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Dahlen B.,Karolinska University Hospital | Gomez F.P.,University of Barcelona | Gomez F.P.,CIBER ISCIII | Casas A.,University of Barcelona | And 5 more authors.
European Journal of Clinical Pharmacology | Year: 2012

Purpose Leukotriene D4 (LTD4) is a central mediator in asthma inducing bronchoconstriction and profound disturbances in pulmonary gas exchange in asthmatic subjects. The aim of the study was to compare, for the first time, the influence of the bronchodilators salbutamol (400 μg) and ipratropium (80 μg) on lung function changes induced by inhaled LTD 4. Methods Treatments were evaluated in a randomized, threeperiod, double-blind, placebo-controlled, cross-over study where spirometric and pulmonary gas exchange indices were followed in 12 subjects with mild asthma before and after LTD4 challenge. Results Compared with placebo, salbutamol provided significant protection against the fall in FEV1 (forced expiratory volume in 1 s) after LTD4 challenge. Salbutamol also abolished the LTD4-induced gas exchange disturbances [decreased arterial oxygen tension (PaO2) and increased alveolar-arterial oxygen tension difference (AaPO2)]. Ipratropium provided significant but less marked attenuation of the changes in FEV1 and arterial oxygenation induced by LTD4. Conclusion Despite the equal bronchodilatory effects of salbutamol and ipratropium before the challenge with LTD4, salbutamolwas superior to ipratropiumin preventing spirometric and gas exchange abnormalities. This result indicates a broader action of salbutamol on several of the disturbances that contribute to airway obstruction including, for example, exudation of plasma in the airway mucosa. The clinical implication of this new finding is that in this model of acute asthmatic airway obstruction, salbutamol was more effective than ipratropium. © Springer-Verlag 2012. Source


Grundstrom J.,Karolinska University Hospital | Neimert-Andersson T.,Karolinska University Hospital | Kemi C.,National Institute of Environmental Medicine | Kemi C.,Karolinska Institutet | And 5 more authors.
International Archives of Allergy and Immunology | Year: 2012

Background: Allergen-specific immunotherapy (SIT) is currently the only curative treatment for allergy but the treatment needs to be improved. We hypothesize that covalent coupling of immunomodulating vitamin D3 to the major cat allergen Fel d 1 can enhance the beneficial effects of SIT to cat allergy. Methods: We treated mice sensitized to Fel d 1 with subcutaneous injections of two doses of recombinant Fel d 1 coupled to 1α,25-dihydroxyvitamin D3 (rFel d 1:VD3) and compared to treatment with the same doses of rFel d 1 in a mouse model for cat allergy. Airway hyperresponsiveness (AHR), cytokines and cells in bronchoalveolar lavage (BAL), in vitro activation of splenocytes to rFel d 1, and Fel d 1-specific immunoglobulins were evaluated. Results: Treatment with both doses of rFel d 1:VD3 decreased AHR, cellular influx and Th2 cytokines in BAL compared to untreated mice. High-and low-dose rFel d 1 treatment also decreased AHR and BAL Th2 cytokines, with less decrease for the low-dose treatment. Importantly, the total number of cells and eosinophils in BAL was markedly reduced at both high-and low-dose rFel d 1:VD3 compared to treatment with rFel d 1 alone. Finally, treatment with both rFel d 1 and rFel d 1:VD3 induced Fel d 1-specific serum IgG. Conclusion: Our results indicate a beneficial therapeutic effect of rFel d 1:VD3 on airway inflammation, AHR and rFel d 1-specific immune responses and thus suggest that this novel immunomodulatory candidate may improve both the efficacy and safety of SIT. © 2011 S. Karger AG, Basel. Source


Bao Y.,Brigham and Womens Hospital | Michaud D.S.,Brown University | Spiegelman D.,Harvard University | Albanes D.,U.S. National Cancer Institute | And 25 more authors.
Journal of the National Cancer Institute | Year: 2011

Background Epidemiological studies evaluating the association between folate intake and risk of pancreatic cancer have produced inconsistent results. The statistical power to examine this association has been limited in previous studies partly because of small sample size and limited range of folate intake in some studies. Methods We analyzed primary data from 14 prospective cohort studies that included 319 716 men and 542 948 women to assess the association between folate intake and risk of pancreatic cancer. Folate intake was assessed through a validated food-frequency questionnaire at baseline in each study. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models and then pooled using a random effects model. All statistical tests were two-sided. Results During 7-20 years of follow-up across studies, 2195 pancreatic cancers were identified. No association was observed between folate intake and risk of pancreatic cancer in men and women (highest vs lowest quintile: dietary folate intake, pooled multivariable RR = 1.06, 95% CI = 0.90 to 1.25, Ptrend = .47; total folate intake [dietary folate and supplemental folic acid], pooled multivariable RR = 0.96, 95% CI = 0.80 to 1.16, Ptrend = .90). No between-study heterogeneity was observed (for dietary folate, Pheterogeneity = .15; for total folate, Pheterogeneity = .22). Conclusion Folate intake was not associated with overall risk of pancreatic cancer in this large pooled analysis. © The Author 2011. Source


Higashi A.,National Institute of Environmental Medicine | Higashi A.,Karolinska Institutet | Kumlin M.,National Institute of Environmental Medicine | Kumlin M.,University of Stockholm | And 22 more authors.
International Archives of Allergy and Immunology | Year: 2012

Background: There is no in vitro test to diagnose aspirin-intolerant asthma (AIA). The aim of this study was to test if challenge with aspirin of sputum cells from subjects with AIA triggers the release of cysteinyl leukotrienes (CysLTs), known to be mediators of bronchoconstriction in AIA. Methods: Sputum induction was performed at baseline and at another visit 2 h after a lysine-aspirin bronchoprovocation in 10 subjects with AIA and 9 subjects with aspirin-tolerant asthma (ATA). The isolated sputum cells were incubated for ex vivo challenge. Results: Release of CysLTs by sputum cells from patients with AIA was not induced by lysine-aspirin ex vivo, neither when cells were collected at baseline nor in sputum cells recovered after lysine-aspirin-induced bronchoconstriction, whereas release of CysLTs from sputum cells was triggered by an ionophore on both occasions. However, the CysLT levels elicited by the ionophore were higher in the AIA group both at baseline (AIA vs. ATA: 3.3 vs. 1.6 ng/million cells; p < 0.05) and after the lysine-aspirin bronchoprovocation (3.9 vs. 1.7 ng/million cells; p < 0.05). This difference in the amount of CysLTs released between the groups appeared to be related to the number of eosinophils. Conclusions: Intolerance to aspirin could not be triggered in sputum cells isolated from subjects with AIA. Together with the previous inability to demonstrate intolerance to non-steroidal anti-inflammatory drugs in isolated blood cells, these results support the requirement of tissue-resident cells in the adverse reaction. However, ex vivo stimulation of sputum cells may be developed into a new test of capacity for LT release in inflammatory cells recovered from airways. Copyright © 2012 S. Karger AG, Basel. Source


Nokela M.,Karolinska University Hospital | Nokela M.,National Institute of Environmental Medicine | Heibert Arnlind M.,Karolinska University Hospital | Heibert Arnlind M.,Medical Management Center | And 7 more authors.
Respiration | Year: 2010

Background: In clinical trials of asthma, the outcomes are often good, but when the same treatment regimens are implemented in primary care, equally good results are not obtained. Objective: To investigate if addition of structured patient information and monitoring by an asthma diary in primary care improves asthma control. Methods: 141 patients from 19 primary care centres were studied. The centres were randomised to a standard care group or to an intervention group. The intervention group received structured written and oral information about asthma and asthma medication, and were instructed to keep an asthma diary. The primary outcome was asthma control as assessed by the Asthma Control Questionnaire. Secondary outcomes were costs of asthma medication, the Mini Asthma Quality of Life Questionnaire score and lung function. Results: Asthma Control Questionnaire score changes differed between the study groups (p < 0.05). In the intervention group, these changes (M = -0.45) in asthma control were close to clinical significance (minimal important difference 0.5). Both groups improved in disease-specific quality of life scores. For the intervention group, which changed the most (p < 0.05), the change exceeded the threshold for the minimal important difference (0.5). The costs of medications increased significantly in the intervention group, where adjustments of medication were made more often than in controls. Conclusion: Disease-specific quality of life of asthma patients could be improved by adding structured information and monitoring by diary to standard care. Copyright © 2009 S. Karger AG, Basel. Source

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