Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans

Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the μ-OR sub-type. In a sample of healthy volunteers, we used [11C]-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4–100 mg) or NTX (range, 2–50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50=7.10 ng ml−1) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-β-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration–RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Modeling of industrial styrene polymerization reactors

Steady-state modeling and simulation of thermally initiated bulk polymerization of styrene in a train of existing industrial reactors is presented. Two reactors of different geometry and flow arrangement, which operate in series, are modeled as plug flow reactors. The model of Arai et al. (8) for the kinetics of thermal polymerization of polystyrene is used. The model predictions agree well with plant data for different operating conditions. A parametric study shows the feed rate, diluent (ethyl benzene) concentration and reactor temperatures to have a significant effect on final conversion and molecular weight

Results of 10-Joule wire-burn test performed on 70 kV rail-gap crowbar protection system for high power klystrons and gyrotron

Pulsed and continuous high power microwave tubes need to be protected against arc faults within the tube. If the energy dumped in such arc fault is more than the critical crater energy of the tube, irreparable damage can occur. Modern switch mode powers supplies (SMPS) that are generally opted for the new systems store little energy and are capable of switching HV in few microseconds. So they do not need separate protection. However, when conventional power supplies feed high power microwave tubes a reliable crowbar protection system, tested separately to limit the energy, must be used to assure the tube safety. Initial testing and commissioning of two klystrons, TH2103D have been carried out at our Institute. Each of these klystrons is capable of delivering 500 kW at 3.7 GHz, to be used for non-inductive lower hybrid current drive (LHCD) In the Steady-State Superconducting Tokamak-1 (SST-1). Commissioning of the gyrotron VGA8000A19, for breakdown and electron cyclotron resonant heating (ECRH) experiments on Aditya tokamak, has also been carried out.© IEE