Effects of the peroxisomal proliferator-activated receptor-gamma agonist pioglitazone on renal and hormonal responses to salt in healthy men.

Glitazones are used in the treatment of type 2 diabetes as efficient insulin sensitizers. They can, however, induce peripheral edema through an unknown mechanism in up to 18% of cases. In this double-blind, randomized, placebo-controlled, four-way, cross-over study, we examined the effects of a 6-wk administration of pioglitazone (45 mg daily) or placebo on the blood pressure, hormonal, and renal hemodynamic and tubular responses to a low (LS) and a high (HS) sodium diet in healthy volunteers. Pioglitazone had no effect on the systemic and renal hemodynamic responses to salt, except for an increase in daytime heart rate. Urinary sodium excretion and lithium clearance were lower with pioglitazone, particularly with the LS diet (P < 0.05), suggesting increased sodium reabsorption at the proximal tubule. Pioglitazone significantly increased plasma renin activity with the LS (P = 0.02) and HS (P = 0.03) diets. Similar trends were observed with aldosterone. Atrial natriuretic levels did not change with pioglitazone. Body weight increased with pioglitazone in most subjects. Pioglitazone stimulates plasma renin activity and favors sodium retention and weight gain in healthy volunteers. These effects could contribute to the development of edema in some subjects treated with glitazones.

Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery.

The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared irinotecan in combination with 5-fluorouracil and leucovorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investigated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are coinvestigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era.

Mechanisms of angiogenesis impairment by radiation therapy

Summary : Clinical evidence indicates that tumors recurring within previously irradiated fields are highly invasive and metastatic, suggesting a role of the tumor stroma in this effect. Angiogenesis plays a critical role in tumor progression. Ionizing radiation is known to induce apoptosis of angiogenic endothelial cells, while the effect on quiescent endothelial cells and de novo angiogenesis is not well characterized. We recently observed that irradiation of normal tissue prevents tumor- and growth factor-induced angiogenesis. The main aim of my thesis work was to characterize the mechanisms of radiation-mediated inhibition of angiogenesis. To this purpose we used a combination of in vivo and ex vivo studies on irradiated healthy tissue, and in vitro irradiation experiments using angiogenesis models and isolated endothelial cells. We found that irradiation did not induce endothelial cell apoptosis and did not disrupt quiescent vessels within irradiated skin. Radiation reduced the recruitment of leukocytes to angiogenic Matrigel plugs, but this effect was rather secondary to decreased angiogenesis, as exogenous addition of leucocytes to Matrigel plugs did not rescue the angiogenesis defects. To ascertain the direct effect of radiation on endothelial cells, we used the mouse aortic ring assay to test the sprouting capacity of irradiated endothelial cells ex vivo and in vitro, and found that irradiation completely suppressed endothelial cell sprouting. Using HUVEC cells, we showed that irradiation of quiescent confluent endothelial cells did not induce cell death but suppressed subsequent migration and cell proliferation and induced senescence. By Western blotting, we observed a rapid and sustained increase in p21 levels, previously shown to be activated by p53 in response to double strand break, and mediating senescence in human cells. Current experiments focus on the mechanism of sustained p21 upregulation and its role in reduced migration. Inhibition of endothelial cell migration and proliferation by radiation may explain reduced angiogenesis in tumors growing in previously irradiated fields.

Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene.

Fasting is associated with significant changes in nutrient metabolism, many of which are governed by transcription factors that regulate the expression of rate-limiting enzymes. One factor that plays an important role in the metabolic response to fasting is the peroxisome proliferator-activated receptor alpha (PPARalpha). To gain more insight into the role of PPARalpha during fasting, and into the regulation of metabolism during fasting in general, a search for unknown PPARalpha target genes was performed. Using subtractive hybridization (SABRE) comparing liver mRNA from wild-type and PPARalpha null mice, we isolated a novel PPARalpha target gene, encoding the secreted protein FIAF (for fasting induced adipose factor), that belongs to the family of fibrinogen/angiopoietin-like proteins. FIAF is predominantly expressed in adipose tissue and is strongly up-regulated by fasting in white adipose tissue and liver. Moreover, FIAF mRNA is decreased in white adipose tissue of PPARgamma +/- mice. FIAF protein can be detected in various tissues and in blood plasma, suggesting that FIAF has an endocrine function. Its plasma abundance is increased by fasting and decreased by chronic high fat feeding. The data suggest that FIAF represents a novel endocrine signal involved in the regulation of metabolism, especially under fasting conditions.

Peroxisome proliferator-activated receptor-alpha-null mice have increased white adipose tissue glucose utilization, GLUT4, and fat mass: Role in liver and brain.

Activation of the peroxisome proliferator-activated receptor (PPAR)-alpha increases lipid catabolism and lowers the concentration of circulating lipid, but its role in the control of glucose metabolism is not as clearly established. Here we compared PPARalpha knockout mice with wild type and confirmed that the former developed hypoglycemia during fasting. This was associated with only a slight increase in insulin sensitivity but a dramatic increase in whole-body and adipose tissue glucose use rates in the fasting state. The white sc and visceral fat depots were larger due to an increase in the size and number of adipocytes, and their level of GLUT4 expression was higher and no longer regulated by the fed-to-fast transition. To evaluate whether these adipocyte deregulations were secondary to the absence of PPARalpha from liver, we reexpresssed this transcription factor in the liver of knockout mice using recombinant adenoviruses. Whereas more than 90% of the hepatocytes were infected and PPARalpha expression was restored to normal levels, the whole-body glucose use rate remained elevated. Next, to evaluate whether brain PPARalpha could affect glucose homeostasis, we activated brain PPARalpha in wild-type mice by infusing WY14643 into the lateral ventricle and showed that whole-body glucose use was reduced. Hence, our data show that PPARalpha is involved in the regulation of glucose homeostasis, insulin sensitivity, fat accumulation, and adipose tissue glucose use by a mechanism that does not require PPARalpha expression in the liver. By contrast, activation of PPARalpha in the brain stimulates peripheral glucose use. This suggests that the alteration in adipocyte glucose metabolism in the knockout mice may result from the absence of PPARalpha in the brain.

The T cell-specific CXC chemokines IP-10, Mig, and I-TAC are expressed by activated human bronchial epithelial cells.

Recruitment of activated T cells to mucosal surfaces, such as the airway epithelium, is important in host defense and for the development of inflammatory diseases at these sites. We therefore asked whether the CXC chemokines IFN-induced protein of 10 kDa (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha-chemoattractant (I-TAC), which specifically chemoattract activated T cells by signaling through the chemokine receptor CXCR3, were inducible in respiratory epithelial cells. The effects of proinflammatory cytokines, including IFN-gamma (Th1-type cytokine), Th2-type cytokines (IL-4, IL-10, and IL-13), and dexamethasone were studied in normal human bronchial epithelial cells (NHBEC) and in two human respiratory epithelial cell lines, A549 and BEAS-2B. We found that IFN-gamma, but not TNF-alpha or IL-1 beta, strongly induced IP-10, Mig, and I-TAC mRNA accumulation mainly in NHBEC and that TNF-alpha and IL-1 beta synergized with IFN-gamma induction in all three cell types. High levels of IP-10 protein (&gt; 800 ng/ml) were detected in supernatants of IFN-gamma/TNF-alpha-stimulated NHBEC. Neither dexamethasone nor Th2 cytokines modulated IP-10, Mig, or I-TAC expression. Since IFN-gamma is up-regulated in tuberculosis (TB), using in situ hybridization we studied the expression of IP-10 in the airways of TB patients and found that IP-10 mRNA was expressed in the bronchial epithelium. In addition, IP-10-positive cells obtained by bronchoalveolar lavage were significantly increased in TB patients compared with normal controls. These results show that activated bronchial epithelium is an important source of IP-10, Mig, and I-TAC, which may, in pulmonary diseases such as TB (in which IFN-gamma is highly expressed) play an important role in the recruitment of activated T cells.

Postmortem angiography: review of former and current methods.

OBJECTIVE: Postmortem investigations are becoming more and more sophisticated. CT and MRI are already being used in pathology and forensic medicine. In this context, the impact of postmortem angiography increases because of the rapid evaluation of organ-specific vascular patterns, vascular alteration under pathologic and physiologic conditions, and tissue changes induced by artificial and unnatural causes. CONCLUSION: In this article, the advantages and disadvantages of former and current techniques and contrast agents are reviewed.

La Gestió policial als esdeveniments públics en espais urbans a l'Àfrica: situació actual i perspectives = Policing public events in urban spaces in Africa : an analysis of the current situation and a perspective on follow-up action

L’informe que es presenta en aquest llibre és el resultat d’un nou acord de col·laboració entre el Programa de les Nacions Unides per als Assentaments Humans (ONU-Habitat) i l’Institut de Seguretat Pública de Catalunya, impulsat amb l’objectiu de millorar la seguretat en esdeveniments públics en els espais urbans a l’Àfrica. La fase pilot es va dur a terme el 2010, durant els dos seminaris de formació realitzats a Mollet del Vallès (Barcelona) com a part de la Plataforma Policia per al Desenvolupament Urbà (PPUD). En aquest informe es descriuen els orígens i l’estat de la iniciativa i resumeix els resultats. També s’inclouen algunes recomanacions per a millorar la seguretat d’esdeveniments públics. Font d'informació: http://www.onuhabitat.org.

Personnes âgées aux urgences: défis actuels et futurs [Older patients at the emergency department: current and future challenges].

Emergency departments are and will be at the front line to face the forthcoming increased use of the health care system by the aging baby boomers cohort. Emergency department services will need to adjust on a quantitative as well as on a qualitative basis to manage the impact of these demographic changes. Various models of care have been developed to improve the care of older geriatric patients in the Emergency department that resulted in favorable results on functional, health, as well as health services utilization outcomes. Key components of these successful models have been identified that require a high level of integration between geriatric and emergency teams.

Eddy current effects on a clinical 7T-68 cm bore scanner.

INTRODUCTION: Eddy currents induced by switching of magnetic field gradients can lead to distortions in short echo-time spectroscopy or diffusion weighted imaging. In small bore magnets, such as human head-only systems, minimization of eddy current effects is more demanding because of the proximity of the gradient coil to conducting structures. METHODS: In the present study, the eddy current behavior achievable on a recently installed 7 tesla-68 cm bore head-only magnet was characterized. RESULTS: Residual effects after compensation were shown to be on the same order of magnitude as those measured on two whole body systems (3 and 4.7 T), while using two to three fold increased gradient slewrates.

Characterization of novel hypertrophic signaling pathways activated by the AKAP-Lbc signaling complex in cardiomyocytes

RÉSUMÉL'hypertrophie cardiaque représente un mécanisme d'adaptation du myocarde en réponse à différents stress. Sur le long terme, l'hypertrophie cardiaque peut évoluer vers l'insuffisance cardiaque, l'une des principales causes de morbidité et de mortalité dans les pays industrialisés, pour cette raison, la communauté scientifique est très intéressée à élucider les voies de signalisation qui régulent ce phénomène pathologique dans le coeur.Notre laboratoire a montré que AKAP-Lbc, une protéine d'ancrage de la protéine kinase A (AKAPs), est principalement exprimée dans le coeur et peut réguler des processus importants tels que l'hypertrophie des cardiomyocytes.AKAP-Lbc fonctionne comme un facteur d'échange de nucléotides guanine (GEF) pour la petite Rho-GTPase RhoA. Cette fonction est activée par différents récepteurs qui activent son domaine Rho-GEF. Des études récentes ont démontré que AKAP-Lbc est impliquée dans la réponse hypertrophique des cardiomyocytes suite à l'activation des récepteurs α1-adrénergiques. Le but général de ce travail de thèse est la caractérisation de la voie de signalisation hypertrophique activée par AKAP-Lbc dans les cardiomyocytes.Mes travaux montrent que AKAP-Lbc organise un complexe macromoléculaire, comprenant les protéines kinases PKN, MLTK, MKK3 et p38 et active la protéine kinase p38 en réponse à l'activation des récepteurs α1-adrénergiques.Nos résultats indiquent que cette voie de signalisation au cours de la réponse hypertrophique active le facteur de transcription GATA4 et la protéine Hsp27.GATA4 est un important facteur de transcription qui régule la transcription de plusieurs gènes au cours de la réponse hypertrophique, alors que Hsp27 est une protéine chaperonne qui interagit avec le cytosquelette des cardiomyocytes et les protége contre le stress hypertrophique.Pris ensembles, ces études contribuent à comprendre comment le complexe de signalisation formé par AKAP-Lbc régule l'hypertrophie dans les cardiomyocytes. Au-delà de leur intérêt au niveau biochimique, ces travaux pourraient aussi contribuer à la compréhension du phénomène de l'hypertrophie dans le coeur.

Iowa Airport Directory, 2003 ***NOTE*** This document is for historical viewing, the internal information is no longer current or accurate! ***NOTE*** Current information can be found at http://www.iowadot.gov/aviation/aircraftregistration/registration.aspx ***NOTE***

Iowa has 8 commercial service airports and 105 general aviation airports, of which three serve as reliever airports. ***NOTE*** This document is for historical viewing, the internal information is no longer current or accurate! ***NOTE*** Current information can be found at http://www.iowadot.gov/aviation/aircraftregistration/registration.aspx ***NOTE***