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Background: The loss of corticosteroid efficacy is an important issue in severe asthma management and may lead to poor asthma control and deterioration of airflow. Recent data indicate that Mucin 1 (MUC1) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis, but the role of MUC1 in uncontrolled severe asthma is unknown. The objective was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in asthma. Methods: Mucin 1 expression was evaluated by real‐time PCR in human bronchial epithelial cells (HBEC) and blood neutrophils from uncontrolled severe asthma (n = 27), controlled mild asthma (n = 16), and healthy subjects (n = 13). IL‐8, MMP9, and GM‐CSF were measured by ELISA in HBEC and neutrophils. An asthma model of ovalbumin (OVA) was used in MUC1 KO and WT C57BL/6 mice according to ARRIVE guidelines. Results: Mucin 1‐CT expression was downregulated in bronchial epithelial cells and peripheral blood neutrophils from severe asthma patients compared with mild asthma and healthy subjects (P < 0.05). Daily dose of inhaled corticosteroids (ICS) inversely correlated with MUC1 expression in neutrophils from mild and severe asthma (ρ = −0.71; P < 0.0001). Dexamethasone showed lower anti‐inflammatory effects in severe asthma peripheral blood neutrophils and HBECs stimulated with lipopolysaccharide (LPS) than in cells from mild asthma. Glucocorticoid receptor (GR)‐α phosphorylated at serine 226 was increased in cells from severe asthma, and the MUC1‐CT/GRα complex was downregulated in severe asthma cells. OVA asthma model in MUC1 KO mice was resistant to the anti‐inflammatory effects of dexamethasone. Conclusion: Mucin 1‐CT modulates corticosteroid efficacy in vitro and in vivo asthma models. Stimulation of TLR2 and TLR4 (1) phosphorylates p38 and ERK1/2 intracellular pathways increasing pro‐inflammatory mediators such as IL‐5, IL‐13 or IL‐8. MUC1‐CT forms a complex with GRα (2) allowing the proper nuclear translocation of MUC1‐CT/GRα complex, thus activating the expression of anti‐inflammatory genes such as MKP1 (3) and inhibiting the production of inflammatory mediators (4). Uncontrolled severe asthma patients show MUC1‐CT decreased expression (5) and reduced MUC1‐CT/GRα complex formation (6), impairing corticosteroid anti‐inflmmatory effects (7). CT: cytoplasmic tail; ERK1/2: extracellular signal–regulated kinases 1/2; Grα: glucocorticoid receptor alpha; MUC: mucin; P38: mitogen activated protein kinase; Toll like receptor (TLR) [ABSTRACT FROM AUTHOR]

The main reason for conducting a clinical trial (CT) is to test the effect of a drug or medical procedure to improve treatment of a disease. CTs contribute most when they are rigorously conducted and the results are published adequately. The aim of this study is to assess, using the CONSORT statement guidelines, the quality of reporting of completed CTs conducted at a tertiary hospital to determine which sections of the articles should be improved. CTs published between 2002 and 2008 were identified by searching the MEDLINE and Cochrane Library. Forty of 127 completed CTs were published. There was a marked increase in the number of articles and the quality of the journals that published the CTs over time. Although the articles were published in high-impact index journals, the Consolidated Standards of Reporting Trials (CONSORT) score reporting quality of the articles varied substantially, which indicates that they should be improved. The title, abstract, introduction, and discussion sections received the highest CONSORT scores and need little improvement. Poor reporting of methodological details and discussion on limitations and strengths were observed. In conclusion, much improvement remains to be made in the quality of reporting of CTs to allow reliable quality assessment of published trials. [ABSTRACT FROM PUBLISHER]

Two asthmatic patients developed unilateral diaphragmatic paralysis from phrenic nerve injury, in one case following cervical chiropractic manipulation and in the other after a motorcycle accident. Both presented with increased dyspnea and orthopnea. Diagnosis, severity, and level of the lesion were established by neurophysiological methods, which are preferred to chest radiography and diaphragmatic ultrasonography. In spite of only partial electrophysiological recovery of the nerve, both patients were asymptomatic 1 year later. Muscle Nerve, 2007 [ABSTRACT FROM AUTHOR]

α4β1 and α4β7 integrins are preferentially expressed on eosinophils and mononuclear leukocytes and play critical roles in their recruitment to inflammatory sites. We investigated the effects of TR14035, a small molecule, α4β1/α4β7 dual antagonist, in a rat model of allergic asthma.Actively sensitized rats were challenged with aerosol antigen or saline on day 21, and the responses evaluated 24 and 48-h later. TR14035 (3 mg kg−1, p.o.) was given 1-h before and 4-h after antigen or saline challenge.Airway hyper-responsiveness to intravenous 5-hydroxytryptamine was suppressed in TR14035-treated rats. Eosinophil, mononuclear cell and neutrophil counts, and eosinophil peroxidase and protein content in the bronchoalveolar lavage fluid (BALF) were decreased in TR14035-treated rats. Histological study showed a marked reduction of lung inflammatory lesions by TR14035.At 24-h postchallenge, antigen-induced lung interleukin (IL)-5 mRNA upregulation was suppressed in TR14035-treated rats. By contrast, IL-4 levels in BALF were not significantly affected by TR14035 treatment.IL-4 selectively upregulates vascular cell adhesion molecule-1 (VCAM-1), which is the main endothelial ligand of α4 integrins. Intravital microscopy within the rat mesenteric microcirculation showed that 24-h exposure to 1 μg per rat of IL-4 induced a significant increase in leukocyte rolling flux, adhesion and emigration. These responses were decreased by 48, 100 and 99%, respectively in animals treated with TR14035.In conclusion, TR14035, by acting on α4β1 and α4β7 integrins, is an orally active inhibitor of airway leukocyte recruitment and hyper-responsiveness in animal models with potential interest for the treatment of asthma.British Journal of Pharmacology (2006) 147, 661–670. doi:10.1038/sj.bjp.0706658; published online 23 January 2006 [ABSTRACT FROM AUTHOR]

Macrolides have long been used as anti-bacterial agents; however, there is some evidence that may exert anti-inflammatory activity. Therefore, erythromycin was used to characterize the mechanisms involved in their in vivo anti-inflammatory activity.Erythromycin pretreatment (30?mg?kg-1?day-1 for 1 week) reduced the lipopolysaccharide (LPS; intratracheal, 0.4?mg?kg-1)-induced increase in neutrophil count and elastase activity in the bronchoalveolar lavage fluid (BALF) and lung tissue myeloperoxidase activity, but failed to decrease tumor necrosis factor-aand macrophage-inflammatory protein-2 augmented levels in BALF. Erythromycin pretreatment also prevented lung P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) mRNA upregulation in response to airway challenge with LPS.Mesentery superfusion with LPS (1?µg?ml-1) induced a significant increase in leukocyte-endothelial cell interactions at 60?min. Erythromycin pretreatment abolished the increases in these parameters.LPS exposure of the mesentery for 4?h caused a significant increase in leukocyte rolling flux, adhesion and emigration, which were inhibited by erythromycin by 100, 93 and 95%, respectively.Immunohistochemical analysis showed that LPS exposure of the mesentery for 4?h caused a significant enhancement in P-selectin, E-selectin, ICAM-1 and VCAM-1 expression that was downregulated by erythromycin pretreatment.Flow cytometry analysis indicated that erythromycin pretreatment inhibited LPS-induced CD11b augmented expression in rat neutrophils.In conclusion, erythromycin inhibits leukocyte recruitment in the lung and this effect appears mediated through downregulation of CAM expression. Therefore, macrolides may be useful in the control of neutrophilic pulmonary diseases.British Journal of Pharmacology (2005) 144, 190-201. doi:10.1038/sj.bjp.0706021 Published online 8 November 2004 [ABSTRACT FROM AUTHOR]

1 The present study has evaluated the effect of two phenanthrene alkaloids, uvariopsine and stephenanthrine, on angiotensin II (Ang-II)-induced leukocyte-endothelial cell interactions in vivo and the mechanisms involved in their activity. Intravital microscopy within the rat mesenteric microcirculation was used. 2 A 60min superfusion with 1 nM Ang-II induced a significant increase in the leukocyte-endothelial cell interactions that were completely inhibited by l μ M uvariopsine cosuperfusion. A lower dose of 0.1 μ M significantly reduced Ang-II-induced leukocyte adhesion by 75%. 3 When Ang-II was cosuperfused with 1 and o.1 μM stephenanthrine. Ang-II-induced leukocyte responses were significantly diminished. A lower dose of 0.01μM only affected Ang-II-induced leukocyte adhesion. 4 Both alkaloids inhibited Ang-II-induced endothelial P-selectin upregulation and the generation of reactive oxygen species (ROS) in endothelial cells stimulated with Ang-II, in fMLP-stimulated human neutrophils (PMNs) and in the hypoxanthine-xanthine oxidase system. However, cyclic AMP levels in PMNs stimulated with fMLP were not affected. 5 Uvariopsine and stephenanthrine inhibited PAF-induced elevations in intracellular calcium levels in PMNs (IC[sub50] values; 15.1 and 6.1 μM respectively) and blocked the binding of [ [sup3] H ]PAF to these leukocytes. They also reduced PAF-induced increases in intracellular levels of superoxide anion and hydrogen peroxide. 6 In conclusion, stephenanthrine and uvariopsine are potent inhibitors of Ang-II-induced leukocyte accumulation in vivo. This effect appears to be mediated through ROS scavenging activity and blockade of PAF receptor. Thus, they have potential therapeutic interest for the control of leukocyte recruitment that occurs in cardiovascular disease stales in which Ang-II is involved. [ABSTRACT FROM AUTHOR]

1 Rolipram, a selective phosphodiesterase (PDE) type 4 inhibitor, was used to characterize leukocyte recruitment mechanisms in models of acute and subacute inflammation. Intravital microscopy within the rat mesenteric microcirculation was employed. 2 Mesentery superfusion with PAF (0.1 μM) induced a significant increase in leukocyte rolling flux, adhesion and emigration at 60 min. Rolipram pretreatment, markedly inhibited these parameters by 100, 95 and 95% respectively. 3 Similar effects were observed when the mesentery was superfused with LPS (1 μg ml[sup-1]) for the same time period and these leukocyte parameters were nearly abrogated by rolipram pretreatment. 4 LPS exposure of the mesentery for 4 h caused a greater increase in leukocyte rolling flux, adhesion and emigration which were inhibited by rolipram administration by 51, 71 and 81% respectively. 5 Immunohistochemistry revealed a significant increase in P-selectin expression after 60 min superfusion with PAF which was attenuated by rolipram. 6 LPS exposure of the mesentery for 4 h caused a significant increase in P- and E-selectiux intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. Rolipram pretreatment down-regulated both P- and E-selectin expression but had no effect on ICAM-1 and VCAM-1 expression. 7 Significant increases in plasma cyclic AMP levels were delected at 4.5 h after rolipram administration. 8 In conclusion, we have demonstrated that rolipram is a potent in vivo inhibitor of leukocyte-endothelial cell interactions. The effects observed are mediated through endothelial P- and E-selectin downregulation. Therefore, selective PDE-4 inhibitors may be useful in the control of different inflammatory disorders. [ABSTRACT FROM AUTHOR]

Assesses the biotransformation of the 22R and 22S epimers of budesonide by steroid concentration measurement. Administration of budesonide for inflammatory bowel diseases; Pharmacokinetic properties of budesonide; Bioavailability of budesonide in the liver.

Presents the corrections to the articles "Effect of Two Phenanthrene Alkaloids on Angiotensin II-Induced Leukocyte-Endothelial Cell Interactions In Vivo," and "Protection by Antioxidants Against Toxocity and Apoptosis Induced by the Sulphur Mustard Analog 2- Chloroethylethyl Sulphide in Jurkat T cells and Normal Human Lymphocytes," previously published in the "British Journal of Pharmacology."