Sustained zero-order delivery of GC-1 from a nanochannel membrane device alleviates metabolic syndrome.

BACKGROUND/OBJECTIVES: Our objective was to assess the sustained, low-dose and constant administration of the thyroid receptor-ß (TRß)-selective agonist GC-1 (sobetirome) from a novel nanochannel membrane device (NMD) for drug delivery. As it known to speed up metabolism, accomplish weight loss, improve cholesterol levels and possess anti-diabetic effects, GC-1 was steadily administered by our NMD, consisting of an implantable nanochannel membrane, as an alternative to conventional daily administration, which is subject to compliance issues in clinical settings. SUBJECTS/METHODS: Diet-induced obese C57BL/J6 male mice were fed a very high-fat diet (VHFD) and received NMD implants subcutaneously. Ten mice per group received capsules containing GC-1 or phosphate-buffered saline (control). Weight, lean and fat mass, as well as cholesterol, triglycerides, insulin and glucose, were monitored for 24 days. After treatment, plasma levels of thyroid-stimulating hormone (TSH) and thyroxine were compared. mRNA levels of a panel of thermogenic markers were examined using real-time PCR in white adipose tissue (WAT) and brown adipose tissue (BAT). Adipose tissue, liver and local inflammatory response to the implant were examined histologically. Pancreatic islet number and ß-cell area were assessed. RESULTS: GC-1 released from the NMD reversed VHFD-induced obesity and normalized serum cholesterol and glycemia. Significant reductions in body weight and fat mass were observed within 10 days, whereas reductions in serum cholesterol and glucose levels were seen within 7 days. The significant decrease in TSH was consistent with TRß selectivity for GC-1. Levels of transcript for Ucp1 and thermogenic genes PGC1a, Cidea, Dio2 and Cox5a showed significant upregulation in WAT in NMD-GC-1-treated mice, but decreased in BAT. Although mice treated by NMD-GC-1 showed a similar number of pancreatic islets, they exhibited significant increase in ß-cell area. CONCLUSIONS: Our data demonstrate that the NMD implant achieves steady administration of GC-1, offering an effective and tightly controlled molecular delivery system for treatment of obesity and metabolic disease, thereby addressing compliance.

Assessing the perception and reality of arguments against thermal waste treatment plants in terms of property prices.

The thermal processing of waste materials, although considered to be an essential part of waste management, is often sharply contested in the UK. Arguments such as health, depletion of resources, cost, noise, odours, traffic movement and house prices are often cited as reasons against the development of such facilities. This study aims to review the arguments and identify any effect on property prices due to the public perception of the plant. A selection of existing energy from waste (EfW) facilities in the UK, operational for at least 7 years, was selected and property sales data, within 5 km of the sites, was acquired and analysed in detail. The locations of the properties were calculated in relation to the plant using GIS software (ArcGIS) and the distances split into 5 zones ranging from 0 to 5 km from the site. The local property sale prices, normalised against the local house price index, were compared in two time periods, before and after the facility became operational, across each of the 5 zones. In all cases analysed no significant negative effect was observed on property prices at any distance within 5 km from a modern operational incinerator. This indicated that the perceived negative effect of the thermal processing of waste on local property values is negligible.

Intraoperative transesophageal echocardiography and epiaortic ultrasound for assessment of atherosclerosis of the thoracic aorta.

OBJECTIVES: This study sought to determine the role of transesophageal echocardiography (TEE) and epiaortic ultrasound in the detection of atherosclerosis of the ascending aorta in patients undergoing cardiac surgery. BACKGROUND: Atherosclerosis of the ascending aorta is a major risk factor for perioperative stroke and systemic embolism in patients undergoing cardiac surgery. METHODS: Forty-four patients underwent prospective evaluation of the ascending aorta with two ultrasound techniques-epiaortic ultrasound and biplane TEE-and by palpation. The severity of atherosclerosis was graded on a four-point scale as normal, mild, moderate or severe. RESULTS: A comparison of results with biplane TEE and those with epiaortic ultrasound yielded a kappa value of 0.12 (95% confidence interval 0 to 0.25), indicating poor correlation between the two. Compared with epiaortic ultrasound, biplane TEE significantly underestimated the severity of ascending aortic atherosclerosis, and this underestimation was more marked in the distal ascending aorta (p < 0.0001). When compared with epiaortic ultrasound and biplane TEE, palpation of the ascending aorta significantly underestimated the presence and severity of atherosclerosis (p < 0.0001 for both). CONCLUSIONS: Epiaortic ultrasound is more accurate than TEE for identification of atherosclerosis of the ascending aorta, but both ultrasound techniques are superior to palpation. Epiaortic ultrasound and TEE provide complementary information regarding thoracic aortic atherosclerosis. Modification of surgical technique on the basis of results of intraoperative epiaortic ultrasound and TEE in elderly patients undergoing cardiac procedures may prevent atheroembolic complications.

Thrombosis of mitral valve bioprostheses in patients requiring circulatory assistance.

Two patients with new mitral valve bioprostheses required implantation of Bio-Medicus centrifugal pumps (Bio-Medicus, Minneapolis, MN) for circulatory support and had evidence of prosthetic valve thrombosis 1 and 4 days later. Both patients died of thromboembolic complications despite surgical removal of the thrombus. Thrombosis is a rare early complication of bioprosthetic valves and in these cases was probably related to low transvalvular flow due to the use of circulatory assist devices. We discuss possible strategies for avoiding and managing this catastrophic complication.

In vitro insulin-stimulated conversion of [U-14C]glucose to 14CO2 by rat thymocytes.

Addition of bovine insulin to thymocytes from adrenalectomized rats resulted in stimulation of [U-14C]glucose conversion to 14CO2. A significant enhancement of 14CO2 formation by insulin occurred by 30 min of incubation, and was consistently observed at an insulin concentration of 10(-8) M. The response to insulin was similar at 0.55 and 1.1 mM glucose, and was obtained at three cell concentrations (0.5, 1.0, 2.0 X 10(8) cells/ml). The incorporation of [3H]leucine into trichloroacetic acid-precipitable material was significantly increased by 10(-6) and 10(-8) M insulin. Cycloheximide, at a level of 2.5 X 10(-5) M, suppressed [3H]leucine incorporation by 93% and inhibited the stimulation of 14CO2 formation by insulin. We conclude that insulin can enhance the formation of 14CO2 from [U-14C]glucose by thymocytes in vitro, and that this response may require the synthesis of one or more proteins.