Effects of PDE4 inhibitors on lipopolysaccharide-induced priming of superoxide anion production from human mononuclear cells.

AIMS: Phosphodiesterase 4 (PDE4) inhibitors have been described as potent anti-inflammatory compounds, involving an increase in intracellular levels of cyclic 3',5'-adenosine monophosphate (AMP). The aim of this study was to compare the effects of selective PDE4 inhibitors, rolipram and RP 73-401 with the cell permeable analogue of cyclic AMP, dibutyryl-cyclic AMP (db-cAMP) and the anti-inflammatory cytokine interleukin-10 (IL-10) on superoxide anion production from peripheral blood mononuclear cells preincubated with lipopolysaccharide (LPS). MAJOR FINDINGS: We report that, after incubation of the cells with LPS, a large increase in superoxide anion production was observed. Rolipram or RP 73-401 (10(-8) to 10(-5) M) induced significant reductions of fMLP-induced superoxide anion production in cells incubated with or without LPS. The db-cAMP (10(-5) to 10(-3) M) also elicited dose-dependent inhibitions of the fMLP-induced superoxide anion production. In contrast, IL-10 (1 or 10 ng/ml) did not elicit a reduction in fMLP-induced superoxide anion production in both conditions. PRINCIPAL CONCLUSION: These results suggest that the inhibitory activity of PDE4 inhibitors on fMLP-induced production of superoxide anion production is mediated by db-cAMP rather than IL-10

Maximum-likelihood estimation of lithospheric flexural rigidity, initial-loading fraction, and load correlation, under isotropy

Topography and gravity are geophysical fields whose joint statistical structure derives from interface-loading processes modulated by the underlying mechanics of isostatic and flexural compensation in the shallow lithosphere. Under this dual statistical-mechanistic viewpoint an estimation problem can be formulated where the knowns are topography and gravity and the principal unknown the elastic flexural rigidity of the lithosphere. In the guise of an equivalent "effective elastic thickness", this important, geographically varying, structural parameter has been the subject of many interpretative studies, but precisely how well it is known or how best it can be found from the data, abundant nonetheless, has remained contentious and unresolved throughout the last few decades of dedicated study. The popular methods whereby admittance or coherence, both spectral measures of the relation between gravity and topography, are inverted for the flexural rigidity, have revealed themselves to have insufficient power to independently constrain both it and the additional unknown initial-loading fraction and load-correlation fac- tors, respectively. Solving this extremely ill-posed inversion problem leads to non-uniqueness and is further complicated by practical considerations such as the choice of regularizing data tapers to render the analysis sufficiently selective both in the spatial and spectral domains. Here, we rewrite the problem in a form amenable to maximum-likelihood estimation theory, which we show yields unbiased, minimum-variance estimates of flexural rigidity, initial-loading frac- tion and load correlation, each of those separably resolved with little a posteriori correlation between their estimates. We are also able to separately characterize the isotropic spectral shape of the initial loading processes.Comment: 41 pages, 13 figures, accepted for publication by Geophysical Journal Internationa

Budesonide/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol

BACKGROUND: To compare the efficacy and safety of budesonide/formoterol (Symbicort(®)) with formoterol (Oxis(®)) in the treatment of patients with acute asthma who showed evidence of refractoriness to short-acting β(2)-agonist therapy. METHODS: In a 3 hour, randomized, double-blind study, a total of 115 patients with acute asthma (mean FEV(1 )40% of predicted normal) and a refractory response to salbutamol (mean reversibility 2% of predicted normal after inhalation of 400 μg), were randomized to receive either budesonide/formoterol (320/9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 1280/36 μg]) or formoterol (9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 36 μg]). The primary efficacy variable was the average FEV(1 )from the first intake of study medication to the measurement at 90 minutes. Secondary endpoints included changes in FEV(1 )at other timepoints and change in respiratory rate at 180 minutes. Treatment success, treatment failure and patient assessment of the effectiveness of the study medication were also measured. RESULTS: FEV(1 )increased after administration of the study medication in both treatment groups. No statistically significant difference between the treatment groups was apparent for the primary outcome variable, or for any of the other efficacy endpoints. There were no statistically significant between-group differences for treatment success, treatment failure or patient assessment of medication effectiveness. Both treatments were well tolerated. CONCLUSION: Budesonide/formoterol and formoterol provided similarly rapid relief of acute bronchoconstriction in patients with asthma who showed evidence of refractoriness to a short-acting β(2)-agonist

Study of 19^{19} Na at SPIRAL

NESTERInternational audienceThe excitation function for the elastic-scattering reaction p18Ne, p18Ne was measured with the first radioactive beam from the SPIRAL facility at the GANIL laboratory and with a solid cryogenic hydrogen target. Several broad resonances have been observed, corresponding to new excited states in the unbound nucleus 19Na. In addition, two-proton emission events have been identified and are discussed

PPARα downregulates airway inflammation induced by lipopolysaccharide in the mouse

BACKGROUND: Inflammation is a hallmark of acute lung injury and chronic airway diseases. In chronic airway diseases, it is associated with profound tissue remodeling. Peroxisome proliferator-activated receptor-α (PPARα) is a ligand-activated transcription factor, that belongs to the nuclear receptor family. Agonists for PPARα have been recently shown to reduce lipopolysaccharide (LPS)- and cytokine-induced secretion of matrix metalloproteinase-9 (MMP-9) in human monocytes and rat mesangial cells, suggesting that PPARα may play a beneficial role in inflammation and tissue remodeling. METHODS: We have investigated the role of PPARα in a mouse model of LPS-induced airway inflammation characterized by neutrophil and macrophage infiltration, by production of the chemoattractants, tumor necrosis factor-α (TNF-α), keratinocyte derived-chemokine (KC), macrophage inflammatory protein-2 (MIP-2) and monocyte chemoattractant protein-1 (MCP-1), and by increased MMP-2 and MMP-9 activity in bronchoalveolar lavage fluid (BALF). The role of PPARα in this model was studied using both PPARα-deficient mice and mice treated with the PPARα activator, fenofibrate. RESULTS: Upon intranasal exposure to LPS, PPARα(-/- )mice exhibited greater neutrophil and macrophage number in BALF, as well as increased levels of TNF-α, KC, MIP-2 and MCP-1, when compared to PPARα(+/+ )mice. PPARα(-/- )mice also displayed enhanced MMP-9 activity. Conversely, fenofibrate (0.15 to 15 mg/day) dose-dependently reduced the increase in neutrophil and macrophage number induced by LPS in wild-type mice. In animals treated with 15 mg/day fenofibrate, this effect was associated with a reduction in TNF-α, KC, MIP-2 and MCP-1 levels, as well as in MMP-2 and MMP-9 activity. PPARα(-/- )mice treated with 15 mg/day fenofibrate failed to exhibit decreased airway inflammatory cell infiltrate, demonstrating that PPARα mediates the anti-inflammatory effect of fenofibrate. CONCLUSION: Using both genetic and pharmacological approaches, our data clearly show that PPARα downregulates cell infiltration, chemoattractant production and enhanced MMP activity triggered by LPS in mouse lung. This suggests that PPARα activation may have a beneficial effect in acute or chronic inflammatory airway disorders involving neutrophils and macrophages

What can Olympus Mons tell us about the Martian lithosphere?

Under gravitational loading, a volcanic edifice deforms, and the underlying lithosphere downflexes. This has been observed on Earth, but is equally true on other planets. We use finite element models to simulate this gravity-driven deformation at Olympus Mons on Mars. Eleven model parameters, including the geometry and material properties of the edifice, lithosphere and underlying asthenosphere, are varied to establish which parameters have the greatest effect on deformation. Values for parameters that affect deformation at Olympus Mons, Mars, are constrained by minimising misfit between modelled and observed measurements of edifice height, edifice radius, and flexural moat width. Our inferred value for the Young's modulus of the Martian lithosphere, 17.8 GPa, is significantly lower than values used previously, suggesting that the Martian lithosphere is more porous than generally assumed. The best-fitting values for other parameters: edifice density (2111 – 2389 kg.m –3) and lithosphere thickness (83.3 km) are within ranges proposed hitherto. The best-fitting values of model parameters are interdependent; a decrease in lithosphere Young's modulus must be accompanied by a decrease in edifice density and/or an increase in lithosphere thickness. Our results identify the parameters that should be considered within all models of gravity-driven volcano deformation; highlight the importance of the often-overlooked Young's modulus; and provide further constraints on the properties of the Martian lithosphere, namely its porosity, which have implications for the transport and storage of fluid throughout Mars' history

Airway and Esophageal Stenting in Patients with Advanced Esophageal Cancer and Pulmonary Involvement

BACKGROUND: Most inoperable patients with esophageal-advanced cancer (EGC) have a poor prognosis. Esophageal stenting, as part of a palliative therapy management has dramatically improved the quality of live of EGC patients. Airway stenting is generally proposed in case of esophageal stent complication, with a high failure rate. The study was conducted to assess the efficacy and safety of scheduled and non-scheduled airway stenting in case of indicated esophageal stenting for EGC. METHODS AND FINDINGS: The study is an observational study conducted in pulmonary and gastroenterology endoscopy units. Consecutive patients with EGC were referred to endoscopy units. We analyzed the outcome of airway stenting in patients with esophageal stent indication admitted in emergency or with a scheduled intervention. Forty-four patients (58+/-\-8 years of age) with esophageal stenting indication were investigated. Seven patients (group 1) were admitted in emergency due to esophageal stent complication in the airway (4 fistulas, 3 cases with malignant infiltration and compression). Airway stenting failed for 5 patients. Thirty-seven remaining patients had a scheduled stenting procedure (group 2): stent was inserted for 13 patients with tracheal or bronchial malignant infiltration, 12 patients with fistulas, and 12 patients with airway extrinsic compression (preventive indication). Stenting the airway was well tolerated. Life-threatening complications were related to group 1. Overall mean survival was 26+/-10 weeks and was significantly shorter in group 1 (6+/-7.6 weeks) than in group 2 (28+/-11 weeks), p<0.001). Scheduled double stenting significantly improved symptoms (95% at day 7) with a low complication rate (13%), and achieved a specific cancer treatment (84%) in most cases. CONCLUSION: Stenting the airway should always be considered in case of esophageal stent indication. A multidisciplinary approach with initial airway evaluation improved prognosis and decreased airways complications related to esophageal stent. Emergency procedures were rarely efficient in our experience

Rhinovirus-induced basic fibroblast growth factor release mediates airway remodeling features

BACKGROUND: Human rhinoviruses, major precipitants of asthma exacerbations, induce lower airway inflammation and mediate angiogenesis. The purpose of this study was to assess the possibility that rhinoviruses may also contribute to the fibrotic component of airway remodeling. METHODS: Levels of basic fibroblast growth factor (bFGF) mRNA and protein were measured following rhinovirus infection of bronchial epithelial cells. The profibrotic effect of epithelial products was assessed by DNA synthesis and matrix metalloproteinase activity assays. Moreover, epithelial cells were exposed to supernatants from cultured peripheral blood mononuclear cells, obtained from healthy donors or atopic asthmatic subjects and subsequently infected by rhinovirus and bFGF release was estimated. bFGF was also measured in respiratory secretions from atopic asthmatic patients before and during rhinovirus-induced asthma exacerbations. RESULTS: Rhinovirus epithelial infection stimulated mRNA expression and release of bFGF, the latter being positively correlated with cell death under conditions promoting rhinovirus-induced cytotoxicity. Supernatants from infected cultures induced lung fibroblast proliferation, which was inhibited by anti-bFGF antibody, and demonstrated increased matrix metalloproteinase activity. Rhinovirus-mediated bFGF release was significantly higher in an in vitro simulation of atopic asthmatic environment and, importantly, during rhinovirus-associated asthma exacerbations. CONCLUSIONS: Rhinovirus infection induces bFGF release by airway epithelium, and stimulates stroma cell proliferation contributing to airway remodeling in asthma. Repeated rhinovirus infections may promote asthma persistence, particularly in the context of atopy; prevention of such infections may influence the natural history of asthma

New approach to the nuclear in beam γ\gamma spectroscopy of neutron rich nuclei at N=20 using projectile fragmentation

In the european political field, the challenge consists in organizing a political debate on the scale of the Union whereas the citizens of this one do not speak the same language, ignore the Community institutions, live in different institutional systems and, during nearly 50 years, lived Wall on both sides, in opposite ideological universes. Television can help to take up this challenge in condition of being put in perspective in its right place: neither obsolete and diabolic object manipulating the masses, nor democratic fairy bringing the rational light to the individual