GATA-3 is a transcription factor that is specifically expressed in T helper 2 (Th2) cells and plays a critical role in the differentiation of Th2 cells from uncommitted CD4+ lymphocytes. In addition GATA-3 is essential for the gene expression of the cytokines IL-4, IL-5 and IL-13 that mediate allergic inflammation. In human T lymphocytes GATA-3 is normally localized to the cytoplasm, but on activation by antigen-presenting cells via the T cell receptor (CD3) and co-stimulatory receptor CD28 GATA-3 is phosphorylated by p38 MAP kinase and translocates to the nucleus via the nuclear import protein importin-α. Corticosteroids bound to glucocorticoid receptors inhibit GATA-3 function by competing for nuclear entry via importin-α and also by inhibiting p38 MAP kinase through the induction of MAP kinase phosphatase-1. GATA-3 is inhibited by the Th1 master regulatory transcription T-bet but in turn inhibits STAT-4 and thus T-bet so that Th2 polarization is maintained. Since GATA-3 appears to be a critical transcription factor for allergic inflammation it is an obvious target for inhibition. However, direct inhibition by inhaled specific oligonucleotides or interference RNA is not yet possible. Corticosteroids act as indirect inhibitors and in patients with corticosteroid resistance p38 MAP kinase inhibitors may also prove to be useful in the future.
Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory disorders of the respiratory tract that are characterized by airflow limitation. They are distinct conditions with different causes, structural changes, and immunopathology. The pathophysiology in asthma and COPD involves not only the proximal large airways, but also the distal small airways, and thus the small airways are an important therapeutic target in the treatment of both diseases. The assessment of diseased distal small airways is challenging. Extensive disease can be present in the small airways with little abnormality in conventional pulmonary function tests. Recent advances in imaging technologies have led to better spatial resolution to assess small airways morphology non-invasively. New physiological tests have been developed to detect disease and response to therapy in regional airways. Improving the efficiency of existing aerosolized therapy to direct drug to the appropriate lung regions may improve clinical efficacy. Approaches to target distal lung regions include developing new drug formulations with smaller aerosol particle size or using inhaler devices that emit aerosolized drug at slow inhalation flows. Large studies are needed to determine whether better distal lung deposition leads to improvements in small airways function that are translated into clinically significant patient outcomes.
No abstract is provided for this article.
Regional ventricular wall motion analysis utilizing three different methods was performed on predischarge left ventriculograms from 291 of 367 patients enrolled in a randomized triai of single chain recombinant tissue-type plasminogen activator (rt-PA), aspirin and heparin with and without immediate angioplasty in patients with acute myocardial infarction. With univariate analysis, no difference in regional wall motion variables between the two treatment groups was observed. However, with individual baseline risk assessment by multivariate linear regression analysis using baseline characteristics known to be related to left ventricular function after thrombolytic therapy or outcome of coronary angioplasty, or both, an excess of high risk patients in the invasive treatment group was detected. To adjust for this unequal distribution of baseline risk, multivariate linear regression analysis was performed. No benefit of immediate coronary angioplasty was observed after adjustment. Reocclusion or reinfarction, or both, occurred more frequently in the invasive than in the noninvasive treatment group (18% versus 13%, respectively). Among patients with a patent infarct-related vessel on angiography between days 10 and 22 and without reinfarction before angiography, there was a trend toward benefit from the invasive strategy, indicating that reocclusion and reinfarction might be responsible for the lack of benefit of the invasive strategy. This implies that immediate coronary angioplasty may be beneficial in selected patients, provided that these complications can be prevented.
"Mechanisms of Action of Glucocorticoids in Asthma." American Journal of Respiratory and Critical Care Medicine, 154(2_pt_2), pp. S21–S27
Mitral regurgitation (MR) is a common disease in developed countries, affecting an estimated 9.3% of the population aged ≥75 years. Although surgical valve repair or replacement is currently the “gold standard” treatment for severe symptomatic MR, almost one-half of the patients are denied surgery. These are usually older patients with moderate left ventricular dysfunction and several non-cardiac co-morbidities. The aim of transcatheter mitral valve repair is to provide a treatment that is at least as effective as conventional valve surgery, and is associated with less morbidity and mortality. Currently an important number of devices are under evaluation, and can be categorized according to the treatment strategy.... (excerpt)
No abstract is provided for this article.
Background Data on optimal antiplatelet treatment regimens in patients who undergo multivessel percutaneous coronary intervention (PCI) are sparse. Objectives This post hoc study investigated the impact of an experimental strategy (1-month dual antiplatelet therapy [DAPT] followed by 23-month ticagrelor monotherapy) versus a reference regimen (12-month DAPT followed by 12-month aspirin monotherapy) according to multivessel PCI. Methods The GLOBAL LEADERS trial is a prospective, multicenter, open-label, randomized controlled trial, allocating all-comer patients in a 1:1 ratio to either the experimental strategy or the reference regimen. The primary endpoint was the composite of all-cause death or new Q-wave myocardial infarction at 2 years. The secondary safety endpoint was Bleeding Academic Research Consortium type 3 or 5 bleeding. Results Among the overall study population (n=15,845), 3,576 patients (22.4%) having multivessel PCI experienced a significantly higher risk of ischemic and bleeding events at 2 years, compared to those having single-vessel PCI. There was an interaction between the experimental strategy and multivessel PCI on the primary endpoint (hazard ratio: 0.62; 95% confidence interval: 0.44 to 0.88; pinteraction = 0.031). This difference was largely driven by a lower risk of all-cause mortality. In contrast, the risk of Bleeding Academic Research Consortium type 3 or 5 bleeding was statistically similar between the 2 regimens (hazard ratio: 0.92; 95% confidence interval: 0.61 to 1.39; pinteraction = 0.754). Conclusions Long-term ticagrelor monotherapy following 1-month DAPT can favorably balance ischemic and bleeding risks in patients with multivessel PCI. These findings should be interpreted as hypothesis-generating and need to be replicated in future dedicated randomized trials. (GLOBAL LEADERS: A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation; NCT01813435).
1. Intracoronary Brachytherapy: A New Treatment for the Prevention of Restenosis 2. Therapeutic Angiogenesis for Coronary Artery Disease 3. Spot Stenting 4. Ostial and Bifurcation Disease 5. Left Main Disease 6. Small Vessel Stenting 7. Direct Stenting 8. Treatment of Chronic Total Coronary Occlusions 9. In-stent Restenosis 10. Restenosis, a Pragmatic Approach 11. Percutaneous Intervention in Acute Coronary Syndromes 12. Pediatrics Coronary Artery Abnormalities and Interventions 13. Post-angioplasty Dissection 14. Alternative Imaging 15. Calcified and Fibrotic Lesions 16. Ablative Techniques 17. Direct Myocardial Revascularization: Surgical and Catheter-based Approaches 18. Stent Retrieval 19. Adjunctive Therapies in Percutaneous Coronary Interventions 20. Local Drug Delivery using Drug-eluting Stents 21. The Significance of Biochemical Markers for Myocardial Damage in Interventional Procedures
