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Buenestado A.,University of Versailles | Grassin-Delyle S.,University of Versailles | Guitard F.,University of Versailles | Naline E.,University of Versailles | And 7 more authors.
British Journal of Pharmacology | Year: 2012

Background and purpose: Lung macrophages are critically involved in respiratory diseases. This study assessed the effects of the PDE4 inhibitor roflumilast and its active metabolite, roflumilast N-oxide on the release of a range of chemokines (CCL2, 3, 4, CXCL1, 8, 10) and of TNF-α, from human lung macrophages, stimulated with bacterial lipopolysaccharide LPS. Experimental approach: Lung macrophages isolated from resected human lungs were incubated with roflumilast, roflumilast N-oxide, PGE 2, the COX inhibitor indomethacin, the COX-2 inhibitor NS-398 or vehicle and stimulated with LPS (24 h). Chemokines, TNF-α, PGE 2 and 6-keto PGF 1α were measured in culture supernatants by immunoassay. COX-2 mRNA expression was assessed with RT-qPCR. PDE activities were determined in macrophage homogenates. Key results: Expression of PDE4 in lung macrophages was increased after incubation with LPS. Roflumilast and roflumilast N-oxide concentration- dependently reduced the LPS-stimulated release of CCL2, CCL3, CCL4, CXCL10 and TNF-α from human lung macrophages, whereas that of CXCL1 or CXCL8 was not altered. This reduction by the PDE4 inhibitors was further accentuated by exogenous PGE 2 (10 nM) but abolished in the presence of indomethacin or NS-398. Conversely, addition of PGE 2(10 nM), in the presence of indomethacin restored inhibition by roflumilast. LPS also increased PGE 2and 6-keto PGF 1α release from lung macrophages which was associated with an up-regulation of COX-2 mRNA. Conclusions and implications: Roflumilast and roflumilast N-oxide reduced LPS-induced release of CCL2, 3, 4, CXCL10 and TNF-α in human lung macrophages. © 2011 The British Pharmacological Society.

Buenestado A.,Laboratory of Pulmonary Pharmacology | Delyle S.G.,Laboratory of Pulmonary Pharmacology | Arnould I.,Sanofi S.A. | Besnard F.,Sanofi S.A. | And 5 more authors.
British Journal of Pharmacology | Year: 2010

Background and purpose: Adenosine is a major endogenous regulator of macrophage function, and activates four specific adenosine receptors (A 1, A 2A, A 2B and A 3). Here, we have assessed in human lung macrophages the modulation of the expression of adenosine receptor mRNA by lipopolysaccharide (LPS), and the relative contributions of the different adenosine receptors to LPS-induced production of tumour necrosis factor (TNF)-α and chemokines. Experimental approach: Lung macrophages isolated from resected lungs were stimulated with LPS and treated with adenosine receptor agonists or/and antagonists. Adenosine receptor expression was assessed with qRT-PCR. Cytokines were measured in lung macrophage supernatants with elisa. Key results: LPS increased (about 400-fold) mRNA for A 2A adenosine receptors, decreased mRNA for A 1 and A 2B, but had no effect on A 3 adenosine receptor mRNA. The adenosine receptor agonist NECA inhibited TNF-α production concentration dependently, whereas the A 1 receptor agonist, CCPA, and the A 3 receptor agonist, AB-MECA, inhibited TNF-α production only at concentrations affecting A 2A receptors. NECA also inhibited the production of CCL chemokines (CCL2, CCL3, CCL4, CCL5) and CXCL chemokines (CXCL9 and CXCL10), but not that of CXCL1, CXCL8 and CXCL5. Reversal of NECA-induced inhibition of TNF-α and chemokine production by the selective A 2A adenosine receptor antagonist ZM 241385, but not the A 2B receptor antagonist, MRS 1754, or the A 3 receptor antagonist, MRS 1220, indicated involvement of A 2A receptors. Conclusions and implications: LPS up-regulated A 2A adenosine receptor gene transcription, and this receptor subtype mediated inhibition of the LPS-induced production of TNF-α and of a subset of chemokines in human lung macrophages. © 2010 The Authors.

Stankiewicz J.,Loyola University | Truitt T.,Cloud Clinic | Atkins Jr. J.,Texas Sinus Center
Ear, Nose and Throat Journal | Year: 2010

A prospective, multicenter research study is under way to demonstrate long-term improvement in chronic rhinosinusitis symptoms after transantral balloon dilation of the ethmoid infundibulum. Trial results from an interim analysis of symptomatic status using the Sino-Nasal Outcome Test 20 survey demonstrate significant and sustained improvement through post-procedure 1-year follow-up. Additionally, these data provide evidence that the symptomatic improvements following balloon expansion within the ostiomeatal unit to treat medically refractory inflammation of the maxillary sinuses, either alone or with concomitant anterior ethmoid disease, are similar.

Brodner D.,The Center for Sinus | Nachlas N.,Facial Plastic and Reconstructive Surgery | Mock P.,Texas Medical and Surgery Associates | Truitt T.,Cloud Clinic | And 4 more authors.
International Forum of Allergy and Rhinology | Year: 2013

Background: A multicenter prospective study was conducted to assess the safety and sustained effectiveness of a new instrument possessing multifunctionality as an ostium seeker, suction-irrigator, and malleable balloon-dilator indicated for treating multiple sinuses. Methods: Endoscopic balloon-only and hybrid-balloon procedures involving dilation of the frontal recesses, maxillary ostia, and/or sphenoid sinus ostia were performed in 175 patients. One-month follow-up was required for all patients. The first 50 patients enrolled also consented to a 1-year follow-up. Complications and sinus symptom severity were assessed at the 1-month visit. Symptom severity and ostial patency of the treated sinuses were evaluated at the 1-year visit. Results: A total of 497 balloon dilations (279 frontal, 138 sphenoid, and 80 maxillary) were attempted in 175 patients. Over 96% (479/497) of the attempted sinus dilations were successfully completed, while 18 dilations were converted to traditional dissection due to an inability to access or dilate the targeted anatomy. Two (1.1%) nonserious adverse events were reported following hybrid-balloon dilation and both were unrelated to the device or the procedure. Forty-four of 50 patients in the extended follow-up cohort completed the 1-year follow-up. Sinus symptom improvement in this group improved significantly from an average severity of 1.9 ± 1.1 to 0.8 ± 0.7 (p < 0.0001) and 1-year ostial patency was 91.6% (76/83). One revision surgery (2.3%) was performed. Conclusion: These results indicate that a multifunctional, malleable, balloon-dilating device can be safely and successfully used to treat multiple sinuses with sustained ostial patency and symptom improvement for at least 1 year. © 2013 ARS-AAOA, LLC.

Mandrekar S.J.,Mayo Medical School | Qi Y.,Mayo Medical School | Hillman S.L.,Mayo Medical School | Allen Ziegler K.L.,Mayo Medical School | And 6 more authors.
Journal of Thoracic Oncology | Year: 2010

INTRODUCTION: We investigated the relationships between progression-free survival (PFS), response, confirmed response, and failure-free survival (FFS) with overall survival (OS) to assess their suitability as primary endpoints in phase II trials for advanced non-small cell lung cancer. METHODS: Individual data of 284 patients from four phase II trials were pooled. Progression status and response were modeled as time dependent variables in a multivariable (adjusted for baseline age, gender, stage, and performance status) Cox proportional hazards model for OS, stratified by trial. Subsequently, Cox proportional hazards models were used to assess the impact of PFS, response, confirmed response, and FFS on subsequent survival, using landmark analysis at 8, 12, 16, 20, and 24 weeks. Model discrimination was evaluated using the concordance index (c-index). RESULTS: The overall median OS, PFS, and FFS were 9.6, 3.7, and 2.8 months, and the response and confirmed response rates were 21 and 15%, respectively. Both progression status and response as time dependent covariates were significantly associated with OS (p < 0.0001; p = 0.009). PFS and FFS at 12 weeks significantly predicted for subsequent survival with the strongest c-index and hazard ratio combination in landmark analyses (hazard ratio, c-index: PFS: 0.39, 0.67; FFS: 0.37, 0.67). The c-indices for response and confirmed response were low (0.59-0.60), indicating their inability to sufficiently discriminate subsequent patient survival outcomes. CONCLUSIONS: FFS or PFS at 12 weeks is a stronger predictor of subsequent patient survival compared with tumor response and should be routinely used as endpoints in phase II trials for advanced non-small cell lung cancer. Copyright © 2009 by the International Association for the Study of Lung Cancer.

Reuter N.P.,Cloud Clinic | Bower M.,University of Louisville | Scoggins C.R.,University of Louisville | Martin R.C.G.,University of Louisville | And 2 more authors.
American Journal of Surgery | Year: 2010

Background: Men have a higher lifetime incidence of melanoma than women. Methods Data from the 2005 Health Interview Survey were analyzed for sex differences in response to sun exposure and reported preventive measures among adults. Results There were 31,428 people surveyed representing the US population. Although women were more likely to burn after 1 hour of sun (8.7% vs 5.4%), they also reported fewer sunburns than men (mean .7 vs .9). Women were also more likely stay in the shade (11.2% vs 6.2%) and always use sunscreen. However, women used a tanning bed more than men (2.1 vs .6 times per year) and were less likely to wear protective clothing when in the sun than men. After controlling preventive behaviors, men were 1.4 times more likely to have had a sunburn during the last 12 months. Conclusions Although men more often wear protective clothing and are less likely to use a tanning bed, women are more likely to avoid sun exposure and use sunscreen. The higher incidence of melanoma in men may be explained, in part, by an increased incidence of preventive measures taken by women. © 2010 Elsevier Inc. All rights reserved.

Holmes D.R.,Mayo Medical School | Aguirre F.V.,Prairie Cardiovascular | Aplin R.,Cloud Clinic | Lennon R.J.,Mayo Medical School | And 4 more authors.
Circulation: Cardiovascular Quality and Outcomes | Year: 2010

Background-Circadian rhythms with regard to time of symptom onset for patients with acute myocardial infarction have been observed, although their relationship to outcomes has been debated. We evaluated these rhythms in patients with ST-elevation myocardial infarction as a function of the 24-hour circadian cycle. Methods and Results-The relationship between onset of symptoms during the 24-hour circadian cycle and prehospital delays from symptom onset to hospital arrival, timeliness of reperfusion, and in-hospital death was assessed in 2143 patients with ST-elevation myocardial infarction presenting from 2004-2008 at 1 of 3 tertiary-care healthcare ST-elevation myocardial infarction systems. There was a significant association between time of onset and the circadian cycle, with the greatest percentage (39%) of patients experiencing onset between 8 AM and 3 PM (P<0.001). Time of onset was associated with prehospital delay and timeliness of reperfusion. Patients with onset from 12 AM to 5:59 AM had median prehospital delays of 121 minutes versus 70 minutes from 12 PM to 5:59 PM (P<0.001). Patients with onset time from 12 AM to 5:59 AM had median door-to-balloon times of 75 minutes versus 60 minutes from 6 AM to 11:59 AM (P<0.001). Using multivariable modeling to control for baseline patient characteristics, prehospital delay, and timeliness of reperfusion, there was no significant association between time of symptom onset with in-hospital death. Conclusions-Patients with ST-elevation myocardial infarction exhibit significant circadian patterns in symptom onset, prehospital delay, and timeliness of reperfusion. Patients who develop symptoms from 12 AM to 5:59 AM present with longer prehospital delays and have longer door-to-balloon times. After multivariable adjustment, there was no significant association between circadian patterns of time of onset and in-hospital death. © 2010 American Heart Association, Inc.

Wahbi K.,University Pierre and Marie Curie | Wahbi K.,Cochin Hospital | Wahbi K.,Pitie Salpetriere Hospital | Meune C.,Cochin Hospital | And 17 more authors.
JAMA - Journal of the American Medical Association | Year: 2012

Context: Up to one-third of patients with myotonic dystrophy type 1 die suddenly. Thus far, no intervention has effectively prevented sudden death. Objective: To determine whether an invasive strategy based on systematic electrophysiological studies and prophylactic permanent pacing is associated with longer survival in patients presenting with myotonic dystrophy type 1 and major infranodal conduction delays than a noninvasive strategy. Design, Setting, and Patients: A retrospective study, the DM1 Heart Registry included 914 consecutive patients older than 18 years with genetically confirmed myotonic dystrophy type 1 who were admitted to the Neurological Unit of the Myology Institute of Pitié-Salpêtrière Hospital, a teaching medical center in Paris, France, between January 2000 and December 2009. Interventions: Among 486 patients whose electrocardiogram showed a PR interval greater than 200 milliseconds, a QRS duration greater than 100 milliseconds, or both, the outcome of 341 (70.2%) who underwent an invasive strategy was compared with 145 (29.8%) who underwent a noninvasive strategy. A propensity score risk adjustment and propensity-based matching analysis was used to account for selection biases. Main Outcome Measures: Rates of overall survival (main outcome measure) and sudden death, respiratory death, and other deaths (secondary outcome measures). Results: Over a median follow-up of 7.4 years (range, 0-9.9 years), 50 patients died in the invasive strategy group and 30 died in the noninvasive strategy group (hazard ratio [HR], 0.74 [95 CI, 0.47-1.16]; P=.19), corresponding to an overall 9-year survival of 74.4% (95% CI, 69.2%-79.9%). Regardless of the technique used to adjust for between-group differences in baseline characteristics, the invasive strategy was associated with a longer survival, with adjusted HRs ranging from 0.47 (95% CI, 0.26-0.84; P=.01) for a covariate-adjusted analysis of propensity-matched data to 0.61 (95% CI, 0.38-0.99; P=.047) for an analysis adjusted for propensity score quintiles. The survival difference was largely attributable to a lower incidence of sudden death, which occurred in 10 patients in the invasive strategy group and in 16 patients in the noninvasive strategy group, with HRs ranging from 0.24 (95% CI, 0.10-0.56; P=.001) for an analysis adjusted for propensity score quintiles and covariates to 0.28 (95% CI, 0.13-0.61; P=.001) for an unadjusted analysis of propensity-matched data. Conclusion: Among patients with myotonic dystrophy type 1, an invasive strategy was associated with a higher rate of 9-year survival than a noninvasive strategy. Trial Registration: Identifier: NCT01136330. ©2012 American Medical Association. All rights reserved.

Stankiewicz J.,Loyola University | Truitt T.,Cloud Clinic | Atkins J.,Texas Sinus Center | Winegar B.,Austin Ear Nose and Throat Clinic | And 4 more authors.
International Forum of Allergy and Rhinology | Year: 2012

Background: Multiple prospective and retrospective studies have reported results from balloon-only procedures and hybrid balloon sinus surgeries through intermediate follow-up periods of up to 1 year. Long-term durability results beyond 2 years are limited. Methods: One-year results from the original study of standalone transantral balloon dilation in patients with computed tomography (CT) evidence of chronic inflammation in the maxillary sinuses alone or maxillary and anterior ethmoid sinuses combined were previously reported. Revision rate, symptom improvement, and productivity improvement were prospectively evaluated after a minimum follow-up of 2 years. Results: Fifty-nine patients (107 maxillary ostia) underwent balloon dilation of the maxillary sinus outflow tract and completed postprocedure follow-up assessment at 27.0 ± 3.6 months. Patient 20-item Sino-Nasal Outcome Test (SNOT-20) score improved from 2.65 ± 0.97 at baseline to 0.79 ± 0.71 at long-term follow-up (p < 0.0001). Improvement in work productivity and activity due to sinus-related health issues for all patients was statistically significant across all survey instrument characteristics (p range, <0.0001 to 0.02). An analysis of the outcomes in a subgroup of patients with maxillary and anterior ethmoid disease (20; 34%) showed similar significant improvement in symptoms (SNOT-20 decrease = -2.1; p < 0.0001). Approximately 92% of all patients reported satisfaction with the balloon procedure. Four (6.8%) patients underwent revision sinus surgery at 11.1 ± 7.3 months after treatment. Conclusion: Patients with chronic rhinosinusitis and radiographic evidence of isolated maxillary disease with or without anterior ethmoid disease have reported clinically meaningful and statistically significant improvement in symptoms, productivity, and activity through a minimum of 2 years following standalone balloon dilation. © 2012 American Rhinologic Society-American Academy of Otolaryngic Allergy, LLC.

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