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

The role of primary healthcare professionals in oral cancer prevention and detection

AIM: To investigate current knowledge, examination habits and preventive practices of primary healthcare professionals in Scotland, with respect to oral cancer, and to determine any relevant training needs. SETTING: Primary care. METHOD: Questionnaires were sent to a random sample of 357 general medical practitioners (GMPs) and 331 dental practitioners throughout Scotland. Additionally, focus group research and interviews were conducted amongst primary healthcare team members. RESULTS: Whilst 58% of dental respondents reported examining regularly for signs of oral cancer, GMPs examined patients' mouths usually in response to a complaint of soreness. The majority of GMPs (85%) and dentists (63%) indicated that they felt less than confident in detecting oral cancer, with over 70% of GMPs identifying lack of training as an important barrier. Many practitioners were unclear concerning the relative importance of the presence of potentially malignant lesions in the oral cavity. A high proportion of the GMPs indicated that they should have a major role to play in oral cancer detection (66%) but many felt strongly that this should be primarily the remit of the dental team. CONCLUSION: The study revealed a need for continuing education programmes for primary care practitioners in oral cancer-related activities. This should aim to improve diagnostic skills and seek to increase practitioners' participation in preventive activities

Middle Neolithic pits and a burial at West Amesbury, Wiltshire

Excavations on the south-eastern slopes of King Barrow Ridge, 1.5 km east of Stonehenge, revealed five pits, a grave and other features of Middle Neolithic date. Analysis of the pit assemblages and the partial inhumation interred in the grave has provided insights into lifeways in this landscape in the late fourth millennium cal BC. Evidence suggests that the area was visited by a pastoralist, mobile community on a semi-regular basis for a significant period, in late autumn or winter. Selected remnants of craft-working and consumption were deposited in pits, before deliberate infilling. These depositions repeatedly memorialised activity on the hillside at a time of contemporary activity elsewhere on King Barrow Ridge and at the future site of Stonehenge. Middle Neolithic pits are present in significant numbers across King Barrow Ridge, and alongside pits in the Durrington area, form one of the densest concentrations of such activity in the region. Long distance mobility is suggested by the possible Irish origins of the inhumation, the first Middle Neolithic individual excavated in the environs of Stonehenge. Whilst of significance for understanding the Middle Neolithic in the WHS and the region, this research also hints at the roots of Late Neolithic monumentalisation of this landscape

Prognostic factors in solitary plasmacytoma of the bone: a multicenter Rare Cancer Network study

BACKGROUND: Solitary plasmacytoma (SP) of the bone is a rare plasma-cell neoplasm. There are no conclusive data in the literature on the optimal radiation therapy (RT) dose in SP. Therefore, in this large retrospective study, we wanted to assess the outcome, prognostic factors, and the optimal RT dose in patients with SP. METHODS: Data from 206 patients with bone SP without evidence of multiple myeloma (MM) were collected. Histopathological diagnosis was obtained for all patients. The majority (n = 169) of the patients received RT alone; 32 chemotherapy and RT, and 5 surgery. Median follow-up was 54 months (7–245). RESULTS: Five-year overall survival, disease-free survival (DFS), and local control was 70%, 46%, and 88%; respectively. Median time to MM development was 21 months (2–135) with a 5-year probability of 51%. In multivariate analyses, favorable factors were younger age and tumor size < 5 cm for survival; younger age for DFS; anatomic localization (vertebra vs. other) for local control. Older age was the only predictor for MM. There was no dose-response relationship for doses 30 Gy or higher, even for larger tumors. CONCLUSION: Younger patients, especially those with vertebral localization have the best outcome when treated with moderate-dose RT. Progression to MM remains the main problem. Further investigation should focus on adjuvant chemotherapy and/or novel therapeutic agents