations, BMI, waist circumference and percentage body fat, and a positive relationship was evident with HDL cholesterol (p = 0.0002). Regression coefficients for HOMAIR, insulin and triglyceride were 43–50% lower for the IPAQ-reported compared to the accelerometer-derived MVPA measure (all p≤0.01).</p> <p><b>Conclusion:</b> Using the IPAQ to determine sitting time and MVPA reveals some, but not all, relationships between these activity measures and metabolic and vascular disease risk factors. Using this self-report method to quantify activity can therefore underestimate the strength of some relationships with risk factors.</p&gt

Behavioral responses to injury and death in wild Barbary macaques (Macaca sylvanus)

The wounding or death of a conspecific has been shown to elicit varied behavioral responses throughout thanatology. Recently, a number of reports have presented contentious evidence of epimeletic behavior towards the dying and dead among non-human animals, a behavioral trait previously considered uniquely human. Here, we report on the behavioral responses of Barbary macaques, a social, non-human primate, to the deaths of four group members (one high-ranking adult female, one high-ranking adult male, one juvenile male, and one female infant), all caused by road traffic accidents. Responses appeared to vary based on the nature of the death (protracted or instant) and the age class of the deceased. Responses included several behaviors with potential adaptive explanations or consequences. These included exploration, caretaking (guarding, carrying, and grooming), and proximity to wounded individuals or corpses, and immediate as well as longer-lasting distress behaviors from other group members following death, all of which have been reported in other non-human primate species. These observations add to a growing body of comparative evolutionary analysis of primate thanatology and help to highlight the multifaceted impacts of human-induced fatalities on an endangered and socially complex primate. © 2016, Japan Monkey Centre and Springer Japan

Excessive TV viewing and cardiovascular disease risk factors in adolescents. The AVENA cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Excessive television (TV) viewing might play an important role in the development of cardiovascular disease (CVD). The aim of this study was to examine the independent associations between TV viewing and CVD risk factors in adolescents.</p> <p>Methods</p> <p>A sample of 425 adolescents, aged 13- to 18.5-year-old, was included in this study. Body mass index (BMI), waist circumference (WC), glucose, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, apolipoprotein (apo) A-1, apo B-100, and lipoprotein(a) levels were determined. A composite CVD risk score was computed based on age-, sex-, sexual maturation- and race-standardized triglycerides, HDL-cholesterol, LDL-cholesterol and glucose. TV viewing was self-reported.</p> <p>Results</p> <p>Two hundred and twenty-five adolescents (53%) who spent >3 hrs/day watching TV were considered as the "high TV viewing" group. Ninety-nine adolescents (23%) from the total sample were classified as overweight according to International age- and sex-specific BMI values. The high TV viewing group had significantly less favorable values of HDL-cholesterol, glucose, apo A1 and CVD score, independent of age, sex, sexual maturation, race and weight status. There was a significant interaction effect of TV viewing × weight status (P = 0.002) on WC, and the negative influence of TV viewing on WC persisted in the overweight group (P = 0.031) but was attenuated in non-overweight adolescents (P > 0.05).</p> <p>Conclusion</p> <p>Excessive TV viewing seems to be related to an unfavorable CVD risk factors profile in adolescence. Reducing TV viewing in overweight adolescents might be beneficial to decrease abdominal body fat.</p

Low back pain as the presenting sign in a patient with primary extradural melanoma of the thoracic spine - A metastatic disease 17 Years after complete surgical resection

Primary spinal melanomas are extremely rare lesions. In 1906, Hirschberg reported the first primary spinal melanoma, and since then only 40 new cases have been reported. A 47-year-old man was admitted suffering from low back pain, fatigue and loss of body weight persisting for three months. He had a 17-year-old history of an operated primary spinal melanoma from T7-T9, which had remained stable for these 17 years. Routine laboratory findings and clinical symptoms aroused suspicion of a metastatic disease. Multislice computed tomography and magnetic resonance imaging revealed stage-IV melanoma with thoracic, abdominal and skeletal metastases without the recurrence of the primary process. Transiliac crest core bone biopsy confirmed the diagnosis of metastatic melanoma. It is important to know that in all cases of back ore skeletal pain and unexplained weight loss, malignancy must always be considered in the differential diagnosis, especially in the subjects with a positive medical history. Patients who have back, skeletal, or joint pain that is unresponsive to a few weeks of conservative treatment or have known risk factors with or without serious etiology, are candidates for imaging studies. The present case demonstrates that complete surgical resection alone may result in a favourable outcome, but regular medical follow-up for an extended period, with the purpose of an early detection of a metastatic disease, is highly recommended

Non-linear stimulus-response behavior of the human stance control system is predicted by optimization of a system with sensory and motor noise

We developed a theory of human stance control that predicted (1) how subjects re-weight their utilization of proprioceptive and graviceptive orientation information in experiments where eyes closed stance was perturbed by surface-tilt stimuli with different amplitudes, (2) the experimentally observed increase in body sway variability (i.e. the “remnant” body sway that could not be attributed to the stimulus) with increasing surface-tilt amplitude, (3) neural controller feedback gains that determine the amount of corrective torque generated in relation to sensory cues signaling body orientation, and (4) the magnitude and structure of spontaneous body sway. Responses to surface-tilt perturbations with different amplitudes were interpreted using a feedback control model to determine control parameters and changes in these parameters with stimulus amplitude. Different combinations of internal sensory and/or motor noise sources were added to the model to identify the properties of noise sources that were able to account for the experimental remnant sway characteristics. Various behavioral criteria were investigated to determine if optimization of these criteria could predict the identified model parameters and amplitude-dependent parameter changes. Robust findings were that remnant sway characteristics were best predicted by models that included both sensory and motor noise, the graviceptive noise magnitude was about ten times larger than the proprioceptive noise, and noise sources with signal-dependent properties provided better explanations of remnant sway. Overall results indicate that humans dynamically weight sensory system contributions to stance control and tune their corrective responses to minimize the energetic effects of sensory noise and external stimuli

A novel therapeutic approach: Blocking Glioblastoma cells’ interaction with their microenvironment

Abstract Due to the highly invasive nature of Glioblastoma (GB), complete surgical resection is not feasible, while motile tumour cells are often associated with several specific brain structures that enhance treatment-resistance. Here, we investigate the therapeutic potential of Disulfiram and Carbenoxolone, that inhibit two distinct interactions between GB and the brain tissue microenvironment: stress-induced cell-matrix adhesion and gap junction mediated cell-cell communication, respectively. Increase in cell numbers of tumour-initiating cells, which are cultured in suspension as cell clusters, and adherent differentiated cells can be blocked to a similar extent by Carbenoxolone, as both cell populations form gap junctions, but the adherent differentiated cells are much more sensitive to Disulfiram treatment, which – via modulation of NF-κB signalling – interferes with cell-substrate adhesion. Interestingly, inducing adhesion in tumour-initiating cells without differentiating them does not sensitize for Disulfiram. Importantly, combining Disulfiram, Carbenoxolone and the standard chemotherapeutic drug Temozolomide reduces tumour size in an orthotopic mouse model. Isolating GB cells from their direct environment within the brain represents an important addition to current therapeutic approaches. The blockage of cellular interactions via the clinically relevant substances Disulfiram and Carbenoxolone, has distinct effects on different cell populations within a tumour, potentially reducing motility and/or resistance to apoptosis