ATP-Citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids and their gamma-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo

A series of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids have been synthesized and evaluated as inhibitors of the recombinant human form of ATP-citrate lyase. The best of these have Ki's in the 200-1000 nM range. As the corresponding thermodynamically favored gamma-lactone prodrugs, a number of compounds are able to inhibit cholesterol and fatty acid synthesis in HepG2 cells and reduce plasma triglyceride levels in vivo. The best of these, compound 77, is able to induce clear hypocholesterolemic and hypotriglyceridaemic responses when administered orally to rat and dog. These results provide evidence to support the hypothesis that compounds which inhibit ATP-citrate lyase have the potential to be a novel class of hypolipidemic agent, which possess combined hypocholesterolemic and hypotriglyceridemic activities.     

Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent

Thalidomide has been shown to be an inhibitor of angiogenesis in a rabbit cornea micropocket model; however, it has failed to demonstrate this activity in other models. These results suggest that the anti-angiogenic effects of thalidomide may only be observed following metabolic activation of the compound. This activation process may be species specific, similar to the teratogenic properties associated with thalidomide. Using a rat aorta model and human aortic endothelial cells, we co-incubated thalidomide in the presence of either human, rabbit, or rat liver microsomes. These experiments demonstrated that thalidomide inhibited microvessel formation from rat aortas and slowed human aortic endothelial cell proliferation in the presence of human or rabbit microsomes, but not in the presence of rat microsomes. In the absence of microsomes, thalidomide had no effect on either microvessel formation or cell proliferation, thus demonstrating that a metabolite of thalidomide is responsible for its anti-angiogenic effects and that this metabolite can be formed in both humans and rabbits, but not in rodents.     

Psychologists as managers: Overcoming old guilts and accessing innovative pathways for enhanced skills.

Management roles for psychologists now offer promising career opportunities for using psychological techniques for enhancing the health as well as the productivity of organizations and their employees. Although many psychologists recognize this, they lack more specific information about bridging the gap between the desire to become a manager and the taking of concrete steps to actually become one. Emerging practice arenas, support systems, and training opportunities for psychologists who want to become managers are discussed. Psychologists can learn to be better managers and can benefit by tying into managerially oriented, educational, and professional networks. At the same time, old guilts about being a managerial or entrepreneurial psychologist may linger and need to be overcome. Specific opportunities for psychologists in innovative areas of practice, research, and consultation that require managerial knowledge and skills are identified. (27 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Use of intra-aortic balloon pumping (IABP) in clinical cardiac surgery and management of patients with IABP

One hundred thirty eight patients were reviewed which required IABP assist. Sixty nine (84 per cent) of 82 patients who had been able to come off cardiopulmonary bypass despite increasing pharmacologic support survived operation and 56 patients (68 per cent) discharged hospital. Twenty three (75 per cent) of 31 patients who took for elective coronary artery surgery as extremely high risk because of extensive three vessel coronary artery disease and severely compromised left ventricular function discharged hospital. In summary, hospital death was 35 per cent, late death 12 per cent and long term survivors 54 per cent. Severe complication concerned with inserting balloon catheter occurred in two cases (1.4 per cent) which were abdominal aortic dissection and laceration of iliac artery. At the present time, the primary indication for IABP is in assistance of the open heart surgical patient. Thre are three important factors in successfully managing the patients with IABP. First, begin IABP assist as soon as possible if indicated. Second, keep an adequate circulating volume with mean left atrial pressure being maintained around 20 mmHg and cardiac index at 2.1 L/min./M or greater. Third, improve the peripheral vascular circulation, which might need peripheral vasodilator.     

Correlation of glucose consumption and tumor cell density in astrocytomas. A stereotactic PET study

To determine histological correlates of the variability of glucose consumption in astrocytomas, the authors performed positron emission tomography (PET) with 18F-2-fluoro-2-deoxy-D-glucose (FDG) and matched the PET scans three-dimensionally with computerized tomography scans obtained in a stereotactic frame before biopsy. Ten patients with astrocytomas of World Health Organization Grade 2 or 3 were studied; patients with glioblastomas, oligodendrogliomas, or oligoastrocytomas were excluded from the study to avoid any confounding effects of different cell types and necroses. In samples of pure tumor, glucose consumption correlated significantly with cell density, but not with nuclear polymorphism. It is concluded that tumor cell density is a major determinant of glucose consumption in astrocytomas. The use of PET with FDG may help to locate the highest cell density and thus improve the diagnostic yield of stereotactic biopsy.