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Over the past 10 years there have been striking improvements in the treatment of asthma, largely as a result of the earlier and more widespread use of inhaled corticosteroids. The development of new treatments for asthma has proved difficult, although several immunologic approaches are undergoing preclinical and clinical assessment.1 Antileukotrienes are the only new class of drugs to treat asthma that have been introduced in the past 25 years, but their efficacy is somewhat limited and unpredictable, as compared with that of inhaled corticosteroids.Mild asthma can be controlled in most patients by relatively low doses of inhaled corticosteroids, and . . .
Introduction: We previously reported that formoterol, a long-acting β 2 -adrenoceptor agonist, activated a serine/threonine protein phosphatase PP2A which is involved in the restoration of corticosteroid (CS) sensitivity by formoterol (Kobayashi et al ERJ 2009;34:583s). We explored other phosphatases and identified dual-specificity phosphatase DUSP4 as a possible novel target of formoterol. Aims: To confirm that DUSP4 is activated by formoterol and is involved in regulation of CS sensitivity. Methods: U937 monocytic cells were incubated with IL-2 and IL-4 for 48 h to induce CS insensitivity. CS sensitivity was determined by the CS budesonide ability to inhibit TNFα-induced IL-8 production and to translocate glucocorticoid receptor (GR) from cell cytoplasm to nucleus. Phosphatase activity of immunopurified DUSP4 was measured by fluorescence-based assay. The nuclear/cytoplasmic GR ratio and phosphorylation levels of GR-Ser 226 and JNK1 kinase were analysed by western-blotting. In some experiments DUSP4 was knocked down by siRNA. Results: Formoterol increased DUSP4 activity, which was reduced under IL-2/IL-4 exposure. Knock-down of DUSP4 reduced GR nuclear translocation and CS sensitivity. Knock-down of DUSP4 also abrogated the dephosphorylation of GR-Ser 226 and JNK1 by formoterol - the effects involved in GR nuclear translocation and restoration of CS sensitivity. Conclusions: Formoterol regulates sensitivity to budesonide through activation of DUSP4 which dephosphorylates JNK1 and which in turn leads to dephosphorylation of GR-Ser 226 . This novel mechanism by formoterol may contribute to the clinical efficacy of combination of formoterol and budesonide.
In conclusion, flow velocity measurements repeated after a 6-month interval show a variability, which is larger for baseline velocity and coronary flow reserve. This variability is correlated with the changes in heart rate and can be reduced by a normalization for the cross-sectional area at the site of the measurement (coronary flow) and for the aortic pressure at the time of the measurement (flow resistance).
indications and dosage and for added warnings and precautions.This is particularly important when the recommended agent is a new and/or infrequently employed drug.
No abstract is provided for this article.
onfluoroscopic electromechanical mapping (NOGA™, Biosense-Webster, a Johnson & Johnson Company) is a recently developed technique that enables the acquisition of on-line information on the electrical and mechanical endoventricular functioning of myocardial tissue. 1 The rationale for this new technique is 2-fold. First, none of the currently available in-cathlab methods can distinguish viable from non-viable myocardium. Accepted techniques, such as radionuclide scintigraphy and dobutamine stress echocardiography, may not be readily available, and can not be performed in the cathlab. Second, applications such as myocardial laser revascularization or intramyocardial gene-injection may prove cumbersome when performed using echocardiography or fluoroscopy with only 2-dimensional (2-D) projections available on-line. 1 A major pitfall of these latter techniques is indeed the inability to accurately associate the 2-D positioning with a specific endocardial site, quite apart from the high X-ray exposure for both patient and physician when using fluoroscopy. 2 Although clinical application of on-line 3-dimensional (3D) echocardiography and magnetic resonance imaging is underway, until recently there has not been a technique for real-time 3-D guiding of intervention tools and assessment of myocardial electromechanical functioning. Nonfluoroscopic electromechanical mapping has become the first navigation technique to accurately determine the trajectory of a tool inside the human heart, to guide the interventional device to a specific site, and to meticulously couple functional and anatomical properties. 1 In this overview, we shall describe the NOGA ™ system components, the left ventricular mapping technique, the current experimental and clinical data available, the ongoing trials and the possible future applications of this technique.
Bronchial hyperresponsiveness (BHR) and asthma symptoms are linked to chronic inflammation in the airway. Corticosteroids reduce BHR and asthma symptoms and, although their precise mode of action is not yet certain, it is likely that they suppress the allergic inflammatory response. They may act on macrophages, eosinophils, lymphocytes, and airway microvascular leak to inhibit the late response and BHR that follows allergen exposure, whereas chronic administration may also reduce the number of mast cells in airways to decrease the immediate response to allergen and exercise. In view of the safety of administration, inhaled corticosteroids should be considered as first line therapy for chronic asthma, with the aim of suppressing inflammation and reducing the need for bronchodilator therapy.
