Disease Progression in MRL/lpr Lupus-Prone Mice Is Reduced by NCS 613, a Specific Cyclic Nucleotide Phosphodiesterase Type 4 (PDE4) Inhibitor

Systemic lupus erythematosus is a polymorphic and multigenic inflammatory autoimmune disease. Cyclic AMP (cAMP) modulates inflammation and the inhibition of cyclic nucleotide phosphodiesterase type 4 (PDE4), which specifically hydrolyzes cAMP, inhibits TNFα secretion. This study was aimed at investigating the evolution of PDE activity and expression levels during the course of the disease in MRL/lpr lupus-prone mice, and to evaluate in these mice the biological and clinical effects of treatments with pentoxifylline, denbufylline and NCS 613 PDE inhibitors. This study reveals that compared to CBA/J control mice, kidney PDE4 activity of MRL/lpr mice increases with the disease progression. Furthermore, it showed that the most potent and selective PDE4 inhibitor NCS 613 is also the most effective molecule in decreasing proteinuria and increasing survival rate of MRL/lpr mice. NCS 613 is a potent inhibitor, which is more selective for the PDE4C subtype (IC50 = 1.4 nM) than the other subtypes (PDE4A, IC50 = 44 nM; PDE4B, IC50 = 48 nM; and PDE4D, IC50 = 14 nM). Interestingly, its affinity for the High Affinity Rolipram Binding Site is relatively low (Ki = 148 nM) in comparison to rolipram (Ki = 3 nM). Finally, as also observed using MRL/lpr peripheral blood lymphocytes (PBLs), NCS 613 inhibits basal and LPS-induced TNFα secretion from PBLs of lupus patients, suggesting a therapeutic potential of NCS 613 in systemic lupus. This study reveals that PDE4 represent a potential therapeutic target in lupus disease

Expression and function of human hemokinin-1 in human and guinea pig airways

<p>Abstract</p> <p>Background</p> <p>Human hemokinin-1 (hHK-1) and endokinins are peptides of the tachykinin family encoded by the <it>TAC4 </it>gene. <it>TAC4 </it>and hHK-1 expression as well as effects of hHK-1 in the lung and airways remain however unknown and were explored in this study.</p> <p>Methods</p> <p>RT-PCR analysis was performed on human bronchi to assess expression of tachykinin and tachykinin receptors genes. Enzyme immunoassay was used to quantify hHK-1, and effects of hHK-1 and endokinins on contraction of human and guinea pig airways were then evaluated, as well as the role of hHK-1 on cytokines production by human lung parenchyma or bronchi explants and by lung macrophages.</p> <p>Results</p> <p>In human bronchi, expression of the genes that encode for hHK-1, tachykinin NK₁-and NK₂-receptors was demonstrated. hHK-1 protein was found in supernatants from explants of human bronchi, lung parenchyma and lung macrophages. Exogenous hHK-1 caused a contractile response in human bronchi mainly through the activation of NK₂-receptors, which blockade unmasked a NK₁-receptor involvement, subject to a rapid desensitization. In the guinea pig trachea, hHK-1 caused a concentration-dependant contraction mainly mediated through the activation of NK₁-receptors. Endokinin A/B exerted similar effects to hHK-1 on both human bronchi and guinea pig trachea, whereas endokinins C and D were inactive. hHK-1 had no impact on the production of cytokines by explants of human bronchi or lung parenchyma, or by human lung macrophages.</p> <p>Conclusions</p> <p>We demonstrate endogenous expression of <it>TAC4 </it>in human bronchi, the encoded peptide hHK-1 being expressed and involved in contraction of human and guinea pig airways.</p

Prognostic value of early, conventional proton magnetic resonance spectroscopy in cooled asphyxiated infants

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) commonly leads to neurodevelopmental impairment, raising the need for prognostic tools which may guide future therapies in time. Prognostic value of proton MR spectroscopy (H-MRS) between 1 and 46 days of age has been extensively studied; however, the reproducibility and generalizability of these methods are controversial in a general clinical setting. Therefore, we investigated the prognostic performance of conventional H-MRS during first 96 postnatal hours in hypothermia-treated asphyxiated neonates. METHODS: Fifty-one consecutive hypothermia-treated HIE neonates were examined by H-MRS at three echo-times (TE = 35, 144, 288 ms) between 6 and 96 h of age, depending on clinical stability. Patients were divided into favorable (n = 35) and unfavorable (n = 16) outcome groups based on psychomotor and mental developmental index (PDI and MDI, Bayley Scales of Infant Development II) scores (>/= 70 versus < 70 or death, respectively), assessed at 18-26 months of age. Associations between 36 routinely measured metabolite ratios and outcome were studied. Age-dependency of metabolite ratios in whole patient population was assessed. Prognostic performance of metabolite ratios was evaluated by Receiver Operating Characteristics (ROC) analysis. RESULTS: Three metabolite ratios showed significant difference between outcome groups after correction for multiple testing (p < 0.0014): myo-inositol (mIns)/N-acetyl-aspartate (NAA) height, mIns/creatine (Cr) height, both at TE = 35 ms, and NAA/Cr height at TE = 144 ms. Assessment of age-dependency showed that all 3 metabolite ratios (mIns/NAA, NAA/Cr and mIns/Cr) stayed constant during first 96 postnatal hours, rendering them optimal for prediction. ROC analysis revealed that mIns/NAA gives better prediction for outcome than NAA/Cr and mIns/Cr with cut-off values 0.6798 0.6274 and 0.7798, respectively, (AUC 0.9084, 0.8396 and 0.8462, respectively, p < 0.00001); mIns/NAA had the highest specificity (95.24%) and sensitivity (84.62%) for predicting outcome of neonates with HIE any time during the first 96 postnatal hours. CONCLUSIONS: Our findings suggest that during first 96 h of age even conventional H-MRS could be a useful prognostic tool in predicting the outcome of asphyxiated neonates; mIns/NAA was found to be the best and age-independent predictor

A genetic algorithm for topology optimization of area-to-point heat conduction problem

International audienceThis paper presents a way of solving the classical area (volume)-to-point heat conduction problem by the means of a simple Genetic Algorithm (GA) in square configuration. After a short description of the numerical method, the optimal solutions proposed for minimizing the peak or mean temperature of a domain are presented. The effects of the conductivity ratio and the filling ratio on the configurations of the conductive tree are also analyzed and discussed. A numerical benchmark is then established to assess the influence of mesh resolution and the reproducibility of the GA optimization. Results show that GA is capable of proposing solutions having almost the same cooling effectiveness for different mesh resolutions or random seed generators. GA is also relevant compared to other optimization techniques presented here. It can be considered as a simple, easy to adapt and robust but computation time consuming method for addressing the general area (volume)-to-point heat conduction problem

A simple Cellular Automaton algorithm to optimise heat transfer in complex configurations

International audienceThe aim of this study is to propose a method for constructing a conductive paths topology in a 2D area-to-point and points-to-points problem. We focus here on heat conduction, with the goal of decreasing the temperature differences across a domain. We propose a method using a Cellular Automaton (CA) to reshape an initial topology by a thermal gradients attraction-repulsion mechanism. The potentiality of the generated conductive trees is proved through the temperature reductions obtained. We also propose a second law analysis of the problem. This algorithm leads to heat drains that tend to equally sustain irreversibility across the domai

Agglomeration of diesel particles by an electrostatic agglomerator under positive DC voltage: Experimental study

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Tree-network structure generation for heat conduction by cellular automaton

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Night cooling with a Ventilated Internal Double Wall during the night

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