The study sought to test whether high-dose statin treatment would result in greater reductions in plaque inflammation than low-dose statins, using fluorodeoxyglucose-positron emission ...tomography/computed tomographic imaging (FDG-PET/CT).
Intensification of statin therapy reduces major cardiovascular events.
Adults with risk factors or with established atherosclerosis, who were not taking high-dose statins (n = 83), were randomized to atorvastatin 10 versus 80 mg in a double-blind, multicenter trial. FDG-PET/CT imaging of the ascending thoracic aorta and carotid arteries was performed at baseline, 4, and 12 weeks after randomization and target-to-background ratio (TBR) of FDG uptake within the artery wall was assessed while blinded to time points and treatment.
Sixty-seven subjects completed the study, providing imaging data for analysis. At 12 weeks, inflammation (TBR) in the index vessel was significantly reduced from baseline with atorvastatin 80 mg (% reduction 95% confidence interval: 14.42% 8.7% to 19.8%; p < 0.001), but not atorvastatin 10 mg (% reduction: 4.2% -2.3% to 10.4%; p > 0.1). Atorvastatin 80 mg resulted in significant additional relative reductions in TBR versus atorvastatin 10 mg (10.6% 2.2% to 18.3%; p = 0.01) at week 12. Reductions from baseline in TBR were seen as early as 4 weeks after randomization with atorvastatin 10 mg (6.4% reduction, p < 0.05) and 80 mg (12.5% reduction, p < 0.001). Changes in TBR did not correlate with lipid profile changes.
Statin therapy produced significant rapid dose-dependent reductions in FDG uptake that may represent changes in atherosclerotic plaque inflammation. FDG-PET imaging may be useful in detecting early treatment effects in patients at risk or with established atherosclerosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Dopaminergic (DA) neurons of substantia nigra in the midbrain control voluntary movement, and their degeneration is the cause of Parkinson's disease. The complete set of genes required to ...specifically determine the development of midbrain DA subgroups is not known yet. We report here that mice lacking the bicoid-related homeoprotein Pitx3 fail to develop DA neurons of the substantia nigra. Other mesencephalic DA neurons of the ventral tegmental area and retrorubral field are unaltered in their dopamine expression and histological organization. These data suggest that Pitx3-dependent gene expression is specifically required for the differentiation of DA progenitors within the mesencephalic DA system.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Objectives The study sought to test whether high-dose statin treatment would result in greater reductions in plaque inflammation than low-dose statins, using fluorodeoxyglucose-positron emission ...tomography/computed tomographic imaging (FDG-PET/CT). Background Intensification of statin therapy reduces major cardiovascular events. Methods Adults with risk factors or with established atherosclerosis, who were not taking high-dose statins (n = 83), were randomized to atorvastatin 10 versus 80 mg in a double-blind, multicenter trial. FDG-PET/CT imaging of the ascending thoracic aorta and carotid arteries was performed at baseline, 4, and 12 weeks after randomization and target-to-background ratio (TBR) of FDG uptake within the artery wall was assessed while blinded to time points and treatment. Results Sixty-seven subjects completed the study, providing imaging data for analysis. At 12 weeks, inflammation (TBR) in the index vessel was significantly reduced from baseline with atorvastatin 80 mg (% reduction 95% confidence interval: 14.42% 8.7% to 19.8%; p < 0.001), but not atorvastatin 10 mg (% reduction: 4.2% –2.3% to 10.4%; p > 0.1). Atorvastatin 80 mg resulted in significant additional relative reductions in TBR versus atorvastatin 10 mg (10.6% 2.2% to 18.3%; p = 0.01) at week 12. Reductions from baseline in TBR were seen as early as 4 weeks after randomization with atorvastatin 10 mg (6.4% reduction, p < 0.05) and 80 mg (12.5% reduction, p < 0.001). Changes in TBR did not correlate with lipid profile changes. Conclusions Statin therapy produced significant rapid dose-dependent reductions in FDG uptake that may represent changes in atherosclerotic plaque inflammation. FDG-PET imaging may be useful in detecting early treatment effects in patients at risk or with established atherosclerosis. (Evaluate the Utility of 18FDG-PET as a Tool to Quantify Atherosclerotic Plaque; NCT00703261 )
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The c-abl proto-oncogene encodes a nonreceptor tyrosine kinase involved in many cellular processes, including signaling from growth factor and antigen receptors, remodeling the cytoskeleton, and ...responding to DNA damage and oxidative stress. Many downstream pathways are affected by c-Abl. Elevated c-Abl kinase activity can inhibit NF-κB activity by stabilizing the inhibitory protein IκBα, raising the possibility that c-Abl-deficient cells might have increased NF-κB activity. We examined the levels of NF-κB activity in primary mouse embryonic fibroblasts (MEFs) derived from wild-type and c-Abl knockout mice and found that the knockout MEFs indeed exhibited elevated NF-κB activity in response to stimulation as well as constitutively elevated NF-κB activity. Thus, endogenous c-Abl is a negative regulator of basal and inducible NF-κB activity. Examination of various points of NF-κB regulation revealed that unstimulated c-Abl knockout MEFs do not exhibit an increase in IκBα degradation, p65/RelA nuclear translocation, or DNA binding of NF-κB subunits. They do, however, show reduced levels of the histone deacetylase HDAC1, a negative regulator of basal NF-κB activity. Unstimulated c-Abl knockout MEFs are less responsive to induction of NF-κB activity by trichostatin A, an HDAC inhibitor, suggesting that c-Abl might play a role in the HDAC-mediated repression of basal NF-κB activity.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
In humans, creatinine is formed by a multistep process in liver and muscle and eliminated via the kidney by a combination of glomerular filtration and active transport. Based on current evidence, ...creatinine can be taken up into renal proximal tubule cells by the basolaterally localized organic cation transporter 2 (OCT2) and the organic anion transporter 2, and effluxed into the urine by the apically localized multidrug and toxin extrusion protein 1 (MATE1) and MATE2K. Drug-induced elevation of serum creatinine (SCr) and/or reduced creatinine renal clearance is routinely used as a marker for acute kidney injury. Interpretation of elevated SCr can be complex, because such increases can be reversible and explained by inhibition of renal transporters involved in active secretion of creatinine or other secondary factors, such as diet and disease state. Distinction between these possibilities is important from a drug development perspective, as increases in SCr can result in the termination of otherwise efficacious drug candidates. In this review, we discuss the challenges associated with using creatinine as a marker for kidney damage. Furthermore, to evaluate whether reversible changes in SCr can be predicted prospectively based on in vitro transporter inhibition data, an in-depth in vitro-in vivo correlation (IVIVC) analysis was conducted for 16 drugs with in-house and literature in vitro transporter inhibition data for OCT2, MATE1, and MATE2K, as well as total and unbound maximum plasma concentration (Cmax and Cmax,u) data measured in the clinic.
Neste artigo, analisam-se os resultados preliminares de pesquisa de Doutorado, vinculada ao Programa de Pós-Graduação em Educação da Universidade Federal do Piauí, que teve como foco o Programa de ...Valorização do Mérito. A viabilização do estudo, de abordagem qualiquantitativa, deu-se mediante: pesquisa bibliográfica; análise documental e análise empírica, envolvendo professores vinculados à referida rede de ensino. Constatou-se, como já evidenciado em outros estudos sobre a utilização da bonificação no contexto educacional, que não há consenso quanto à utilização de políticas que associam o pagamento de bônus aos profissionais do magistério com base no desempenho dos alunos. Por outro lado, a análise empírica indicou que a maioria dos professores concorda, ainda que parcialmente, com a política de bônus implementada por meio do Programa de Valorização do Mérito.
Abstract Background The development of antihypertensives requires efficient and accurate tools for identifying pedal edema. Methodologies used to gauge the potential of an agent to induce pedal edema ...in short-term (<4-week) clinical trials have not been reported in the literature. Objective The purpose of this study was to identify a robust and practical method for measuring drug-induced pedal edema for use in the clinical development of antihypertensives. The efficacy of segmental bioimpedance in the detection of increased pedal edema was compared with that of clinical pitting assessment, ankle circumference, and water displacement volumetry. Methods The study population consisted of male and female healthy subjects and patients with stage 1 or 2 hypertension who were otherwise healthy. Participants were randomly assigned to receive amlodipine 10 mg or placebo once daily in this 6-week, double-blind, parallel-group study. Amlodipine was used as a means of inducing ankle edema, and not for the treatment of hypertension. Patients with hypertension were required to undergo a washout of antihypertensive therapies. Edema was evaluated using segmental bioimpedance at 10 kHz, clinical pitting assessment, ankle circumference, and water displacement at weeks 2, 4, and 6. The ANOVA model used included treatment and baseline values as covariates, with treatment pairs compared via t tests derived from the model. Results A total of 47 individuals were randomized (49% male; 29 62% with hypertension; mean SD age, 59 5.9 years; baseline body mass index, 28.6 kg/m2 2.8; blood pressure 146.6 10.7/93.5 6.5 and 139.3 8.3/89.5 4.5 in individuals with and without hypertension, respectively; amlodipine 10 mg, n = 24; placebo, n = 23). At weeks 2, 4, and 6, statistically significant treatment differences in changes from baseline were detected using water displacement (mean 90% CI treatment differences, +39.0 g +17.9 to +60.1, +61.9 g +36.1 to +87.6, and +72.2 g +42.3 to +102.1, respectively; all, P ≤ 0.001), ankle circumference (+4.74 mm +2.38 to +7.11; P < 0.001, +2.92 mm +0.33 to +5.49; P = 0.032, and +5.16 mm +2.21 to +8.11; P = 0.002), and bioimpedance (−11.7 Ω −18.1 to −5.4, −18.3 Ω −26.2 to −10.4, and −20.9 Ω −29.7 to −12.0; all, P ≤0.001), but no significant differences were detected using clinical assessment of pitting. Conclusion In this population of healthy subjects and patients with hypertension, segmental bioimpedance was comparable to water displacement and ankle circumference and outperformed clinical assessment of pitting for the detection of ankle edema, supporting the use of segmental bioimpedance as a drug-development tool to objectively quantify amlodipine-induced pedal edema. ClinicalTrials.gov identifier: NCT00789321.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Vamos comentar algumas breves narrativas que figuram no Livro de Linhagens do Conde D. Pedro e que nos remetem para figuras sobrenaturais que estariam na origem de certas famílias nobres. Veremos ...como elas se ligam a um imaginário comum occidental que nos faz remontar do extremo ocidente português, através do mundo hispânico e da França, até à longínqua Bretanha e à sua “matéria”.
La littérature médiévale portugaise possède quelques trésors méconnus qui appartiennent au patrimoine littéraire de l'Europe. La présente anthologie en restitue quelques pages décisives. Les ...aventures des derniers rois wisigothiques emportés par l'Islam conquérant s'écrivent en chroniques royales préfigurant les glorieuses péripéties de la Reconquête. La figure héroïque de Pierre le Cruel associée étroitement à celle de son amante, la belle Inès de Castro, compose une nouvelle tragique pleine de ferveur et de grandeur. L'histoire de la dame au pied de chèvre et celle de la dame venue de la mer rappellent étrangement les avatars de la fée Mélusine. Quant à la légende d'Amaro, extraordinaire récit de navigation vers le Paradis terrestre, n'est-elle pas une étonnante anticipation des grandes découvertes portugaises ? Dans ces textes parfois brefs se tissent souvent des liens étroits entre mythe, littérature et merveilleux, comme pour célébrer les noces inattendues de l'Imaginaire et de l'Histoire présidant à la naissance d'un peuple de conquérants.
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