Angiotensin type 1 receptor antagonists induce human in-vitro adipogenesis through peroxisome proliferator-activated receptor-gamma activation

OBJECTIVE: In clonal animal cells, certain angiotensin receptor blockers (ARB) activate the peroxisome proliferator-activated receptor-gamma (PPARgamma). The aim of this work was to validate that observation in human cells and humans. METHODS: We investigated the induction of in-vitro adipogenesis and the activation of PPARgamma-target genes, adiponectin and lipoprotein lipase, by ARB in human preadipocytes. We also studied PPARgamma response-element-driven luciferase reporter gene activation in human adipocytes. Finally, we treated 14 obese men for 10 days with placebo crossed over with 150 mg/day irbesartan. Subcutaneous fat was analyzed for mRNA expression of adiponectin and lipoprotein lipase. RESULTS: Telmisartan and irbesartan, and to a lesser degree losartan, induced adipogenesis and activated PPARgamma-target genes. This stimulation of PPARgamma-target genes was prevented by the PPARgamma antagonist GW9662. Eprosartan had no effect. Paradoxically, all ARB activated the luciferase reporter gene. PPARgamma activity increased approximately two-fold with pioglitazone and 1.5-fold with the ARB in all assays. In the cross-over clinical study, irbesartan lowered blood pressure but had no effect on adiponectin or lipoprotein lipase mRNA expression. CONCLUSIONS: Our data are the first to show that ARB induce adipogenesis and PPARgamma-target gene expression in human adipocytes. Pharmacokinetic differences may contribute to the heterogeneous effects on metabolism and preadipocyte differentiation. In humans, larger doses of ARB, longer treatments, or both may be required to activate PPARgamma in adipose cells.     

Beta-adrenergic and atrial natriuretic peptide interactions on human cardiovascular and metabolic regulation

CONTEXT: Atrial natriuretic peptide (ANP) has well-known cardiovascular effects and modifies lipid and carbohydrate metabolism in humans. OBJECTIVE: The objective of the study was to determine the metabolic and cardiovascular interaction of beta-adrenergic receptors and ANP. DESIGN: This was a crossover study, conducted 2004-2005. Setting: The study was conducted at an academic clinical research center. Patients: Patients included 10 healthy young male subjects (body mass index 24 +/- 1 kg/m2). INTERVENTION: We infused iv incremental ANP doses (6.25, 12.5, and 25 ng/kg.min) with and without propranolol (0.20 mg/kg in divided doses followed by 0.033 mg/kg.h infusion). Metabolism was monitored through venous blood sampling, im, and sc microdialysis and indirect calorimetry. Cardiovascular changes were monitored by continuous electrocardiogram and beat-by-beat blood pressure recordings. MAIN OUTCOME MEASURES: Venous nonesterified fatty acid, glycerol, glucose, and insulin; and microdialysate glucose, glycerol, lactate, and pyruvate were measured. RESULTS: ANP increased heart rate dose dependently. beta-Adrenergic receptor blockade abolished the response. ANP elicited a dose-dependent increase in serum nonesterified fatty acid and glycerol concentrations. The response was not suppressed with propranolol. Venous glucose and insulin concentrations increased with ANP, both without or with propranolol. ANP induced lipid mobilization in sc adipose tissue. In skeletal muscle, microdialysate lactate increased, whereas the lactate to pyruvate ratio decreased, both with and without propranolol. Higher ANP doses increased lipid oxidation, whereas energy expenditure remained unchanged. Propranolol tended to attenuate the increase in lipid oxidation. CONCLUSIONS: Selected cardiovascular ANP effects are at least partly mediated by beta-adrenergic receptor stimulation. ANP-induced changes in lipid mobilization and glycolysis are mediated by another mechanism, presumably stimulation of natriuretic peptide receptors, whereas substrate oxidation might be modulated through adrenergic mechanisms.     

A family with hereditary thrombocythaemia and normal genes for thrombopoietin and c-Mpl

Hereditary thrombocythaemia (HT) is an inherited autosomal dominant disorder. Recent studies reported six different mutations, four within the thrombopoietin (TPO) gene and two within c-Mpl (TPO receptor) gene in six unrelated families with HT. This study investigated the molecular basis of hereditary thrombocythaemia in an Israeli-Jewish family. We screened the genes for TPO and c-Mpl by amplification and sequencing of all the corresponding exons including exon/intron boundaries and promoters. In addition, plasma levels of TPO and erythropoietin (EPO) were measured. No abnormality in the TPO/c-Mpl genes has been identified in affected HT family members. Plasma TPO and EPO levels were found to be normal/low or normal respectively in the individuals affected. In conclusion, lack of a molecular lesion within either TPO or cMpl genes indicate that HT may be caused by factors other than TPO-cMpl axis in this family.     

Statistical Mapping of Speckle Autocorrelation for Visualization of Hyperaemic Responses to Cortical Stimulation

Statistically mapped speckle autocorrelation images (SAR) were used to track the hemodynamically active perfusion regions in the rat cortex during and following DC current stimulation with high transverse spatial resolution (38 um). The SAR images provided a spatio-temporal information about the net activation patterns of Cerebral Blood Flow (CBF) changes over a period of time as against those changes for each frame interval estimated using spatial contrasts derived from the first order spatial statistics. Thus the information about the relative maxima of perfusion during a Transient Hyperaemic Episode (THE) across different regions in the imaging window could be identified without the need for actually having to estimate the spatial contrast maps of the imaged region for each frame contained in the time window of observation. With the application of DC stimulation, the regions with a high correlation in the temporal fluctuations were representative of the areas that underwent least changes in activation. By varying the intensity of stimulation, THEs were observed for stimulation current densities in the range 0.1–3.8 mA/mm² using both the derived speckle contrast maps and concurrently on a Laser Doppler Flow meter, with its probe positioned 1 mm from the site of stimulation. For current densities below the lower threshold of stimulation, the SAR images revealed an unprecedented reduction in the surge amplitude at sites distal to the region of stimulation. This was accompanied by an increase in pixel areas representing minimally active regions of perfusion (“perfusion islets”) with no identifiable peak in the hemodynamic responses estimated from speckle contrast variations. The SAR images can be a useful tool for visualization of slow wave perfusion dynamics during cortical stimulation.     

The Israel Center for Medical Simulation: a paradigm for cultural change in medical education.

Simulation-based medical education (SBME) is a rapidly growing field, as is illustrated by the increased development of simulation centers worldwide. SBME is becoming a powerful force in addressing the need to increase patient safety through quality-care training. Recognizing the benefits of SBME, increasing numbers of bodies involved in medical and health care education and training are establishing simulation centers worldwide. The general model of most facilities focuses on a single simulation modality or a specific branch of medicine or health care, limiting their overall impact on patient safety and quality of care across the health care systems. MSR, the Israel Center for Medical Simulation, is a comprehensive, national, multimodality, multidisciplinary medical simulation center dedicated to enhancing hands-on medical education, performance assessment, patient safety, and quality of care by improving clinical and communication skills. The center uses an "error-driven" educational approach, which recognizes that errors provide an opportunity to create a unique beneficial learning experience. The authors present the Israeli experience as an alternative model, and describe the impact of the MSR model on the Israeli medical community during four years of activity. They also describe the opportunities this model has opened towards changing the culture of medical education and patient safety within Israel Although this model may require modification when implemented in other medical systems, it highlights important lessons regarding the power of SBME in triggering and bringing about cultural changes in traditional medical education.     

Long-term memory for aversive training is impaired in Idua(-/-) mice, a genetic model of mucopolysaccharidosis type I

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease that leads to neurodegeneration and neurological deficits, among other pathological and clinical consequences. The aim of the present study was to evaluate neurobehavioral parameters in a genetic mouse model of mucopolysaccharidosis type I (MPS I). During exploration of an open field, adult MPS I (Idua(-/-)) mice showed normal locomotion and anxiety but reduced number of rearings. Idua(-/-) mice performed normally in a novel object recognition memory task and showed normal short-term retention of inhibitory avoidance training. By contrast, long-term retention of inhibitory avoidance was impaired in Idua(-/-) mice. The deficit in inhibitory avoidance memory could not be attributed to reduced footshock reactivity. The results indicate that Idua(-/-) mice present deficits in long-term memory for aversive training and reduced exploratory behavior.